Sample records for taxol response cancer

  1. Insulin-Like Growth Factor 2 Silencing Restores Taxol Sensitivity in Drug Resistant Ovarian Cancer

    PubMed Central

    Brouwer-Visser, Jurriaan; Lee, Jiyeon; McCullagh, KellyAnne; Cossio, Maria J.; Wang, Yanhua; Huang, Gloria S.

    2014-01-01

    Drug resistance is an obstacle to the effective treatment of ovarian cancer. We and others have shown that the insulin-like growth factor (IGF) signaling pathway is a novel potential target to overcome drug resistance. The purpose of this study was to validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and to determine the efficacy of targeting IGF2 in vivo. An analysis of The Cancer Genome Atlas (TCGA) data in the serous ovarian cancer cohort showed that high IGF2 mRNA expression is significantly associated with shortened interval to disease progression and death, clinical indicators of drug resistance. In a genetically diverse panel of ovarian cancer cell lines, the IGF2 mRNA levels measured in cell lines resistant to various microtubule-stabilizing agents including Taxol were found to be significantly elevated compared to the drug sensitive cell lines. The effect of IGF2 knockdown on Taxol resistance was investigated in vitro and in vivo. Transient IGF2 knockdown significantly sensitized drug resistant cells to Taxol treatment. A Taxol-resistant ovarian cancer xenograft model, developed from HEY-T30 cells, exhibited extreme drug resistance, wherein the maximal tolerated dose of Taxol did not delay tumor growth in mice. Blocking the IGF1R (a transmembrane receptor that transmits signals from IGF1 and IGF2) using a monoclonal antibody did not alter the response to Taxol. However, stable IGF2 knockdown using short-hairpin RNA in HEY-T30 effectively restored Taxol sensitivity. These findings validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and show that directly targeting IGF2 may be a preferable strategy compared with targeting IGF1R alone. PMID:24932685

  2. Androgen and taxol cause cell type-specific alterations of centrosome and DNA organization in androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cells

    NASA Technical Reports Server (NTRS)

    Schatten, H.; Ripple, M.; Balczon, R.; Weindruch, R.; Chakrabarti, A.; Taylor, M.; Hueser, C. N.

    2000-01-01

    We investigated the effects of androgen and taxol on the androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cell lines. Cells were treated for 48 and 72 h with 0.05-1 nM of the synthetic androgen R1881 and with 100 nM taxol. Treatment of LNCaP cells with 0.05 nM R1881 led to increased cell proliferation, whereas treatment with 1 nM R1881 resulted in inhibited cell division, DNA cycle arrest, and altered centrosome organization. After treatment with 1 nM R1881, chromatin became clustered, nuclear envelopes convoluted, and mitochondria accumulated around the nucleus. Immunofluorescence microscopy with antibodies to centrosomes showed altered centrosome structure. Although centrosomes were closely associated with the nucleus in untreated cells, they dispersed into the cytoplasm after treatment with 1 nM R1881. Microtubules were only faintly detected in 1 nM R1881-treated LNCaP cells. The effects of taxol included microtubule bundling and altered mitochondria morphology, but not DNA organization. As expected, the androgen-independent prostate cancer cell line DU145 was not affected by R1881. Treatment with taxol resulted in bundling of microtubules in both cell lines. Additional taxol effects were seen in DU145 cells with micronucleation of DNA, an indication of apoptosis. Simultaneous treatment with R1881 and taxol had no additional effects on LNCaP or DU145 cells. These results suggest that LNCaP and DU145 prostate cancer cells show differences not only in androgen responsiveness but in sensitivity to taxol as well. Copyright 2000 Wiley-Liss, Inc.

  3. Activation of acetyl-coenzyme A carboxylase is involved in Taxol-induced ovarian cancer cell death

    PubMed Central

    WU, JIANG; JI, FANG; DI, WEN; CHEN, HONGDUO; WAN, YINSHENG

    2011-01-01

    Acetyl-coenzyme A carboxylase (ACC) is an attractive target for research into the treatment of a variety of human diseases, including diabetes, obesity and cancer. Mounting evidence suggests that the inhibition of ACC induced of cancer cell apoptosis. However, whether the inhibition of ACC regulates apoptosis in CaOV3 cancer cells has yet to be addressed. This study investigated the cytotoxic mechanism of action of ACC inhibition. Results showed that 5-(tetradecyloxy)-2-furoic acid (TOFA), an ACC inhibitor, enhanced Taxol-induced CaOV3 human ovarian cancer cell apoptosis. Notably, when TOFA was administered as a monotherapy, it induced CaOV3 cell apoptosis. Pre-treatment with the EGFR inhibitor PD153035 was found to markedly enhance ACC phosphorylation, whereas AMP-activated protein kinase (AMPK) activator AICAR was found to marginally enhance ACC phosphorylation. Taken together, the data showed ACC is a potential novel molecular target of Taxol. Additionally, ACC inhibition partially contributed to the cytotoxic effect of Taxol in ovarian cancer cells. PMID:22866118

  4. Activation of acetyl-coenzyme A carboxylase is involved in Taxol-induced ovarian cancer cell death.

    PubMed

    Wu, Jiang; Ji, Fang; DI, Wen; Chen, Hongduo; Wan, Yinsheng

    2011-05-01

    Acetyl-coenzyme A carboxylase (ACC) is an attractive target for research into the treatment of a variety of human diseases, including diabetes, obesity and cancer. Mounting evidence suggests that the inhibition of ACC induced of cancer cell apoptosis. However, whether the inhibition of ACC regulates apoptosis in CaOV3 cancer cells has yet to be addressed. This study investigated the cytotoxic mechanism of action of ACC inhibition. Results showed that 5-(tetradecyloxy)-2-furoic acid (TOFA), an ACC inhibitor, enhanced Taxol-induced CaOV3 human ovarian cancer cell apoptosis. Notably, when TOFA was administered as a monotherapy, it induced CaOV3 cell apoptosis. Pre-treatment with the EGFR inhibitor PD153035 was found to markedly enhance ACC phosphorylation, whereas AMP-activated protein kinase (AMPK) activator AICAR was found to marginally enhance ACC phosphorylation. Taken together, the data showed ACC is a potential novel molecular target of Taxol. Additionally, ACC inhibition partially contributed to the cytotoxic effect of Taxol in ovarian cancer cells.

  5. Anti-proliferative effect of fungal taxol extracted from Cladosporium oxysporum against human pathogenic bacteria and human colon cancer cell line HCT 15

    NASA Astrophysics Data System (ADS)

    Gokul Raj, K.; Manikandan, R.; Arulvasu, C.; Pandi, M.

    2015-03-01

    Cladosporium oxysporum a new taxol producing endophytic fungus was identified and production of taxol were characterized using UV-visible spectroscopy (UV-vis), high-performance liquid chromatography (HPLC), infrared (IR) nuclear magnetic resonance spectroscopy (NMR (13C and 1H)) and liquid chromatography-mass spectrometry (LC-MS). The taxol biosynthetic gene (dbat) was evaluated for new taxol producing fungus. Antibacterial activity against six different human pathogenic bacteria was done by agar well diffusion method. The anticancer efficacy of isolated fungal taxol were also evaluated in human colon cancer cell HCT 15 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cytotoxicity and nuclear morphology analysis. The isolated fungal taxol showed positive towards biosynthetic gene (dbat) and effective against both Gram positive as well as Gram negative. The fungal taxol suppress growth of cancer cell line HCT 15 with an IC50 value of 3.5 μM concentration by 24 h treatment. Thus, the result reveals that C. oxysporum could be a potential alternative source for production of taxol and have antibacterial as well as anticancer properties with possible clinical applications.

  6. Occurrence of taxol and related taxanes in the wood of Pacific yew

    Treesearch

    John R. Obst

    1993-01-01

    Maximizing the yield of taxol per tree is important for the best management of the yew resource. Therefore, the possibility of obtaining additional taxol from the wood was explored. Initial reports form our laboratory, in cooperation with the National Cancer Institute, indicated relatively high concentrations of taxol in Pacific yew heartwood. Although these taxol...

  7. Circumvention of Taxol-Resistance in Human Breast Cancers by Improved Water Soluble Taxanes

    DTIC Science & Technology

    2001-10-01

    possible roles of interferon alpha, tumor necrosis factor alpha and transforming growth factor beta in Mn-SOD induction by polysaccharide K. Cancer ...chemoembolization in combination with local hyperthermia. Japanese Journal of Cancer & Chemotherapy. 16:2957-2960 61. Kidd P. (2000) The use of mushroom glucans ...Circumvention of Taxol-Resistance in Human Breast Cancers by Improved Water Soluble Taxanes PRINCIPAL INVESTIGATOR: Li-Xi Yang, M.D., Ph.D. CONTRACTING

  8. Live morphological analysis of taxol-induced cytoplasmic vacuolization [corrected] in human lung adenocarcinoma cells.

    PubMed

    Wang, Xiao-Ping; Chen, Tong-Sheng; Sun, Lei; Cai, Ji-Ye; Wu, Ming-Qian; Mok, Martin

    2008-12-01

    Taxol (paclitaxel), one of the most active cancer chemotherapeutic agents, can cause programmed cell death (PCD) and cytoplasmic vacuolization. The objective of this study was to analyze the morphological characteristics induced by taxol. Human lung adenocarcinoma (ASTC-a-1) cells were exposed to various concentration of taxol. CCK-8 was used to assay the cell viability. Atomic force microscopy (AFM), plasmid transfection and confocal fluorescence microscopy were performed to image the cells morphological change induced by taxol. Fluorescence resonance energy transfer (FRET) was used to monitor the caspase-3 activation in living cells during taxol-induced cell death. Cells treated with taxol exhibited significant swelling and cytoplasmic vacuolization which may be due to endoplasmic reticulum (ER) vacuolization. Caspase-3 was not activated during taxol-induced cytoplasmic vacuolization and cell death. These findings suggest that taxol induces caspase-3-independent cytoplasmic vacuolization, cell swelling and cell death through ER vacuolization.

  9. Polysaccharide-based Noncovalent Assembly for Targeted Delivery of Taxol

    NASA Astrophysics Data System (ADS)

    Yang, Yang; Zhang, Ying-Ming; Chen, Yong; Chen, Jia-Tong; Liu, Yu

    2016-01-01

    The construction of synthetic straightforward, biocompatible and biodegradable targeted drug delivery system with fluorescent tracking abilities, high anticancer activities and low side effects is still a challenge in the field of biochemistry and material chemistry. In this work, we constructed targeted paclitaxel (Taxol) delivery nanoparticles composed of permethyl-β-cyclodextrin modified hyaluronic acid (HApCD) and porphyrin modified paclitaxel prodrug (PorTaxol), through host-guest and amphiphilic interactions. The obtained nanoparticles (HATXP) were biocompatible and enzymatic biodegradable due to their hydrophilic hyaluronic acid (HA) shell and hydrophobic Taxol core, and exhibited specific targeting internalization into cancer cells via HA receptor mediated endocytosis effects. The cytotoxicity experiments showed that the HATXP exhibited similar anticancer activities to, but much lower side effects than commercial anticancer drug Taxol. The present work would provide a platform for targeted paclitaxel drug delivery and a general protocol for the design of advanced multifunctional nanoscale biomaterials for targeted drug/gene delivery.

  10. Taxol-producing [corrected] fungal endophyte, Pestalotiopsis species isolated from Taxus cuspidata.

    PubMed

    Kumaran, Rangarajulu Senthil; Kim, Hyung Joo; Hur, Byung-Ki

    2010-11-01

    The endophytic fungi, Pestalotiopsis versicolor and Pestalotiopsis neglecta, were isolated from the healthy leaves and bark of the Japanese Yew tree, Taxus cuspidata. The fungal species were identified by their characteristic culture morphology and molecular analysis. For the first time, the test fungi were screened for the production of taxol in modified liquid medium. The presence of taxol was confirmed by HPLC, (1)H NMR, and LC-MS methods of analysis. The maximum amount of taxol production in P. versicolor was recorded as 478 μg/l. The production rate was increased to 9560-fold than that found in the culture broth of earlier reported fungus, Taxomyces andreanae. The extracted fungal taxol showed a strong cytotoxic activity in the in vitro culture of tested human cancer cells by apoptotic assay indicating that the increase in taxol concentration induces increased cell death. A PCR-based screening for ts, a unique gene in the formation of the taxane skeleton, confirmed the molecular blueprint for taxol biosynthesis. The results designate that the fungal endophyte, P. versicolor, is an excellent candidate for an alternate source of taxol supply and can also serve as a potential species for genetic engineering to enhance the production of taxol to a higher level. Copyright © 2010 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  11. Effect of taxol from Pestalotiopsis mangiferae on A549 cells-In vitro study.

    PubMed

    Kathiravan, Govindarajan; Sureban, Sripathi M

    2009-12-01

    Pestalotiopsis mangiferae Coelomycete fungi were used to examine the production of taxol. The taxol isolated from this fungus is biologically active against cancer cell lines were investigated for its antiproliferative activity in human Non Small Cell Lung Cancer A549 cells. The results showed that the methylene chloride extraction of Pestalotiopsis mangiferae inhibited the proliferation of A 549 cells as measured by MTT and Trypan blue assay. Flow cytometric analysis showed that methylene chloride extraction of Pestalotiopsis mangiferae blocked cell cycle progression in G0/G1 phase. In addition fungal taxol induced A549 cell apoptosis as determined by propidium iodide staining. Further the percentage of LDH release was increased at increasing concentrations which is a measure of cell death. The levels of sialic acid levels and DNA, RNA and protein levels were decreased after treatment with methylene chloride extraction of Pestalotiopsis mangiferae. We suggests that methylene chloride extraction of Pestalotiopsis mangiferae might be considered for future therapeutic application with further studies against lung cancer.

  12. Isolation, Purification, and Identification of Taxol and Related Taxanes from Taxol-Producing Fungus Aspergillus niger subsp. taxi.

    PubMed

    Li, Dan; Fu, Dongwei; Zhang, Yue; Ma, Xueling; Gao, Liguo; Wang, Xioahua; Zhou, Dongpo; Zhao, Kai

    2017-08-28

    The content of taxol in the bark of yews is very low, and this is not affordable from the environmental point of view. Thus, it is a necessity to look for alternative sources of taxol production to solve its supply. Currently, a large portion of the taxol in the market comes from chemical semi-synthesis, but the semi-synthetic precursors such as baccatin III and 10-deacetyl-baccatin III are extracted from needles and twigs of yew trees. Taxol-producing fungi as a renewable resource is a very promising way to increase the scale of taxol production. Our group has obtained a taxol-producing endophytic fungus, Aspergillus niger subsp. taxi HD86-9, to examine if A. niger can produce the taxanes. Six compounds from the fermentation broth of strain HD86-9 were isolated and identified by 1 H NMR, 13 C NMR, and ESI-MS. The results showed that the six compounds included four taxane diterpenoids (taxol, cephalomannine, baccatin III, and 10-deacetyl-baccatin III) and two non-taxane compounds (β-sitosterol and flavonoid isovitexin). The study verified that the taxanes can be produced by the A. niger , which is very important to taxol production via chemical semi-synthesis. Additionally, the finding is potentially very significant to solve the taxol semi-synthetic precursors extracted from needles and twigs of yew trees, and the precursor production can be easily increased through the culture condition optimization, genetic breeding, and metabolic engineering of the A. niger .

  13. Fluorescence imaging analysis of taxol-induced ASTC-a-1 cell death with cell swelling and cytoplasmic vacuolization

    NASA Astrophysics Data System (ADS)

    Chen, Tong-sheng; Sun, Lei; Wang, Longxiang; Wang, Huiying

    2008-02-01

    Taxol (Paclitaxel), an isolated component from the bark of the Pacific yew Taxus brevifolia, exhibits a broad spectrum of clinical activity against human cancers. Taxol can promote microtubule (MT) assembly, inhibit depolymerization, and change MT dynamics, resulting in disruption of the normal reorganization of the microtubule network required for mitosis and cell proliferation. However, the molecular mechanism of taxol-induced cell death is still unclear. In this report, CCK-8 was used to assay the inhibition of taxol on the human lung adenocarcinoma (ASTC-a-1) cells viability, confocal fluorescence microscope was used to monitor the morphology changes of cells with taxol treatment. We for the first time describe the characteristics of taxol-induced cells swelling, cytoplasmic vacuolization and cell death. Taxol induced swelling, cytoplasmatic vacuolization and cell death without cell shrinkage and membrane rupture. These features differ from those of apoptosis and resemble the paraptosis, a novel nonapoptotic PCD.

  14. Effect of taxol from Pestalotiopsis mangiferae on A549 cells-In vitro study

    PubMed Central

    Kathiravan, Govindarajan; Sureban, Sripathi M.

    2009-01-01

    Pestalotiopsis mangiferae Coelomycete fungi were used to examine the production of taxol. The taxol isolated from this fungus is biologically active against cancer cell lines were investigated for its antiproliferative activity in human Non Small Cell Lung Cancer A549 cells. The results showed that the methylene chloride extraction of Pestalotiopsis mangiferae inhibited the proliferation of A 549 cells as measured by MTT and Trypan blue assay. Flow cytometric analysis showed that methylene chloride extraction of Pestalotiopsis mangiferae blocked cell cycle progression in G0/G1 phase. In addition fungal taxol induced A549 cell apoptosis as determined by propidium iodide staining. Further the percentage of LDH release was increased at increasing concentrations which is a measure of cell death. The levels of sialic acid levels and DNA, RNA and protein levels were decreased after treatment with methylene chloride extraction of Pestalotiopsis mangiferae. We suggests that methylene chloride extraction of Pestalotiopsis mangiferae might be considered for future therapeutic application with further studies against lung cancer. PMID:25206246

  15. Analysis of Breast Cell-Lineage Response Differences to Taxol Using a Novel Co-Culture System

    DTIC Science & Technology

    2005-06-01

    as the Hayflick limit [159], is thought to be a "mitotic clock" preventing cumulative cell damage from progressing to tumorigenesis [164-166] and...TERMS Breast cancer, co-culture, gene expression profiles, Taxol, transport mechanisms 16. SECURITY CLASSIFICATION OF: 17. LIMITATION 18. NUMBER 19a...proteins have been shown to bind and inactivate p53 and pRb respectively [25]. While the mortal cells have limited replicative potential in culture and

  16. Growth-inhibiting effects of taxol on human liver cancer in vitro and in nude mice

    PubMed Central

    Yuan, Jin Hui; Zhang, Ru Ping; Zhang, Ru Gang; Guo, Li Xia; Wang, Xing Wang; Luo, Dan; Xie, Yong; Xie, Hong

    2000-01-01

    AIM: To investigate the effects of taxol on SMMC-7721 human hepatoma and its mechanisms. METHODS: In vitro cell growth was assessed by trypan blue exclusion method. Experimental hepatoma model was established by seeding SMMC-7721 cells subcutaneously into Balb/c (nu/nu) nude mice. In vivo tumor growth was determined by measurement of tumor diameter with Vernier calipers. The syntheses of DNA, RNA and protein were analyzed by incorporation of 3H-thymidine, 3H-uridine and 3H-leucine respectively. Using light and electron microscopes to observe the morphological changes of cells including mitosis and apoptosis. RESULTS: Taxol was effective against SMMC-7721 human hepatoma cell growth in the ranges of 2.5 nmol/L-10 nmol/L- with mitotic arrest and apoptosis in vitro. DNA, RNA and protein syntheses in cells were also obviously suppressed by in vitro treatment of taxol for 72 h. Taxol at 2.5 nmol/L reduced 3H-thymidine uptake to about 34% of the control value (P < 0.05). Increasing the dose of taxol to 20 nmol/L resulted in a greater decrease in 3H-thymidine incorporation to 60% of the control value (P < 0.01). At a concentration of 20 nmol/L, the 3H-uridine and 3H-leucine uptakes were reduced to 52% (P < 0.05) and 63% (P < 0.01), respectively. In vivo, taxol significantly inhibited SMMC-7721 tumor growth at 10 mg/kg, i.p. once daily for 10 d. A more than 90% decrease in tumor volume was observed by day 11 (P < 0.01) similarly with mitotic arrest and cell apoptosis. CONCLUSION: Taxol has a marked anticancer activity in SMMC-7721 human hepatoma both in vitro and in nude mice. Its mechanisms might be associated with mitotic arrest, subsequently, apoptosis of the hepatoma cells. No obvious toxicity was observed with in vivo administration of taxol. PMID:11819558

  17. Rethinking production of Taxol® (paclitaxel) using endophyte biotechnology.

    PubMed

    Kusari, Souvik; Singh, Satpal; Jayabaskaran, Chelliah

    2014-06-01

    Taxol® (generic name paclitaxel) represents one of the most clinically valuable natural products known to mankind in the recent past. More than two decades have elapsed since the notable discovery of the first Taxol®-producing endophytic fungus, which was followed by a plethora of reports on other endophytes possessing similar biosynthetic potential. However, industrial-scale Taxol® production using fungal endophytes, although seemingly promising, has not seen the light of the day. In this opinion article, we embark on the current state of knowledge on Taxol® biosynthesis focusing on the chemical ecology of its producers, and ask whether it is actually possible to produce Taxol® using endophyte biotechnology. The key problems that have prevented the exploitation of potent endophytic fungi by industrial bioprocesses for sustained production of Taxol® are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Association between Twist and multidrug resistance gene-associated proteins in Taxol®-resistant MCF-7 cells and a 293 cell model of Twist overexpression.

    PubMed

    Wang, Li; Tan, Rui-Zhi; Zhang, Zhi-Xia; Yin, Rui; Zhang, Yong-Liang; Cui, Wei-Jia; He, Tao

    2018-01-01

    Multidrug resistance (MDR) severely limits the effectiveness of chemotherapy. Previous studies have identified Twist as a key factor of acquired MDR in breast, gastric and prostate cancer. However, the underlying mechanisms of action of Twist in MDR remain unclear. In the present study, the expression levels of MDR-associated proteins, including lung resistance-related protein (LRP), topoisomerase IIα (TOPO IIα), MDR-associated protein (MRP) and P-glycoprotein (P-gp), and the expression of Twist in cancerous tissues and pericancerous tissues of human breast cancer, were examined. In order to simulate Taxol ® resistance in cells, a Taxol ® -resistant human mammary adenocarcinoma cell subline (MCF-7/Taxol ® ) was established by repeatedly exposing MCF-7 cells to high concentrations of Taxol ® (up to 15 µg/ml). Twist was also overexpressed in 293 cells by transfecting this cell line with pcDNA5/FRT/TO vector containing full-length hTwist cDNA to explore the dynamic association between Twist and MDR gene-associated proteins. It was identified that the expression levels of Twist, TOPO IIα, MRP and P-gp were upregulated and LRP was downregulated in human breast cancer tissues, which was consistent with the expression of these proteins in the Taxol ® -resistant MCF-7 cell model. Notably, the overexpression of Twist in 293 cells increased the resistance to Taxol ® , Trichostatin A and 5-fluorouracil, and also upregulated the expression of MRP and P-gp. Taken together, these data demonstrated that Twist may promote drug resistance in cells and cancer tissues through regulating the expression of MDR gene-associated proteins, which may assist in understanding the mechanisms of action of Twist in drug resistance.

  19. Induction of taxol metabolism in the rat by dexamethasone

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Anderson, C.D.; Gondi, K.N.; Walle, T.

    1994-12-31

    The antitumor drug taxol was metabolized to two major metabolites (RM1 and RM2) in adult male and female rat liver microsomes. The male rats produced RM1 2.6 fold faster than the females, and they produced RM2 3 fold faster than the females. This correlated well with the sex differences noticed in liver microsomal cytochrome P450 (CYP) 3A content (4.4 fold greater in male) and 6{beta}-hydroxylation of testosterone (2.4 fold greater in male). Taxol was metabolized to three major metabolites (RM1, RM2, and RM3) in adult male and female rat liver microsomes from rats pretreated with dexamethasone. Production of RM1 andmore » RM2 was increased in these rats (2.3 and 3.3 fold respectively in males; 6.5 and 8.7 fold respectively in females) as compared to the untreated rats. These results compared well with the induction of CYP 3A proteins (3.5 fold in male, 10 fold in female) and induction of 6{beta}-hydroxylation (1.9 fold in males, 3.8 fold in females). RM3, which was produced only by the rats pretreated with dexamethasone, had a retention time of 0.58 relative to taxol which corresponds to 6{alpha}- hydroxytaxol, the major human metabolite of taxol. This study indicates that taxol metabolism in the rat is likely due to CYP 3A enzymes. Although the evidence points toward CYP 3A1 as the major isoform involved, it does not rule out others. The findings also suggest that CYP 3A1 is responsible for the induced metabolite, RM3.« less

  20. In vitro TAXOL production, by Pestalotiopsis breviseta--a first report.

    PubMed

    Kathiravan, Govindarajan; Sri Raman, Vithiyanathan

    2010-09-01

    Coelomycetous fungi were screened for the production of TAXOL. TAXOL production of Pestalotiopsis breviseta fungi is confirmed by Ultra Violet (UV) spectroscopic analysis, Infra Red (IR) analysis, high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) and LC-MASS spectroscopy. TAXOL isolated from the P. breviseta fungus was identical with authentic TAXOL and produces 0.064 mg/L (0.128% dry weight of fungal mat). Copyright (c) 2010 Elsevier B.V. All rights reserved.

  1. Cordyceps sinensis health supplement enhances recovery from taxol-induced leukopenia.

    PubMed

    Liu, Wei-Chung; Chuang, Wei-Ling; Tsai, Min-Lung; Hong, Ji-Hong; McBride, William H; Chiang, Chi-Shiun

    2008-04-01

    This study aimed to evaluate the ability of the health food supplement Cordyceps sinensis (CS) to ameliorate suppressive effects of chemotherapy on bone marrow function as a model for cancer treatment. Mice were treated with Taxol (17 mg/kg body wt) one day before oral administration of a hot-water extract of CS (50 mg/kg daily) that was given daily for 3 weeks. White blood cell counts in peripheral blood of mice receiving Taxol were at 50% of normal levels on day 28 but had recovered completely in mice treated with CS. In vitro assays showed that CS enhanced the colony-forming ability of both granulocyte macrophage colony forming unit (GM-CFU) and osteogenic cells from bone marrow preparations and promoted the differentiation of bone marrow mesenchymal stromal cells into adipocytes, alkaline phosphatase-positive osteoblasts, and bone tissue. This result could be attributed to enhanced expression of Cbfa1 (core binding factor a) and BMP-2 (bone morphogenetic protein) with concurrent suppression of ODF (osteoclast differentiation factor/RANK [receptor activator of NF-kappaB]) ligand. In summary, CS enhances recovery of mice from leukopenia caused by Taxol treatment. It appears to do so by protecting both hematopoietic progenitor cells directly and the bone marrow stem cell niche through its effects on osteoblast differentiation.

  2. Downstream reactions and engineering in the microbially reconstituted pathway for Taxol.

    PubMed

    Jiang, Ming; Stephanopoulos, Gregory; Pfeifer, Blaine A

    2012-05-01

    Taxol (a trademarked product of Bristol-Myers Squibb) is a complex isoprenoid natural product which has displayed potent anticancer activity. Originally isolated from the Pacific yew tree (Taxus brevifolia), Taxol has been mass-produced through processes reliant on plant-derived biosynthesis. Recently, there have been alternative efforts to reconstitute the biosynthetic process through technically convenient microbial hosts, which offer unmatched growth kinetics and engineering potential. Such an approach is made challenging by the need to successfully introduce the significantly foreign enzymatic steps responsible for eventual biosynthesis. Doing so, however, offers the potential to engineer more efficient and economical production processes and the opportunity to design and produce tailored analog compounds with enhanced properties. This mini review will specifically focus on heterologous biosynthesis as it applies to Taxol with an emphasis on the challenges associated with introducing and reconstituting the downstream reaction steps needed for final bioactivity.

  3. The flavonoid quercetin transiently inhibits the activity of taxol and nocodazole through interference with the cell cycle

    PubMed Central

    Samuel, Temesgen; Fadlalla, Khalda; Turner, Timothy; Yehualaeshet, Teshome E.

    2010-01-01

    Quercetin is a flavonoid with anticancer properties. In this study, we examined the effects of quercetin on cell cycle, viability and proliferation of cancer cells, either singly or in combination with the microtubule-targeting drugs taxol and nocodazole. Although quercetin induced cell death in a dose dependent manner, 12.5-50μM quercetin inhibited the activity of both taxol and nocodazole to induce G2/M arrest in various cell lines. Quercetin also partially restored drug-induced loss in viability of treated cells for up to 72 hours. This antagonism of microtubule-targeting drugs was accompanied by a delay in cell cycle progression and inhibition of the buildup of cyclin-B1 at the microtubule organizing center of treated cells. However, quercetin did not inhibit the microtubule targeting of taxol or nocodazole. Despite the short-term protection of cells by quercetin, colony formation and clonogenicity of HCT116 cells were still suppressed by quercetin or quercetin-taxol combination. The status of cell adherence to growth matrix was critical in determining the sensitivity of HCT116 cells to quercetin. We conclude that while long-term exposure of cancer cells to quercetin may prevent cell proliferation and survival, the interference of quercetin with cell cycle progression diminishes the efficacy of microtubule-targeting drugs to arrest cells at G2/M. PMID:21058190

  4. Isolation and characterization of endophytic taxol-producing fungi from Taxus chinensis.

    PubMed

    Liu, Kaihui; Ding, Xiaowei; Deng, Baiwan; Chen, Wenqiang

    2009-09-01

    This study investigated the endophytic fungi diversity of Taxus chinensis and screened the taxol-producing fungi in the host. A total of 115 endophytic fungi isolates obtained from bark segments of T. chinensis were grouped into 23 genera based on the morphological traits and sequence analysis of the internal transcribed spacers (ITS1-5.8S-ITS2), indicating endophytic fungi in T. chinensis are diverse and abundant. Diaporthe, Phomopsis (anamorph of Diaporthe), Acremonium, and Pezicula were the dominant genera, whereas the remaining genera were infrequent groups. The 13 representative species of the distinct genera were capable of producing taxol verified by reverse-phase high performance liquid chromatography (HPLC). Among the taxol-producing fungi, the yield of taxol produced by the Metarhizium anisopliae, H-27 was 846.1 microg l(-1) in reformative potato dextrose liquid medium, and the fungal taxol was further validated by mass spectrometry (MS). The taxol-producing fungi (92.3%) were infrequent communities, suggesting that infrequent fungi associated with T. chinensis might be a fascinating reservoir of taxol-generating fungi.

  5. Interactions between Co-Habitating fungi Elicit Synthesis of Taxol from an Endophytic Fungus in Host Taxus Plants

    PubMed Central

    Soliman, Sameh S. M.; Raizada, Manish N.

    2012-01-01

    Within a plant, there can exist an ecosystem of pathogens and endophytes, the latter described as bacterial and fungal inhabitants that thrive without causing disease to the host. Interactions between microbial inhabitants represent a novel area of study for natural products research. Here we analyzed the interactions between the fungal endophytes of Taxus (yew) trees. Fungal endophytes of Taxus have been proposed to produce the terpenoid secondary metabolite, Taxol, an anti-cancer drug. It is widely reported that plant extracts stimulate endophytic fungal Taxol production, but the underlying mechanism is not understood. Here, Taxus bark extracts stimulated fungal Taxol production 30-fold compared to a 10-fold induction with wood extracts. However, candidate plant-derived defense compounds (i.e., salicylic acid, benzoic acid) were found to act only as modest elicitors of fungal Taxol production from the endophytic fungus Paraconiothyrium SSM001, consistent with previous studies. We hypothesized the Taxus plant extracts may contain elicitors derived from other microbes inhabiting these tissues. We investigated the effects of co-culturing SSM001 with other fungi observed to inhabit Taxus bark, but not wood. Surprisingly, co-culture of SSM001 with a bark fungus (Alternaria) caused a ∼threefold increase in Taxol production. When SSM001 was pyramided with both the Alternaria endophyte along with another fungus (Phomopsis) observed to inhabit Taxus, there was an ∼eightfold increase in fungal Taxol production from SSM001. These results suggest that resident fungi within a host plant interact with one another to stimulate Taxol biosynthesis, either directly or through their metabolites. More generally, our results suggest that endophyte secondary metabolism should be studied in the context of its native ecosystem. PMID:23346084

  6. A new large-scale process for taxol and related taxanes from Taxus brevifolia.

    PubMed

    Rao, K V; Hanuman, J B; Alvarez, C; Stoy, M; Juchum, J; Davies, R M; Baxley, R

    1995-07-01

    In view of the demonstrated antitumor activity of taxol, ready availability of the drug is important. The current isolation methods starting from the bark of Taxus brevifolia involve multiple manipulations, leading to only taxol and in a yield of 0.01%. A new process consisting of a single reverse phase column is introduced here, and the present purpose is to determine its large scale applicability. The chloroform extractable fraction of the bark of T. brevifolia is applied directly on to a C-18 bonded silica column in 25% acetonitrile/water, with elution using a step gradient: 30-50% acetonitrile/water. On standing, eight different taxanes, including taxol, crystallize out directly from different fractions. The crystals are filtered and purified further by recrystallization. Taxol and four other taxanes are purified this way. The other three require a short silica column. Taxol is freed from cephalomannine by selective ozonolysis. The large scale process gave taxol (0.04%), 10-deacetylbaccatin III (0.02%), 10-deacetyl taxol-7-xyloside (0.1%), 10-deacetyl taxol-C-7-xyloside (0.04%), 10-deacetyl cephalomannine-7-xyloside (0.006%), taxol-7-xyloside (0.008%), 10-deacetyl taxol (0.008%) and cephalomannine (0.004%). Processing of the needles of T. brevifolia gave brevifoliol (0.17%), and that of the wood, 10-deacetyl taxol-C-7-xyloside (0.01%) and 10-deacetyl taxol-C. The reverse phase column process is simpler (one column, direct crystallization), more efficient (eight taxanes obtained simultaneously) and also gives higher yields.

  7. Direct effect of Taxol on free radical formation and mitochondrial permeability transition.

    PubMed

    Varbiro, G; Veres, B; Gallyas, F; Sumegi, B

    2001-08-15

    To elucidate the potential role of mitochondria in Taxol-induced cytotoxicity, we studied its direct mitochondrial effects. In Percoll-gradient purified liver mitochondria, Taxol induced large amplitude swelling in a concentration-dependent manner in the microM range. Opening of the permeability pore was also confirmed by the access of mitochondrial matrix enzymes for membrane impermeable substrates in Taxol-treated mitochondria. Taxol induced the dissipation of mitochondrial membrane potential (DeltaPsi) determined by Rhodamine123 release and induced the release of cytochrome c from the intermembrane space. All these effects were inhibited by 2.5 microM cyclosporine A. Taxol significantly increased the formation of reactive oxygen species (ROS) in both the aqueous and the lipid phase as determined by dihydrorhodamine123 and resorufin derivative. Cytochrome oxidase inhibitor CN(-), azide, and NO abrogated the Taxol-induced mitochondrial ROS formation while inhibitors of the other respiratory complexes and cyclosporine A had no effect. We confirmed that the Taxol-induced collapse of DeltaPsi and the induction of ROS production occurs in BRL-3A cells. In conclusion, Taxol-induced adenine nucleotide translocase-cyclophilin complex mediated permeability transition, and cytochrome oxidase mediated ROS production. Because both cytochrome c release and mitochondrial ROS production can induce suicide pathways, the direct mitochondrial effects of Taxol may contribute to its cytotoxicity.

  8. Lipid-laden macrophage infiltration of human adenocarcinoma in vivo associated with taxol and GCSF treatment.

    PubMed

    Abramson, N; Castro, S; Goldstein, J D

    1997-01-01

    This brief report illustrates the presence of lipid-laden macrophages in proximity to metastatic adenocarcinoma cells within the bone marrow of a patient receiving taxol and GCSF therapy. The pathophysiological mechanism is uncertain. Taxol, which is associated with macrophage function in vitro, may have been responsible for the recruitment of macrophages in this patient. GCSF could have contributed as well; however, GCSF usually has little effect on monocytes and macrophages.

  9. Investigation of genotoxic effect of taxol plus radiation on mice bone marrow cells.

    PubMed

    Ozkan, Lütfi; Egeli, Unal; Tunca, Berrin; Aydemir, Nilüfer; Ceçener, Gülşah; Akpinar, Gürler; Ergül, Emel; Cimen, Ciğdem; Ozuysal, Sema; Kahraman-Cetintaş, Sibel; Engin, Kayihan; Ahmed, Mansoor M

    2002-01-01

    In this study, we investigated the genotoxic effect of taxol, radiation, or taxol plus radiation on highly proliferative normal tissue-bone marrow cells of Swiss albino mice. Swiss-albino mice, 3-4 months old, were used in this study. Taxol was administered bolus intravenously through the tail vein. Radiation was given by using a linear accelerator. There were four treatment categories, which had a total of 34 groups. Each group consisted of five animals. The first was the control category that had one group (n = 5). The second treatment category was taxol alone, which had three groups as per taxol dose alone (n = 15). The third treatment category was radiation alone, which had three groups as per the radiation dose (n = 15). The fourth treatment category was taxol plus radiation, which had 27 groups as per combined radiation dose plus taxol dose concentration and as per pre-treatment timing sequence of taxol before radiation (n = 135). Mice were sacrificed 24 h after taxol or radiation or combined administration using ether anesthesia. The cells were then dropped on two labeled slides, flamed, air dried, and stained in 7% Giemsa; 20-30 well-spread mitotic metaphases were analyzed for each animal; the cells with chromosome breaks, acentric fragments, and rearrangements were evaluated on x1,000 magnification with light microscope (Zeiss axioplan). The mitotic index was determined by counting the number of mitotic cells among 1,000 cells per animal. Differences between groups were evaluated with Student's t-test statistically. Taxol caused a dose-dependent increase in chromosomal aberrations (P = 0.027). Similarly, radiation caused a dose-dependent increase in chromosomal aberrations (P = 0.003) and decreased mitotic index (P = 0.002). In combination, there were a small enhancements at the 40 mg/kg taxol dose level and at 0.25 and 0.5 Gy radiation doses in the 48 h group. However, an increase in chromosomal aberrations was observed after 48 hours of taxol exposure

  10. [Apoptosis mechanism of taxol combined with resveratrol on human laryngeal carcinoma Hep-2 cells].

    PubMed

    Lu, Chen-Xin; Sun, Jing-Hui; Wu, Chun-Lian

    2016-02-01

    Laryngeal cancer is one of the most common malignant tumors in the respiratory tumors, and its incidence ranks second highest in the respiratory tumors. Resveratrol (Res) is a kind of polyphenols, which can inhibit nucleotides can inhibit the growth of liver cancer cells, gastric cancer cells, pancreatic cells and other tumor cells by inhibiting ribonucleotide reductase in the cells. Taxol (Tax) is a kind of secondary metabolites of Taxus chinensis, which has anti-tumor activity for breast cancer, cervical cancer, ovarian cancer and other tumors by inhibiting cellular microtubule depolymerization. But at present the effects of resveratrol combined with taxol on human laryngeal carcinoma cell strain Hep-2 and their underlying molecular mechanisms are rarely reported. After human laryngeal cancer cell Hep-2 cells were processed with resveratrol (Res) and taxol (Tax), CCK-8 assay was used to evaluate the effect of these two herbs on the proliferation of cancer cells; AO/PI staining and JC-1 were used to detect Hep-1 cells apoptosis; the expression of Bax, Bcl-2, PARP, TRIB3, and XIAP genes was detected by real time quantitative PCR; the activity of caspase-3 and caspase-8 was determined with quantitative fluorescence method. The experimental results showed that compared with Tax, Res medication alone, joint group significantly enhanced inhibition of Hep-2 cells activity, decreased the dosage of Tax, increased the expression of Bax and PARP, TRIB3, reduced the expression of the Bcl-2 and XIAP, and promoted the activity of caspase-3 and caspase-8. The test results showed that compared with the single medication, combined group could significantly increase the inhibitory effect on Hep-2 cells, significantly reduce Tax dosage, increase expressions of Bax, PARP, TRIB3, reduce expressions of Bcl-2, XIAP, and promote activity of caspase-3, caspase-8. This indicated apoptosis of human laryngeal carcinoma cell strain Hep-2 may be induced with Res, Tax, and the combination of

  11. Greater taxol yield of fungus Pestalotiopsis hainanensis from dermatitic scurf of the giant panda (Ailuropoda melanoleuca).

    PubMed

    Gu, Yu; Wang, Yanlin; Ma, Xiaoping; Wang, Chengdong; Yue, Guizhou; Zhang, Yuetian; Zhang, Yunyan; Li, Shanshan; Ling, Shanshan; Liu, Xiaomin; Wen, Xintian; Cao, Sanjie; Huang, Xiaobo; Deng, Junliang; Zuo, Zhicai; Yu, Shumin; Shen, Liuhong; Wu, Rui

    2015-01-01

    While taxol yields of fungi from non-animal sources are still low, whether Pestalotiopsis hainanensis isolated from the scurf of a dermatitic giant panda, Ailuropoda melanoleuca, provides a greater taxol yield remains unknown. The objective of the study was to determine the corresponding taxol yield. The structure of the taxol produced by the fungus was evaluated by thin layer chromatography (TLC), ultraviolet (UV) spectroscopy, high-performance liquid chromatography (HPLC), (1)H and (13)C nuclear magnetic resonance spectroscopy ((1)H-NMR and (13)C-NMR), and time-of-flight mass spectrometry (TOF-MS), with standard taxol as a control. The results demonstrated that the P. hainanensis fungus produced taxol, which had the same structure as the standard taxol and yield of 1,466.87 μg/L. This fungal taxol yield from the dermatitic giant panda was significantly greater than those of fungus from non-animal sources. The taxol-producing fungus may be a potential candidate for the production of taxol on an industrial scale.

  12. Controlled Breast Cancer Microarrays for the Deconvolution of Cellular Multilayering and Density Effects upon Drug Responses

    PubMed Central

    Håkanson, Maria; Kobel, Stefan; Lutolf, Matthias P.; Textor, Marcus; Cukierman, Edna; Charnley, Mirren

    2012-01-01

    Background Increasing evidence shows that the cancer microenvironment affects both tumorigenesis and the response of cancer to drug treatment. Therefore in vitro models that selectively reflect characteristics of the in vivo environment are greatly needed. Current methods allow us to screen the effect of extrinsic parameters such as matrix composition and to model the complex and three-dimensional (3D) cancer environment. However, 3D models that reflect characteristics of the in vivo environment are typically too complex and do not allow the separation of discrete extrinsic parameters. Methodology/Principal Findings In this study we used a poly(ethylene glycol) (PEG) hydrogel-based microwell array to model breast cancer cell behavior in multilayer cell clusters that allows a rigorous control of the environment. The innovative array fabrication enables different matrix proteins to be integrated into the bottom surface of microwells. Thereby, extrinsic parameters including dimensionality, type of matrix coating and the extent of cell-cell adhesion could be independently studied. Our results suggest that cell to matrix interactions and increased cell-cell adhesion, at high cell density, induce independent effects on the response to Taxol in multilayer breast cancer cell clusters. In addition, comparing the levels of apoptosis and proliferation revealed that drug resistance mediated by cell-cell adhesion can be related to altered cell cycle regulation. Conversely, the matrix-dependent response to Taxol did not correlate with proliferation changes suggesting that cell death inhibition may be responsible for this effect. Conclusions/Significance The application of the PEG hydrogel platform provided novel insight into the independent role of extrinsic parameters controlling drug response. The presented platform may not only become a useful tool for basic research related to the role of the cancer microenvironment but could also serve as a complementary platform for in

  13. Effects of Taxol plus radiation on the apoptotic and mitotic indices of mouse intestinal crypt cells.

    PubMed

    Ozkan, L; Ozuysal, S; Egeli, U; Adim, S B; Tunca, B; Aydemir, N; Ceçener, G; Ergül, E; Akpinar, G; Cimen, C; Engin, K; Ahmed, M M

    2001-07-01

    In this study we investigated the effect of Taxol, radiation, or Taxol plus radiation on highly proliferative normal tissue--the intestinal crypt cells of Swiss albino mice. Swiss-albino mice, 3-4 months old, were used in this study. Taxol was administered by bolus intravenously through the tail vein. Radiation was given using a linear accelerator. There were four treatment categories, which comprised a total of 34 groups. Each group consisted of five animals. The first category was a control category which comprised one group (n = 5). The second treatment category was Taxol alone which comprised three groups (n = 15). The third treatment category was radiation alone which comprised three groups (n = 15). The fourth treatment category was Taxol plus radiation which comprised 27 groups (n = 135). Mice were killed 24 h after Taxol or radiation or combined administration using ether anesthesia. Using a light microscope, apoptotic and mitotic indices were counted on jejunal crypt cells of mice that were stained with hematoxylin-eosin. Differences between groups were statistically evaluated with Student's t-test. Taxol caused a dose-dependent increase in apoptosis (P = 0.045) and decreased the mitotic index (P = 0.006) at high doses. Similarly, radiation caused a dose-dependent increase in apoptosis (P = 0.046) and decreased the mitotic index (P = 0.299) at higher radiation doses. Compared to radiation alone, Taxol caused a significant induction of apoptosis (P = 0.010). In combination, no significant radiosensitizing effect of Taxol was observed (enhancement ratio < 1), when compared to radiation alone. However, an increase in apoptosis was observed after 24 h of Taxol exposure when compared to 12 or 48 h of Taxol exposure (P = 0.0001 and P = 0.0001). These findings suggest that Taxol did not cause a radiosensitizing effect in intestinal crypt cells. However, a 24-hour pretreatment of Taxol exposure followed by radiation caused significant induction of apoptosis and

  14. Transformation of taxol-producing endophytic fungi by restriction enzyme-mediated integration (REMI).

    PubMed

    Wang, Yechun; Guo, Binhui; Miao, Zhiqi; Tang, Kexuan

    2007-08-01

    The REMI method was used to introduce the plasmid pV2 harboring the hygromycin B phosphotransferase (hph) gene controlled by the Aspergillus nidulans trpC promoter and the trpC terminator into a taxol-producing endophytic fungus BT2. REMI transformation yielded stable transformants capable of continuing to grow on PDA medium containing 125 mug mL(-1) hygromycin B. The transformation efficiency was about 5-6 transformants mug(-1) plasmid DNA. The presence of hph gene in transformants was confirmed by PCR and Southern blot analyses. To the authors' knowledge, this is the first report on the transformation of taxol-producing endophytic fungi by the REMI technique. This study provides an effective approach for improving taxol production of endophytic fungi by the genetic engineering of taxol biosynthetic pathway genes in the future.

  15. Taxol induces concentration-dependent phosphatidylserine (PS) externalization and cell cycle arrest in ASTC-a-1 cells

    NASA Astrophysics Data System (ADS)

    Guo, Wen-jing; Chen, Tong-sheng

    2010-02-01

    Taxol (Paclitaxel) is an important natural product for the treatment of solid tumors. Different concentrations of taxol can trigger distinct effects on both the cellular microtubule network and biochemical pathways. Apoptosis induced by low concentrations (5-30 nM) of taxol was associated with mitotic arrest, alteration of microtubule dynamics and/or G2/M cell cycle arrest, whereas high concentrations of this drug (0.2-30 μM) caused significant microtubule damage, and was found recently to induce cytoplasm vacuolization in human lung adenocarcinoma (ASTC-a-1) cells. In present study, cell counting kit (CCK-8) assay, confocal microscope, and flow cytometry analysis were used to analyze the cell death form induced by 35 nM and 70 μM of taxol respectively in human lung adenocarcinoma (ASTC-a-1) cells. After treatment of 35 nM taxol for 48 h, the OD450 value was 0.80, and 35 nM taxol was found to induce dominantly cell death in apoptotic pathway such as phosphatidylserine (PS) externalization, G2/M phase arrest after treatment for 24 h, and nuclear fragmentation after treatment for 48 h. After 70 μM taxol treated the cell for 24 h, the OD450 value was 1.01, and 70 μM taxol induced cytoplasm vacuolization programmed cell death (PCD) and G2/M phase as well as the polyploidy phase arrest in paraptotic-like cell death. These findings imply that the regulated signaling pathway of cell death induced by taxol is dependent on taxol concentration in ASTC-a-1 cells.

  16. Extracellular biosynthesis of gadolinium oxide (Gd2O3) nanoparticles, their biodistribution and bioconjugation with the chemically modified anticancer drug taxol

    PubMed Central

    Khan, Shadab Ali; Gambhir, Sanjay

    2014-01-01

    Summary As a part of our programme to develop nanobioconjugates for the treatment of cancer, we first synthesized extracellular, protein-capped, highly stable and well-dispersed gadolinium oxide (Gd2O3) nanoparticles by using thermophilic fungus Humicola sp. The biodistribution of the nanoparticles in rats was checked by radiolabelling with Tc-99m. Finally, these nanoparticles were bioconjugated with the chemically modified anticancer drug taxol with the aim of characterizing the role of this bioconjugate in the treatment of cancer. The biosynthesized Gd2O3 nanoparticles were characterized by UV–vis spectroscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoemission spectroscopy (XPS). The Gd2O3–taxol bioconjugate was confirmed by UV–vis spectroscopy and fluorescence microscopy and was purified by using high performance liquid chromatography (HPLC). PMID:24778946

  17. In vitro cell cultures obtained from different explants of Corylus avellana produce Taxol and taxanes

    PubMed Central

    Bestoso, Federica; Ottaggio, Laura; Armirotti, Andrea; Balbi, Alessandro; Damonte, Gianluca; Degan, Paolo; Mazzei, Mauro; Cavalli, Francesca; Ledda, Bernardetta; Miele, Mariangela

    2006-01-01

    Background Taxol is an effective antineoplastic agent, originally extracted from the bark of Taxus brevifolia with a low yield. Many attempts have been made to produce Taxol by chemical synthesis, semi-synthesis and plant tissue cultures. However, to date, the availability of this compound is not sufficient to satisfy the commercial requirements. The aim of the present work was to produce suspension cell cultures from plants not belonging to Taxus genus and to verify whether they produced Taxol and taxanes. For this purpose different explants of hazel (Corylus avellana species) were used to optimize the protocol for inducing in vitro callus, an undifferentiated tissue from which suspension cell cultures were established. Results Calli were successfully induced from stems, leaves and seeds grown in various hormone concentrations and combinations. The most suitable callus to establish suspension cell cultures was obtained from seeds. Media recovered from suspension cell cultures contained taxanes, and showed antiproliferative activity on human tumour cells. Taxol, 10-deacetyltaxol and 10-deacetylbaccatin III were the main taxanes identified. The level of Taxol recovered from the media of hazel cultures was similar to that found in yew cultures. Moreover, the production of taxanes in hazel cell cultures increased when elicitors were used. Conclusion Here we show that hazel cell cultures produce Taxol and taxanes under controlled conditions. This result suggests that hazel possesses the enzymes for Taxol production, which until now was considered to be a pathway particular to Taxus genus. The main benefit of producing taxanes through hazel cell cultures is that hazel is widely available, grows at a much faster rate in vivo, and is easier to cultivate in vitro than yew. In addition, the production of callus directly from hazel seeds shortens the culture time and minimizes the probability of contamination. Therefore, hazel could become a commercial source of Taxol and

  18. Bioreactor engineering as an enabling technology to tap biodiversity. The case of taxol.

    PubMed

    Shuler, M L

    1994-11-30

    One barrier to exploiting the chemical and genetic diversity in nature is the difficulty of cultivating many organisms in a controlled manner. In some cases it is difficult to achieve growth. In many others, good growth is achieved, but the expression of the organism's genetic potential to make a desired product is not realized. The thesis of this paper is that a coupling of an understanding of reactor engineering principles with the basic knowledge of the biology is often necessary to circumvent these barriers. In many cases the construction of appropriate cultivation systems is a necessary step to better understanding of cellular physiology. In some cases the chemical of interest is of high social utility and comes from a natural source that is uncommon and difficult to secure. In these cases a method of controlled cultivation becomes a prerequisite for commercial exploitation. These points were illustrated using a taxol. Taxol is an important new anticancer drug whose development has been greatly impeded by supply problems. Taxol has been derived from the park of the pacific yew tree, a process that kills the tree. The pacific yew is a relatively uncommon tree and very slow growing. One alternative to the natural source is plant cell culture. Such cultures can produce significant levels of taxol with substantial release into the medium. Taxane products not observed in typical extracts from field-grown plants can be found in cell cultures, indicating the potential unmasking of pathways. These cultures are quite responsive to changes in their environments as illustrated by the summary of initial observations. With regard to natural compounds, biochemical engineers can play a major role in the capture and preservation of producing systems, in the discovery of useful compounds, and in providing the basis for commercial production of natural compounds.

  19. The influence of the combined treatment with Vadimezan (ASA404) and taxol on the growth of U251 glioblastoma xenografts

    PubMed Central

    2012-01-01

    Background One of the most important biological characteristics of Glioblastoma multiforme (GBM) is high vascular density. Vadimezan (ASA404, DMXAA) belongs to the class of small molecule vascular disrupting agents (VDA) that cause disruption of established tumor vessels and subsequent tumor hemorrhagic necrosis. Its selective antivascular effect is mediated by intratumoral induction of several cytokines including tumor necrosis factor-α (TNF-α), granulocyte-colony-stimulating factor (G-CSF), interleukin 6 (IL-6) and macrophage inflammatory protein 1α (MIP-1α). Preclinical studies have demonstrated that ASA404 acts synergistically with taxanes. In this study, we investigated if treatment of mice bearing U251 human glioblastoma xenografts with ASA404 and taxol may be synergistic. Therapy response was evaluated by measuring changes in tumor size and metabolic activity using 18F-FDG PET (Fluorodeoxyglucose - positron emision tomography) imaging. Methods U251 cells were inoculated s.c. in the right hind limb of NMRI-Foxn1nu athymic female nude mice. Animals were randomly assigned into 4 groups (7–9 animals/group) for treatment: control, taxol, ASA404, and ASA404 plus taxol. The animals received either a single dose of taxol (10 mg/kg), ASA404 (27.5 mg/kg), or taxol (10 mg/kg) plus ASA404 (27.5 mg/kg) administered i.p.; ASA404 was administred 24 h after the treatment with taxol. 4 and 24 h after treatment with ASA404 (28 and 48 h hours after treatment with taxol) 18 F-FDG PET scans were performed. Results The treatment with taxol did not affect the tumor growth in comparison to untreated controls. The treatment of animals with single dose ASA404 alone or in combination with taxol caused a significant delay in tumor growth. The combined treatment did not decrease the growth of the xenografts significantly more than ASA404 alone, but early changes in tumor 18 F-FDG uptake preceded subsequent growth inhibition. The tumor weights, which were

  20. Isolation of anticancer drug TAXOL from Pestalotiopsis breviseta with apoptosis and B-Cell lymphoma protein docking studies.

    PubMed

    Kathiravan, G; Sureban, Sripathi M; Sree, Harsha N; Bhuvaneshwari, V; Kramony, Evelin

    2012-12-01

    Extraction and investigation of TAXOL from Pestalotiopsis breviseta (Sacc.) using protein docking, which is a computational technique that samples conformations of small molecules in protein-binding sites. Scoring functions are used to assess which of these conformations best complements the protein binding site and active site prediction. Coelomycetous fungi P. breviseta (Sacc.) Steyaert was screened for the production of TAXOL, an anticancer drug. TAXOL PRODUCTION WAS CONFIRMED BY THE FOLLOWING METHODS: Ultraviolet (UV) spectroscopic analysis, Infrared analysis, High performance liquid chromatography analysis (HPLC), and Liquid chromatography mass spectrum (LC-MASS). TAXOL produced by the fungi was compared with authentic TAXOL, and protein docking studies were performed. The BCL2 protein of human origin showed a higher affinity toward the compound paclitaxel. It has the binding energy value of -13.0061 (KJ/Mol) with four hydrogen bonds.

  1. Isolation of anticancer drug TAXOL from Pestalotiopsis breviseta with apoptosis and B-Cell lymphoma protein docking studies

    PubMed Central

    Kathiravan, G.; Sureban, Sripathi M.; Sree, Harsha N.; Bhuvaneshwari, V.; Kramony, Evelin

    2012-01-01

    Background: Extraction and investigation of TAXOL from Pestalotiopsis breviseta (Sacc.) using protein docking, which is a computational technique that samples conformations of small molecules in protein-binding sites. Scoring functions are used to assess which of these conformations best complements the protein binding site and active site prediction. Materials and Methods: Coelomycetous fungi P. breviseta (Sacc.) Steyaert was screened for the production of TAXOL, an anticancer drug. Results: TAXOL production was confirmed by the following methods: Ultraviolet (UV) spectroscopic analysis, Infrared analysis, High performance liquid chromatography analysis (HPLC), and Liquid chromatography mass spectrum (LC-MASS). TAXOL produced by the fungi was compared with authentic TAXOL, and protein docking studies were performed. Conclusion: The BCL2 protein of human origin showed a higher affinity toward the compound paclitaxel. It has the binding energy value of −13.0061 (KJ/Mol) with four hydrogen bonds. PMID:24808664

  2. Induction of oxidative stress by Taxol® vehicle Cremophor-EL triggers production of interleukin-8 by peripheral blood mononuclear cells through the mechanism not requiring de novo synthesis of mRNA.

    PubMed

    Ilinskaya, Anna N; Clogston, Jeffrey D; McNeil, Scott E; Dobrovolskaia, Marina A

    2015-11-01

    Understanding the ability of cytotoxic oncology drugs, and their carriers and formulation excipients, to induce pro-inflammatory responses is important for establishing safe and efficacious formulations. Literature data about cytokine response induction by the traditional formulation of paclitaxel, Taxol®, are controversial, and no data are available about the pro-inflammatory profile of the nano-albumin formulation of this drug, Abraxane®. Herein, we demonstrate and explain the difference in the cytokine induction profile between Taxol® and Abraxane®, and describe a novel mechanism of cytokine induction by a nanosized excipient, Cremophor EL, which is not unique to Taxol® and is commonly used in the pharmaceutical industry for delivery of a wide variety of small molecular drugs. Advances in nanotechnology have enabled the production of many nano-formulation drugs. The cellular response to drugs has been reported to be different between traditional and nano-formulations. In this article, the authors investigated and compared cytokine response induction profiles between Taxol® and Abraxane®. The findings here provided further understanding to create drugs with better safety profiles. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Alterations in Taxol production in plant cell culture via manipulation of the phenylalanine ammonia lyase pathway.

    PubMed

    Brincat, Michelle C; Gibson, Donna M; Shuler, Michael L

    2002-01-01

    One approach to increasing secondary metabolite production in plant cell culture is to manipulate metabolic pathways to utilize more resources toward production of one desired compound or class of compounds, such as diverting carbon flux from competing secondary pathways. Since phenylalanine provides both the phenylisoserine side chain and the benzoyl moiety at C-2 of Taxol, we speculated that blockage of the phenylpropanoid pathway might divert phenylalanine into Taxol biosynthesis. We used specific enzyme inhibitors to target the first enzyme in the phenylpropanoid pathway, phenylalanine ammonia lyase (PAL), the critical control point for conversion of L-phenylalanine to trans-cinnamic acid. Cinnamic acid acted quickly in reducing PAL activity by 40-50%, without affecting total protein levels, but it generally inhibited the taxane pathway, reducing Taxol by 90% of control levels. Of the taxanes produced, 13-acetyl-9-dihydro-baccatin III and 9-dihydrobaccatin III doubled as a percentage of total taxanes in C93AD and CO93P cells treated with 0.20 and 0.25 mM cinnamic acid, when all other taxanes were lowered. The PAL inhibitor alpha-aminooxyacetic acid (AOA) almost entirely shut down Taxol production at both 0.5 and 1.5 mM, whereas L-alpha-aminooxy-beta-phenylpropionic acid (AOPP) had the opposite effect, slightly enhancing Taxol production at 1 microM but having no effect at 10 microM. The discrepancy in the effectiveness of AOA and AOPP and the lack of effect with addition of phenylalanine or benzoic acid derivatives further indicates that the impact of cinnamic acid on Taxol is related not to its effect on PAL but rather to a specific effect on the taxane pathway. On the basis of these results, a less direct route for inhibiting the phenylpropanoid pathway may be required to avoid unwanted side effects and potentially enhance Taxol production.

  4. Montelukast is a potent and durable inhibitor of multidrug resistance protein 2 (MRP2)-mediated efflux of taxol and saquinavir

    PubMed Central

    Roy, Upal; Chakravarty, Geetika; Honer Zu Bentrup, Kerstin; Mondal, Debasis

    2009-01-01

    The ATP binding cassette (ABC)-transporters are energy dependent efflux pumps which regulate the pharmacokinetics of both anti-cancer chemotherapeutic agents, e.g. taxol, and of HIV-1 protease inhibitors (HPIs), e.g. saquinavir. Increased expression of several ABC-transporters, especially P-gp and MRP2, are observed in multidrug resistant (MDR) tumor cells and on HIV-1 infected lymphocytes. In addition, due to their apical expression on vascular endothelial barriers, both P-gp and MRP2 are of crucial importance towards dictating drug access into sequestered tissues. However, although a number of P-gp inhibitors are currently in clinical trials, possible inhibitors of MRP2 are not being thoroughly investigated. The experimental leukotriene receptor antagonist (LTRA), MK-571 is known to be a potent inhibitor of MRP transporters. Using the MRP2 over-expressing cell line, MDCKII-MRP2, we evaluated whether the clinically approved LTRAs, e.g. montelukast (Singulair™) and zafirlukast (Accolate™), can similarly suppress MRP2-mediated efflux. We compared the efficacy of increasing concentrations (20-100 μM) of MK-571, montelukast, and zafirlukast, in suppressing the efflux of calcein-AM, a fluorescent MRP substrate, and the radiolabeled [3H-] drugs, taxol and saquinavir. Montelukast was the most potent inhibitor (p<0.01) of MRP2-mediated efflux of all three substrates. Montelukast also increased (p<0.01) the duration of intracellular retention of both taxol and saquinavir. More than 50% of the drugs were retained in cells even after 90 mins post removal of montelukast from the medium. Our findings implicate that montelukast, a relatively safe anti-asthmatic agent, may be used as an adjunct therapy to suppress the efflux of taxol and saquinavir from MRP2 overexpressing cells. PMID:19952419

  5. Inhibition of the MUC1-C oncoprotein is synergistic with cytotoxic agents in the treatment of breast cancer cells

    PubMed Central

    Uchida, Yasumitsu; Raina, Deepak; Kharbanda, Surender; Kufe, Donald

    2013-01-01

    Mucin 1 (MUC1) is a heterodimeric glycoprotein that is aberrantly overexpressed in most human breast cancers. The oncogenic MUC1-C subunit promotes survival and blocks the apoptotic response to genotoxic anticancer agents. In the present studies, human MCF-7 and ZR-75-1 breast cancer cells were treated with the MUC1-C inhibitor, GO-203, a cell-penetrating peptide that blocks MUC1-C homodimerization and thereby its oncogenic function. Treatment with GO-203 was found to promote the apoptotic response of MCF-7 and ZR-75-1 cells to the therapeutic drugs taxol and doxorubicin (DOX). This effect was (1) attenuated by a pan-caspase inhibitor, and (2) mediated, at least in part, by activation of the effector caspase-7 and cleavage of the downstream substrate PARP. Further analysis of the interaction between GO-203 and taxol using isobolograms, which evaluate the nature of the interaction of two drugs, demonstrated that the combination is highly synergistic. These results were supported by combination index (CI) analysis with values of less than 1. GO-203 was also highly synergistic with DOX in studies of both MCF-7 and ZR-75-1 breast cancer cells. These findings indicate that blocking MUC1-C function could be effective in combination with taxol and DOX for the treatment of breast cancer. PMID:23114713

  6. Metabolomics Analysis of Hormone-Responsive and Triple-Negative Breast Cancer Cell Responses to Paclitaxel Identify Key Metabolic Differences.

    PubMed

    Stewart, Delisha A; Winnike, Jason H; McRitchie, Susan L; Clark, Robert F; Pathmasiri, Wimal W; Sumner, Susan J

    2016-09-02

    To date, no targeted therapies are available to treat triple negative breast cancer (TNBC), while other breast cancer subtypes are responsive to current therapeutic treatment. Metabolomics was conducted to reveal differences in two hormone receptor-negative TNBC cell lines and two hormone receptor-positive Luminal A cell lines. Studies were conducted in the presence and absence of paclitaxel (Taxol). TNBC cell lines had higher levels of amino acids, branched-chain amino acids, nucleotides, and nucleotide sugars and lower levels of proliferation-related metabolites like choline compared with Luminal A cell lines. In the presence of paclitaxel, each cell line showed unique metabolic responses, with some similarities by type. For example, in the Luminal A cell lines, levels of lactate and creatine decreased while certain choline metabolites and myo-inositol increased with paclitaxel. In the TNBC cell lines levels of glutamine, glutamate, and glutathione increased, whereas lysine, proline, and valine decreased in the presence of drug. Profiling secreted inflammatory cytokines in the conditioned media demonstrated a greater response to paclitaxel in the hormone-positive Luminal cells compared with a secretion profile that suggested greater drug resistance in the TNBC cells. The most significant differences distinguishing the cell types based on pathway enrichment analyses were related to amino acid, lipid and carbohydrate metabolism pathways, whereas several biological pathways were differentiated between the cell lines following treatment.

  7. Endogenous lung surfactant inspired pH responsive nanovesicle aerosols: Pulmonary compatible and site-specific drug delivery in lung metastases

    NASA Astrophysics Data System (ADS)

    Joshi, Nitin; Shirsath, Nitesh; Singh, Ankur; Joshi, Kalpana S.; Banerjee, Rinti

    2014-11-01

    Concerns related to pulmonary toxicity and non-specificity of nanoparticles have limited their clinical applications for aerosol delivery of chemotherapeutics in lung cancer. We hypothesized that pulmonary surfactant mimetic nanoparticles that offer pH responsive release specifically in tumor may be a possible solution to overcome these issues. We therefore developed lung surfactant mimetic and pH responsive lipid nanovesicles for aerosol delivery of paclitaxel in metastatic lung cancer. 100-200 nm sized nanovesicles showed improved fusogenicity and cytosolic drug release, specifically with cancer cells, thereby resulting in improved cytotoxicity of paclitaxel in B16F10 murine melanoma cells and cytocompatibility with normal lung fibroblasts (MRC 5). The nanovesicles showed airway patency similar to that of endogenous pulmonary surfactant and did not elicit inflammatory response in alveolar macrophages. Their aerosol administration while significantly improving the biodistribution of paclitaxel in comparison to Taxol (i.v.), also showed significantly higher metastastes inhibition (~75%) in comparison to that of i.v. Taxol and i.v. Abraxane. No signs of interstitial pulmonary fiborisis, chronic inflammation and any other pulmonary toxicity were observed with nanovesicle formulation. Overall, these nanovesicles may be a potential platform to efficiently deliver hydrophobic drugs as aerosol in metastatic lung cancer and other lung diseases, without causing pulmonary toxicity.

  8. Transcriptome-wide identification and screening of WRKY factors involved in the regulation of taxol biosynthesis in Taxus chinensis.

    PubMed

    Zhang, Meng; Chen, Ying; Nie, Lin; Jin, Xiaofei; Liao, Weifang; Zhao, Shengying; Fu, Chunhua; Yu, Longjiang

    2018-03-26

    WRKY, a plant-specific transcription factor family, plays important roles in pathogen defense, abiotic cues, phytohormone signaling, and regulation of plant secondary metabolism. However, little is known about the roles, functions, and mechanisms of WRKY in taxane biosynthesis in Taxus spp. In this study, 61 transcripts were identified from Taxus chinensis transcriptome datasets by using hidden Markov model search. All of these transcripts encoded proteins containing WRKY domains, which were designated as TcWRKY1-61. After phylogenetic analysis of the WRKY domains of TcWRKYs and AtWRKYs, 16, 8, 10, 14, 5, 7, and 1 TcWRKYs were cladded into Group I, IIa-IIe, and III, respectively. Then, six representative TcWRKYs were selected to classify their effects on taxol biosynthesis. After MeJA (methyl jasmonate acid) and SA (salicylic acid) treatments, all of the six TcWRKYs were upregulated by MeJA treatment. TcWRKY44 (IId) and TcWRKY47 (IIa) were upregulated, whereas TcWRKY8 (IIc), TcWRKY20 (III), TcWRKY26 (I), TcWRKY41 (IIe), and TcWRKY52 (IIb) were downregulated by SA treatment. Overexpression experiments showed that the six selected TcWRKYs exerted different effects on taxol biosynthesis. In specific, TcWRKY8 and TcWRKY47 significantly improved the expression levels of taxol-biosynthesis-related genes. Transcriptome-wide identification of WRKY factors in Taxus not only enhances our understanding of plant WRKY factors but also identifies candidate regulators of taxol biosynthesis.

  9. Ionic-Liquid-Based Paclitaxel Preparation: A New Potential Formulation for Cancer Treatment.

    PubMed

    Chowdhury, Md Raihan; Moshikur, Rahman Md; Wakabayashi, Rie; Tahara, Yoshiro; Kamiya, Noriho; Moniruzzaman, Muhammad; Goto, Masahiro

    2018-06-04

    Paclitaxel (PTX) injection (i.e., Taxol) has been used as an effective chemotherapeutic treatment for various cancers. However, the current Taxol formulation contains Cremophor EL, which causes hypersensitivity reactions during intravenous administration and precipitation by aqueous dilution. This communication reports the preliminary results on the ionic liquid (IL)-based PTX formulations developed to address the aforementioned issues. The formulations were composed of PTX/cholinium amino acid ILs/ethanol/Tween-80/water. A significant enhancement in the solubility of PTX was observed with considerable correlation with the density and viscosity of the ILs, and with the side chain of the amino acids used as anions in the ILs. Moreover, the formulations were stable for up to 3 months. The driving force for the stability of the formulation was hypothesized to be the involvement of different types of interactions between the IL and PTX. In vitro cytotoxicity and antitumor activity of the IL-based formulations were evaluated on HeLa cells. The IL vehicles without PTX were found to be less cytotoxic than Taxol, while both the IL-based PTX formulation and Taxol exhibited similar antitumor activity. Finally, in vitro hypersensitivity reactions were evaluated on THP-1 cells and found to be significantly lower with the IL-based formulation than Taxol. This study demonstrated that specially designed ILs could provide a potentially safer alternative to Cremophor EL as an effective PTX formulation for cancer treatment giving fewer hypersensitivity reactions.

  10. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yadav, N.; Kumar, S.; Marlowe, T.

    Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrialmore » biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS

  11. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents.

    PubMed

    Yadav, N; Kumar, S; Marlowe, T; Chaudhary, A K; Kumar, R; Wang, J; O'Malley, J; Boland, P M; Jayanthi, S; Kumar, T K S; Yadava, N; Chandra, D

    2015-11-05

    Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrial biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency

  12. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents

    DOE PAGES

    Yadav, N.; Kumar, S.; Marlowe, T.; ...

    2015-11-05

    Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrialmore » biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS

  13. Regulation of drug resistance by human pregnane X receptor in breast cancer

    PubMed Central

    Chen, Yakun; Tang, Yong; Chen, Shuqing; Nie, Daotai

    2012-01-01

    Drug resistance is a significant barrier to an effective treatment of breast cancer. Human pregnane X receptor (hPXR), an orphan nuclear receptor known for its activation by many important clinical drugs, is a major transcription factor of drug metabolism enzymes (DMEs), such as cytochrome P450 3A4 (CYP3A4), and efflux transporters such as multi-drug resistance gene (MDR1). hPXR has been detected in human breast cancers but its role in responses of cancers toward drugs remains unknown. In this study, hPXR expression was confirmed in breast cancer cell lines and in normal and cancerous human breast specimens. Preactivation of hPXR by SR12813 in MDA-MB-231 cells led to an increased resistance to Taxol at concentrations of 20 and 50 nmol/L. A significant increase in resistance toward tamoxifen was also observed in MCF-7 with hPXR preactivation. Activation of hPXR led to an increased expression of CYP3A4 and MDR1, two possible mediators for hPXR-mediated drug resistance in breast cancers. Furthermore, knockdown of hPXR via small hairpin RNA (shRNA) sensitized MDA-MB-231 and MCF-7 cells to the treatment of Taxol, vinblastine or tamoxifen. The reduction in resistance of hPXR knockdown cells was further confirmed by reduced colony formation under the pressure of cancer treatment drugs. Taken together, our data suggest a potential role of hPXR in breast cancer resistance to drug treatments. PMID:19746521

  14. Evaluation of chemotherapy response in patients with advanced head and neck cancer using [F-18]fluorodeoxyglucose positron emission tomography.

    PubMed

    Lowe, V J; Dunphy, F R; Varvares, M; Kim, H; Wittry, M; Dunphy, C H; Dunleavy, T; McDonough, E; Minster, J; Fletcher, J W; Boyd, J H

    1997-12-01

    [F-18]Fluorodeoxyglucose (FDG)-positron emission tomography (PET) can measure the metabolic activity of tissues; FDG-PET may be able to predict response to chemotherapy by identifying changes in tumor metabolism. Measurement of response to treatment may help improve survival in the management of advanced head and neck cancer. We evaluated this particular use of FDG-PET in patients participating in a neoadjuvant organ-preservation protocol using taxol and carboplatin and compared pathologic response after chemotherapy with changes in tumor metabolism measured by FDG-PET. Serial FDG-PET studies (n = 56) were performed in patients (n = 28) with stage III/IV head and neck cancer participating in a neoadjuvant organ-preservation protocol. The FDG-PET studies were performed before and after chemotherapy. All patients had tissue biopsies before and after chemotherapy. Patients were classified as pathologic complete response (PCR) or residual disease (RD) based on tissue biopsies. Visual analysis of PET scans was performed to identify patients with complete response by PET, and these findings were compared with pathology results. Metabolic changes were also evaluated using standardized uptake ratios (SUR) of FDG. The sensitivity and specificity of PET for residual cancer after therapy was 90% (19/21) and 83% (5/6), respectively. Two patients had initially negative biopsies and positive PET studies for persistent disease. Pathology review and rebiospy led to confirmation of the PET results in these cases, giving a sensitivity of 90% for initial tissue biopsy. In this preliminary analysis, FDG-PET was accurate in classifying response to chemotherapy in most patients. Fluorodeoxyglucose-PET may identify residual viable tumor when it is otherwise undetectable.

  15. In vitro synergistic efficacy of conjugated linoleic acid, oleic acid, safflower oil and taxol cytotoxicity on PC3 cells.

    PubMed

    Kızılşahin, Sadi; Nalbantsoy, Ayşe; Yavaşoğlu, N Ülkü Karabay

    2015-01-01

    The aim of this study was to determine in vitro synergistic efficacy of conjugated linoleic acid (CLA), oleic acid (OLA), safflower oil and taxol (Tax) cytotoxicity on human prostate cancer (PC3) cell line. To determine synergistic efficacy of oil combinations, PC3 treated with different doses of compounds alone and combined with 10 μg/mL Tax. The MTT results indicated that OLA-Tax combinations exhibited cytotoxicity against PC3 at doses of 30 nM+10 μg-Tax, 15 nM+5 μg-Tax and 7.5 nM+2.5 μg-Tax. The treatment of OLA or Tax did not show significant inhibition on PC3, while OLA-Tax combinations showed effective cytotoxicity at treated doses. CLA-Tax combinations demonstrated the same effect on PC3 as combined form with 45.72% versus the alone form as 74.51% viability. Cytotoxic synergy between Tax, OLA and CLA shows enhanced cytotoxicity on PC3 which might be used in the therapy of prostate cancer.

  16. SMIFH2-mediated mDia formin functional inhibition potentiates chemotherapeutic targeting of human ovarian cancer spheroids.

    PubMed

    Ziske, Megan A; Pettee, Krista M; Khaing, MaNada; Rubinic, Kaitlin; Eisenmann, Kathryn M

    2016-03-25

    Due to a lack of effective screening or prevention protocol for epithelial ovarian cancer (EOC), there is a critical unmet need to develop therapeutic interventions for EOC treatment. EOC metastasis is unique. Initial dissemination is not primarily hematogenous, yet is facilitated through shedding of primary tumor cells into the peritoneal fluid and accumulating ascites. Increasingly, isolated patient spheroids point to a clinical role for spheroids in EOC metastasis. EOC spheroids are highly invasive structures that disseminate upon peritoneal mesothelium, and visceral tissues including liver and omentum. Selection for this subset of chemoresistant EOC cells could influence disease progression and/or recurrence. Thus, targeting spheroid integrity/structure may improve the chemotherapeutic responsiveness of EOC. We discovered a critical role for mammalian Diaphanous (mDia)-related formin-2 in maintaining EOC spheroid structure. Both mDia2 and the related mDia1 regulate F-actin networks critical to maintain cell-cell contacts and the integrity of multi-cellular epithelial sheets. We investigated if mDia2 functional inhibition via a small molecule inhibitor SMIFH2 combined with chemotherapeutics, such as taxol and cisplatin, inhibits the viability of EOC monolayers and clinically relevant spheroids. SMIFH2-mediated mDia formin inhibition significantly reduced both ES2 and Skov3 EOC monolayer viability while spheroid viability was minimally impacted only at the highest concentrations. Combining either cisplatin or taxol with SMIFH2 did not significantly enhance the effects of either drug alone in ES2 monolayers, while Skov3 monolayers treated with taxol or cisplatin and SMIFH2 showed significant additive inhibition of viability. ES2 spheroids were highly responsive with clear additive anti-viability effects with dual taxol or cisplatin when combined with SMIFH2 treatments. While combined taxol with SMIFH2 in spheroids showed an additive effect relative to single

  17. Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl-2 family proteins.

    PubMed

    Colin, Didier J; Hain, Karolina O; Allan, Lindsey A; Clarke, Paul R

    2015-03-01

    Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-xL by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies.

  18. Nanoparticle drug-delivery systems for peritoneal cancers: a case study of the design, characterization and development of the expansile nanoparticle.

    PubMed

    Colby, Aaron H; Oberlies, Nicholas H; Pearce, Cedric J; Herrera, Victoria L M; Colson, Yolonda L; Grinstaff, Mark W

    2017-05-01

    Nanoparticle (NP)-based drug-delivery systems are frequently employed to improve the intravenous administration of chemotherapy; however, few reports explore their application as an intraperitoneal therapy. We developed a pH-responsive expansile nanoparticle (eNP) specifically designed to leverage the intraperitoneal route of administration to treat intraperitoneal malignancies, such as mesothelioma, ovarian, and pancreatic carcinomatoses. This review describes the design, evaluation, and evolution of the eNP technology and, specifically, a Materials-Based Targeting paradigm that is unique among the many active- and passive-targeting strategies currently employed by NP-delivery systems. pH-responsive eNP swelling is responsible for the extended residence at the target tumor site as well as the subsequent improvement in tumoral drug delivery and efficacy observed with paclitaxel-loaded eNPs (PTX-eNPs) compared to the standard clinical formulation of paclitaxel, Taxol®. Superior PTX-eNP efficacy is demonstrated in two different orthotopic models of peritoneal cancer-mesothelioma and ovarian cancer; in a third model-of pancreatic cancer-PTX-eNPs demonstrated comparable efficacy to Taxol with reduced toxicity. Furthermore, the unique structural and responsive characteristics of eNPs enable them to be used in three additional treatment paradigms, including: treatment of lymphatic metastases in breast cancer; use as a highly fluorescent probe to visually guide the resection of peritoneal implants; and, in a two-step delivery paradigm for concentrating separately administered NP and drug at a target site. This case study serves as an important example of using the targeted disease-state's pathophysiology to inform the NP design as well as the method of use of the delivery system. WIREs Nanomed Nanobiotechnol 2017, 9:e1451. doi: 10.1002/wnan.1451 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

  19. A novel paclitaxel-loaded poly(d,l-lactide-co-glycolide)-Tween 80 copolymer nanoparticle overcoming multidrug resistance for lung cancer treatment

    PubMed Central

    Yuan, Xun; Ji, Wenxiang; Chen, Si; Bao, Yuling; Tan, Songwei; Lu, Shun; Wu, Kongming; Chu, Qian

    2016-01-01

    Drug resistance has become a main obstacle for the effective treatment of lung cancer. To address this problem, a novel biocompatible nanoscale package, poly(d,l-lactide-co-glycolide)-Tween 80, was designed and synthesized to overcome paclitaxel (PTX) resistance in a PTX-resistant human lung cancer cell line. The poly(d,l-lactide-co-glycolide) (PLGA)-Tween 80 nanoparticles (NPs) could efficiently load PTX and release the drug gradually. There was an increased level of uptake of PLGA-Tween 80 in PTX-resistant lung cancer cell line A549/T, which achieved a significantly higher level of cytotoxicity than both PLGA NP formulation and Taxol®. The in vivo antitumor efficacy also showed that PLGA-Tween 80 NP was more effective than Taxol®, indicating that PLGA-Tween 80 copolymer was a promising carrier for PTX in resistant lung cancer. PMID:27307727

  20. MCAK and Stathmin Upregulation in Breast Cancer Cells: Etiology and Response to Pharmacologic Reagents

    DTIC Science & Technology

    2004-07-01

    and the affinity for MTs are cells (Maney et al., 2001). Finally, the neck domain is not molecular refinements that adapt motile kinesins for specific...1,500 nM taxol-stabilized MTs in 80 p.I of BRB80 (80 mM molecular motor. Nature. 389:93-96. Pipes, pH 6.8, 1 mM EGTA, and 1 mM MgCI2), 12.5 p.M taxol, 1...summarizes the biological functions and examines the possible molecular the r egio immeiatel iete mt core mechanisms of Kin C and Kin I unconventional

  1. Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl-2 family proteins

    PubMed Central

    Colin, Didier J.; Hain, Karolina O.; Allan, Lindsey A.; Clarke, Paul R.

    2015-01-01

    Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-xL by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies. PMID:25761368

  2. Redistribution of fluorescently labeled tubulin in the mitotic apparatus of sand dollar eggs and the effects of taxol.

    PubMed

    Hamaguchi, Y; Toriyama, M; Sakai, H; Hiramoto, Y

    1987-02-01

    Fluorescently labeled tubulin was quickly incorporated into the mitotic apparatus when injected into a live sand dollar egg. After a rectangular area (1.6 X 16 microns) of the mitotic spindle was photobleached at metaphase or anaphase by the irradiation of a laser microbeam, redistribution of fluorescence was almost complete within 30 sec. The photobleached area did not change in shape during the redistribution. During the period of redistribution, the bleached area moved slightly toward the near pole at metaphase and anaphase (means: 1.6 and 1.8 micron/min, respectively). These results indicate that redistribution was not due to the exchange of tubulin subunits only at the ends of microtubules but to their rapid exchange at sites along the microtubules in the bleached region. Furthermore, treadmilling of tubulin molecules along with the spindle microtubules possibly occurred at the rate of 1.6 micron/min at metaphase. Birefringence of the mitotic apparatus increased with a large increase in both the number and length of astral rays shortly after taxol was injected. However, the microtubules did not all seem to elongate at the same rate but appeared to become equalized in length. Chromosome movement stopped within 60 sec after the injection. Centrospheres became large and the labeled tubulin already incorporated into the centrospheres was excluded from the enlarged centrospheres. Shortly after the labeled tubulin was injected following the injection of taxol, it accumulated in the peripheral region of the centrospheres, suggesting that microtubules first assembled at this region. Fluorescently labeled tubulin in the mitotic apparatus in the egg after injection of taxol was redistributed much more slowly after photobleaching than in uninjected eggs.

  3. Design and synthesis of new hybrids from 2-cyano-3,12-dioxooleana- 9-dien-28-oic acid and O2-(2,4-dinitrophenyl) diazeniumdiolate for intervention of drug-resistant lung cancer.

    PubMed

    Kang, Fenghua; Ai, Yong; Zhang, Yihua; Huang, Zhangjian

    2018-04-10

    To search for new drugs for intervention of drug-resistant lung cancer, a series of hybrids 4-15 from 2-cyano-3,12-dioxooleana-9-dien-28-oic acid (CDDO) and O 2 -(2,4-dinitrophenyl) diazeniumdiolate were designed, synthesized and biologically evaluated. The most active compound 7 produced relatively high levels of nitric oxide (NO) and reactive oxygen species (ROS) in drug-resistant lung cancer A549/Taxol cells which over-express glutathione S-transferase π (GSTπ), and significantly inhibited the cells' proliferation (IC 50  = 0.349 ± 0.051 μM), superior to the positive controls CDDO-Me, JS-K and Taxol. The inhibitory activity of 7 could be attenuated by an NO scavenger, ROS scavenger or GSTπ inhibitor. In addition, 7 suppressed the Lon protease expression as well as induced cell apoptosis and cycle arrest in A549/Taxol cells more strongly than CDDO-Me or JS-K. Together, our findings suggest that 7 may be worth studying further for intervention of drug-resistant lung cancer. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  4. Patent Survey of Resveratrol, Taxol, Podophyllotoxin, Withanolides and Their Derivatives Used in Anticancer Therapy.

    PubMed

    Routh, Shreya; Nandagopal, Krishnadas

    2017-01-01

    Resveratrol, taxol, podophyllotoxin, withanolides and their derivatives find applications in anti-cancer therapy. They are plant-derived compounds whose chemical structures and synthesis limit their natural availability and restrict a large-scale industrial production. Hence, their production by various biotechnological approaches may hold promise for a continuous and reliable mode of supply. We review process and product patents in this regard. Accordingly, we provide a general outline to search the freely accessible WIPO, EPO, USPTO and Cambia databases with several keywords and patent codes. We have tabulated both granted and filed patents from the said databases. We retrieved ~40 patents from these databases. Novel biotechnological processes for production of these anticancer compounds include Agrobacterium rhizogenes-mediated hairy root culture, suspension culture, cell culture with elicitors, use of recombinant microorganisms, and bioreactors among others. The results are indicative of being both database-specific as well as queryspecific. A ten-year search window yielded 33 patents. The utility of the search strategy is discussed in the light of biotechnological developments in the field. Those who examine patent literature using similar search strategies may complement their knowledge obtained from perusal of mainstream journal resources. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Low-dose naltrexone suppresses ovarian cancer and exhibits enhanced inhibition in combination with cisplatin.

    PubMed

    Donahue, Renee N; McLaughlin, Patricia J; Zagon, Ian S

    2011-07-01

    Ovarian cancer is the leading cause of death from gynecological malignancies. Although initial therapeutic modalities are successful, 65% of these women relapse with only palliative treatments available thereafter. Endogenous opioids repress the proliferation of human ovarian cancer cells in vitro, and do so in a receptor-mediated manner. The present study examined whether modulation of opioid systems by the opioid antagonist naltrexone (NTX), alone or in combination with standard of care therapies (taxol/paclitaxel, cisplatin), alters human ovarian cancer cell proliferation in tissue culture and tumor progression in mice. Administration of NTX for six hours every two days, but not continuously, reduced DNA synthesis and cell replication from vehicle-treated controls in tissue culture. Moreover, brief exposure to NTX in combination with taxol or cisplatin had an enhanced anticancer action. Mice with established ovarian tumors and treated with a low dosage of NTX (LDN), which invokes a short period of opioid receptor blockade, repressed tumor progression in a non-toxic fashion by reducing DNA synthesis and angiogenesis but not altering cell survival. The combination of LDN with cisplatin, but not taxol, resulted in an additive inhibitory effect on tumorigenesis with enhanced depression of DNA synthesis and angiogenesis. LDN combined with cisplatin alleviated the toxicity (e.g. weight loss) associated with cisplatin. LDN treatment upregulated the expression of the opioid growth factor (OGF, chemical term ([Met(5)]-enkephalin) and its receptor, OGFr. Previous tissue culture studies have reported that OGF is the only opioid peptide with antiproliferative activity on ovarian cancer cells, with OGF action mediated by OGFr. Thus, the common denominator of intermittent opioid receptor blockade by short-term NTX or LDN on ovarian cancer proliferation and tumorigenesis recorded herein appears to be related to the OGF-OGFr axis. These preclinical data may offer a non

  6. Expression of LIM kinase 1 is associated with reversible G1/S phase arrest, chromosomal instability and prostate cancer.

    PubMed

    Davila, Monica; Jhala, Darshana; Ghosh, Debashis; Grizzle, William E; Chakrabarti, Ratna

    2007-06-08

    LIM kinase 1 (LIMK1), a LIM domain containing serine/threonine kinase, modulates actin dynamics through inactivation of the actin depolymerizing protein cofilin. Recent studies have indicated an important role of LIMK1 in growth and invasion of prostate and breast cancer cells; however, the molecular mechanism whereby LIMK1 induces tumor progression is unknown. In this study, we investigated the effects of ectopic expression of LIMK1 on cellular morphology, cell cycle progression and expression profile of LIMK1 in prostate tumors. Ectopic expression of LIMK1 in benign prostatic hyperplasia cells (BPH), which naturally express low levels of LIMK1, resulted in appearance of abnormal mitotic spindles, multiple centrosomes and smaller chromosomal masses. Furthermore, a transient G1/S phase arrest and delayed G2/M progression was observed in BPH cells expressing LIMK1. When treated with chemotherapeutic agent Taxol, no metaphase arrest was noted in these cells. We have also noted increased nuclear staining of LIMK1 in tumors with higher Gleason Scores and incidence of metastasis. Our results show that increased expression of LIMK1 results in chromosomal abnormalities, aberrant cell cycle progression and alteration of normal cellular response to microtubule stabilizing agent Taxol; and that LIMK1 expression may be associated with cancerous phenotype of the prostate.

  7. A conversation with Susan Band Horwitz.

    PubMed

    Horwitz, Susan Band; Goldman, I David

    2015-01-01

    Susan Band Horwitz is a Distinguished Professor and holds the Falkenstein Chair in Cancer Research at Albert Einstein College of Medicine in New York. She is co-chair of the Department of Molecular Pharmacology and associate director for therapeutics at the Albert Einstein Cancer Center. After graduating from Bryn Mawr College, Dr. Horwitz received her PhD in biochemistry from Brandeis University. She has had a continuing interest in natural products as a source of new drugs for the treatment of cancer. Her most seminal research contribution has been in the development of Taxol(®). Dr. Horwitz and her colleagues made the discovery that Taxol had a unique mechanism of action and suggested that it was a prototype for a new class of antitumor drugs. Although Taxol was an antimitotic agent blocking cells in the metaphase stage of the cell cycle, Dr. Horwitz recognized that Taxol was blocking mitosis in a way different from that of other known agents. Her group demonstrated that the binding site for Taxol was on the β-tubulin subunit. The interaction of Taxol with the β-tubulin subunit resulted in stabilized microtubules, essentially paralyzing the cytoskeleton, thereby preventing cell division. Dr. Horwitz served as president (2002-2003) of the American Association for Cancer Research (AACR). She is a member of the National Academy of Sciences, the Institute of Medicine, the American Academy of Arts and Sciences, and the American Philosophical Society. She has received numerous honors and awards, including the C. Chester Stock Award from Memorial Sloan Kettering Cancer Center, the Warren Alpert Foundation Prize from Harvard Medical School, the Bristol-Myers Squibb Award for Distinguished Achievement in Cancer Research, the American Cancer Society's Medal of Honor, and the AACR Award for Lifetime Achievement in Cancer Research. The following interview was conducted on January 23, 2014.

  8. Taxol: a review

    Treesearch

    Walter C. Shortle; Rakesh Minocha

    1999-01-01

    Cancer is one of the most feared diseases. It involves the rapid and uncontrolled proliferation of "abnormal" cells in the body. The cancerous cell mass disrupts normal functioning of the organ or tissue in which it is found. Current treatments involve surgery, radiotherapy, and chemotherapy often applied in some combination. Naturally occurring...

  9. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tang, Xiao-han; Deng, Suo; Li, Meng

    Highlights: Black-Right-Pointing-Pointer HB-EGF over-expression in A2780/Taxol, A2780/CDDP cells and the matched xenografts. Black-Right-Pointing-Pointer CRM197 induces enhanced apoptosis in A2780/Taxol and A2780/CDDP cells. Black-Right-Pointing-Pointer CRM197 arrests A2780/Taxol and A2780/CDDP cells at G0/G1 phase. Black-Right-Pointing-Pointer CRM197 suppressed the A2780/Taxol and A2780/CDDP growth of xenografts. -- Abstract: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a promising target for ovarian cancer therapy. Cross-reacting material 197 (CRM197), a specific HB-EGF inhibitor, has been proven to represent possible chemotherapeutic agent for ovarian cancer. However, the effect of CRM197 on the resistant ovarian carcinoma cells has not been sufficiently elucidated. Here, we found that HB-EGF wasmore » over-expressed in a paclitaxel-resistant human ovarian carcinoma cell line (A2780/Taxol) and a cisplatin-resistant cell line (A2780/CDDP), as well as the xenograft mouse tissue samples with these cells. To investigate the possible significance of the HB-EGF over-expression in A2780/Taxol and A2780/CDDP cells, we inhibited HB-EGF expression by CRM197 to investigate the effect of CRM197 treatment on these cells. We observed that CRM197 significantly induced anti-proliferative activity in a dose-dependent manner with the cell-cycle arrest at the G0/G1 phase and enhanced apoptosis in A2780/Taxol and A2780/CDDP cells. The sensitive ovarian carcinoma parental cell line (A2780), A2780/Taxol and A2780/CDDP cells formed tumors in nude mice, and enhanced tumorigenicity was observed in drug-resistant tumors. Furthermore, we observed that CRM197 significantly suppressed the growth of drug-resistant ovarian cancer xenografts in vivo (p < 0.001). These results suggest that CRM197 as an HB-EGF-targeted agent has potent anti-tumor activity in paclitaxel- and cisplatin-resistant ovarian cancer which over-express HB-EGF.« less

  10. Prevention of chemotherapy-induced alopecia in rodent models

    PubMed Central

    Jimenez, Joaquin J.; Roberts, Stephen M.; Mejia, Jessica; Mauro, Lucia M.; Munson, John W.; Elgart, George W.; Connelly, Elizabeth Alvarez; Chen, Qingbin; Zou, Jiangying; Goldenberg, Carlos

    2008-01-01

    Alopecia (hair loss) is experienced by thousands of cancer patients every year. Substantial-to-severe alopecia is induced by anthracyclines (e.g., adriamycin), taxanes (e.g., taxol), alkylating compounds (e.g., cyclophosphamide), and the topisomerase inhibitor etoposide, agents that are widely used in the treatment of leukemias and breast, lung, ovarian, and bladder cancers. Currently, no treatment appears to be generally effective in reliably preventing this secondary effect of chemotherapy. We observed in experiments using different rodent models that localized administration of heat or subcutaneous/intradermal injection of geldanamycin or 17-(allylamino)-17-demethoxygeldanamycin induced a stress protein response in hair follicles and effectively prevented alopecia from adriamycin, cyclophosphamide, taxol, and etoposide. Model tumor therapy experiments support the presumption that such localized hair-saving treatment does not negatively affect chemotherapy efficacy. PMID:18347939

  11. The fate of chemoresistance in triple negative breast cancer (TNBC)

    PubMed Central

    O’Reilly, Elma A.; Gubbins, Luke; Sharma, Shiva; Tully, Riona; Guang, Matthew Ho Zhing; Weiner-Gorzel, Karolina; McCaffrey, John; Harrison, Michele; Furlong, Fiona; Kell, Malcolm; McCann, Amanda

    2015-01-01

    Background Treatment options for women presenting with triple negative breast cancer (TNBC) are limited due to the lack of a therapeutic target and as a result, are managed with standard chemotherapy such as paclitaxel (Taxol®). Following chemotherapy, the ideal tumour response is apoptotic cell death. Post-chemotherapy, cells can maintain viability by undergoing viable cellular responses such as cellular senescence, generating secretomes which can directly enhance the malignant phenotype. Scope of Review How tumour cells retain viability in response to chemotherapeutic engagement is discussed. In addition we discuss the implications of this retained tumour cell viability in the context of the development of recurrent and metastatic TNBC disease. Current adjuvant and neo-adjuvant treatments available and the novel potential therapies that are being researched are also reviewed. Major conclusions Cellular senescence and cytoprotective autophagy are potential mechanisms of chemoresistance in TNBC. These two non-apoptotic outcomes in response to chemotherapy are inextricably linked and are neglected outcomes of investigation in the chemotherapeutic arena. Cellular fate assessments may therefore have the potential to predict TNBC patient outcome. General Significance Focusing on the fact that cancer cells can bypass the desired cellular apoptotic response to chemotherapy through cellular senescence and cytoprotective autophagy will highlight the importance of targeting non-apoptotic survival pathways to enhance chemotherapeutic efficacy. PMID:26676166

  12. Novel anticancer activity of phloroglucinol against breast cancer stem-like cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kim, Rae-Kwon; Uddin, Nizam; Hyun, Jin-Won

    Poor prognosis of breast cancer patients is closely associated with metastasis and relapse. There is substantial evidence supporting that cancer stem-like cells (CSCs) are primarily responsible for relapse in breast cancer after anticancer treatment. However, there is a lack of suitable drugs that target breast cancer stem-like cells (BCSCs). Here, we report that phloroglucinol (PG), a natural phlorotannin component of brown algae, suppresses sphere formation, anchorage-independent colony formation and in vivo tumorigenicity. In line with these observations, treatment with PG also decreased CD44{sup +} cancer cell population as well as expression of CSC regulators such as Sox2, CD44, Oct4, Notch2more » and β-catenin. Also, treatment with PG sensitized breast cancer cells to anticancer drugs such as cisplatin, etoposide, and taxol as well as to ionizing radiation. Importantly, PG inhibited KRAS and its downstream PI3K/AKT and RAF-1/ERK signaling pathways that regulate the maintenance of CSCs. Taken together, our findings implicate PG as a good candidate to target BCSCs and to prevent the disease relapse. - Highlights: • Phloroglucinol suppresses in vivo tumor formation. • Phloroglucinol sensitizes breast cancer cells to anticancer agents. • Phloroglucinol inhibits breast cancer stem-like cells. • Phloroglucinol inhibits PI3K/AKT and KRAS/RAF/ERK signaling pathways.« less

  13. A novel paclitaxel-loaded poly(epsilon-caprolactone)/Poloxamer 188 blend nanoparticle overcoming multidrug resistance for cancer treatment.

    PubMed

    Zhang, Yangqing; Tang, Lina; Sun, Leilei; Bao, Junbo; Song, Cunxian; Huang, Laiqiang; Liu, Kexin; Tian, Yan; Tian, Ge; Li, Zhen; Sun, Hongfan; Mei, Lin

    2010-06-01

    Multidrug resistance (MDR) of tumor cells is a major obstacle to the success of cancer chemotherapy. Poloxamers have been used in cancer therapy to overcome MDR. The objective of this research is to test the feasibility of paclitaxel-loaded poly(epsilon-caprolactone)/Poloxamer 188 (PCL/Poloxamer 188) nanoparticles to overcome MDR in a paclitaxel-resistant human breast cancer cell line. Paclitaxel-loaded nanoparticles were prepared by a water-acetone solvent displacement method using commercial PCL and self-synthesized PCL/Poloxamer 188 compound, respectively. PCL/Poloxamer 188 nanoparticles were found to be of spherical shape and tended to have a rough and porous surface. The nanoparticles had an average size of around 220nm, with a narrow size distribution. The in vitro drug release profile of both nanoparticle formulations showed a clear biphasic release pattern. There was an increased level of uptake of PCL/Poloxamer 188 nanoparticles (PPNP) in the paclitaxel-resistant human breast cancer cell line MCF-7/TAX, in comparison with PCL nanoparticles. The cytotoxicity of PCL nanoparticles was higher than commercial Taxol in the MCF-7/TAX cell culture, but the differences were not significant. However, the PCL/Poloxamer 188 nanoparticles achieved a significantly higher level of cytotoxicity than both of PCL nanoparticle formulation and Taxol(R), indicating that paclitaxel-loaded PCL/Poloxamer 188 nanoparticles could overcome MDR in human breast cancer cells and therefore could have considerable therapeutic potential for breast cancer. Copyright 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  14. Trial of Cisplatin Plus Radiation Followed by Carbo and Taxol Vs. Sandwich Therapy of Carbo and Taxol Followed Radiation Then Further Carbo and Taxol

    ClinicalTrials.gov

    2017-10-30

    Endometrial Clear Cell Adenocarcinoma; Endometrial Serous Adenocarcinoma; Stage IIIA Uterine Corpus Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer

  15. Blockade of epidermal growth factor receptor signaling in tumor cells and tumor-associated endothelial cells for therapy of androgen-independent human prostate cancer growing in the bone of nude mice.

    PubMed

    Kim, Sun-Jin; Uehara, Hisanori; Karashima, Takashi; Shepherd, David L; Killion, Jerald J; Fidler, Isaiah J

    2003-03-01

    We determined whether blockade of the epidermal growth factor receptor (EGF-R) signaling pathway by oral administration of the EGF-R tyrosine kinase inhibitor (PKI 166) alone or in combination with injectable Taxol inhibits the growth of PC-3MM2 human prostate cancer cells in the bone of nude mice. Male nude mice implanted with PC-3MM2 cells in the tibia were treated with oral administrations of PKI 166 or PKI 166 plus injectable Taxol beginning 3 days after implantation. The incidence and size of bone tumors and destruction of bone were determined by digitalized radiography. Expression of epidermal growth factor (EGF), EGF-R, and activated EGF-R in tumor cells and tumor-associated endothelial cells was determined by immunohistochemistry. Oral administration of PKI 166 or PKI 166 plus injectable Taxol reduced the incidence and size of bone tumors and destruction of bone. Immunohistochemical analysis revealed that PC-3MM2 cells growing adjacent to the bone expressed high levels of EGF and activated EGF-R, whereas tumor cells in the adjacent musculature did not. Moreover, endothelial cells within the bone tumor lesions, but not in uninvolved bone or tumors in the muscle, expressed high levels of activated EGF-R. Treatment with PKI 166 and more so with PKI 166 plus Taxol significantly inhibited phosphorylation of EGF-R on tumor and endothelial cells and induced significant apoptosis and endothelial cells within tumor lesions. These data indicate that endothelial cells exposed to EGF produced by tumor cells express activated EGF-R and that targeting EGF-R can produce significant therapeutic effects against prostate cancer bone metastasis.

  16. Preclinical Evaluation of Genexol-PM, a Nanoparticle Formulation of Paclitaxel, as a Novel Radiosensitizer for the Treatment of Non-Small Cell Lung Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Werner, Michael E.; Cummings, Natalie D.; Sethi, Manish

    2013-07-01

    Purpose: A key research objective in radiation oncology is to identify agents that can improve chemoradiation therapy. Nanoparticle (NP) chemotherapeutics possess several properties, such as preferential accumulation in tumors, that are uniquely suited for chemoradiation therapy. To facilitate the clinical translation of NP chemotherapeutics in chemoradiation therapy, we conducted preclinical evaluation of Genexol-PM, the only clinically approved NP chemotherapeutic with a controlled drug release profile, as a radiosensitizer using non-small cell lung cancer (NSCLC) as a model disease. Methods and Materials: The physical characteristics and drug release profile of Genexol-PM were characterized. Genexol-PM's efficacy as a radiosensitizer was evaluated inmore » vitro using NSCLC cell lines and in vivo using mouse xenograft models of NSCLC. Paclitaxel dose to normal lung and liver after Genexol-PM administration were quantified and compared with that after Taxol administration. Results: Genexol-PM has a size of 23.91 ± 0.41 nm and surface charge of −8.1 ± 3.1 mV. It releases paclitaxel in a controlled release profile. In vitro evaluation of Genexol-PM as a radiosensitizer showed it is an effective radiosensitizer and is more effective than Taxol, its small molecule counterpart, at the half maximal inhibitory concentration. In vivo study of Genexol-PM as a radiosensitizer demonstrated that it is more effective as a radiosensitizer than Taxol. We also found that Genexol-PM leads to lower paclitaxel exposure to normal lung tissue than Taxol at 6 hours postadministration. Conclusions: We have demonstrated that Genexol-PM is more effective than Taxol as a radiosensitizer in the preclinical setting and holds high potential for clinical translation. Our data support the clinical evaluation of Genexol-PM in chemoradiation therapy for NSCLC.« less

  17. An endophytic Basidiomycete, Grammothele lineata, isolated from Corchorus olitorius, produces paclitaxel that shows cytotoxicity

    PubMed Central

    Das, Avizit; Rahman, Mohammad Imtiazur; Ferdous, Ahlan Sabah; Amin, Al-; Rahman, Mohammad Mahbubur; Nahar, Nilufar; Uddin, Md. Aftab; Islam, Mohammad Riazul; Khan, Haseena

    2017-01-01

    Grammothele lineata, an endophyte isolated in our laboratory from jute (Corchorus olitorius acc. 2015) was found to be a substantial paclitaxel producer. Taxol and its related compounds, produced by this endophyte were extracted by growing the fungus in simple nutrient media (potato dextrose broth, PDB). Taxol was identified and characterized by different analytical techniques (TLC, HPLC, FTIR, LC-ESI-MS/MS) following its extraction by ethyl acetate. In PDB media, this fungus was found to produce 382.2 μgL-1 of taxol which is about 7.6 x103 fold higher than the first reported endophytic fungi, Taxomyces andreanae. The extracted taxol exhibited cytotoxic activity in an in vitro culture of HeLa cancer cell line. The fungal extract also exhibited antifungal and antibacterial activities against different pathogenic strains. This is the first report of a jute endophytic fungus harboring the capacity to produce taxol and also the first reported taxol producing species that belongs to the Basidiomycota phylum, so far unknown to be a taxol producer. These findings suggest that the fungal endophyte, Grammothele lineata can be an excellent source of taxol and can also serve as a potential species for chemical and genetic engineering to enhance further the production of taxol. PMID:28636663

  18. An endophytic Basidiomycete, Grammothele lineata, isolated from Corchorus olitorius, produces paclitaxel that shows cytotoxicity.

    PubMed

    Das, Avizit; Rahman, Mohammad Imtiazur; Ferdous, Ahlan Sabah; Amin, Al-; Rahman, Mohammad Mahbubur; Nahar, Nilufar; Uddin, Md Aftab; Islam, Mohammad Riazul; Khan, Haseena

    2017-01-01

    Grammothele lineata, an endophyte isolated in our laboratory from jute (Corchorus olitorius acc. 2015) was found to be a substantial paclitaxel producer. Taxol and its related compounds, produced by this endophyte were extracted by growing the fungus in simple nutrient media (potato dextrose broth, PDB). Taxol was identified and characterized by different analytical techniques (TLC, HPLC, FTIR, LC-ESI-MS/MS) following its extraction by ethyl acetate. In PDB media, this fungus was found to produce 382.2 μgL-1 of taxol which is about 7.6 x103 fold higher than the first reported endophytic fungi, Taxomyces andreanae. The extracted taxol exhibited cytotoxic activity in an in vitro culture of HeLa cancer cell line. The fungal extract also exhibited antifungal and antibacterial activities against different pathogenic strains. This is the first report of a jute endophytic fungus harboring the capacity to produce taxol and also the first reported taxol producing species that belongs to the Basidiomycota phylum, so far unknown to be a taxol producer. These findings suggest that the fungal endophyte, Grammothele lineata can be an excellent source of taxol and can also serve as a potential species for chemical and genetic engineering to enhance further the production of taxol.

  19. New perspectives of cobalt tris(bipyridine) system: anti-cancer effect and its collateral sensitivity towards multidrug-resistant (MDR) cancers

    PubMed Central

    Mok, Simon Wing Fai; Liu, Hauwei; Zeng, Wu; Han, Yu; Gordillo-Martinez, Flora; Chan, Wai-Kit; Wong, Keith Man-Chung; Wong, Vincent Kam Wai

    2017-01-01

    Platinating compounds including cisplatin, carboplatin, and oxaliplatin are common chemotherapeutic agents, however, patients developed resistance to these clinical agents after initial therapeutic treatments. Therefore, different approaches have been applied to identify novel therapeutic agents, molecular mechanisms, and targets for overcoming drug resistance. In this study, we have identified a panel of cobalt complexes that were able to specifically induce collateral sensitivity in taxol-resistant and p53-deficient cancer cells. Consistently, our reported anti-cancer functions of cobalt complexes 1–6 towards multidrug-resistant cancers have suggested the protective and non-toxic properties of cobalt metal-ions based compounds in anti-cancer therapies. As demonstrated in xenograft mouse model, our results also confirmed the identified cobalt complex 2 was able to suppress tumor growth in vivo. The anti-cancer effect of the cobalt complex 2 was further demonstrated to be exerted via the induction of autophagy, cell cycle arrest, and inhibition of cell invasion and P-glycoprotein (P-gp) activity. These data have provided alternative metal ion compounds for targeting drug resistance cancers in chemotherapies. PMID:28903398

  20. Elevated levels of Ser/Thr protein phosphatase 5 (PP5) in human breast cancer

    PubMed Central

    Golden, Teresa; Aragon, Ileana V.; Rutland, Beth; Tucker, J. Allan; Shevde, Lalita A.; Samant, Rajeev S.; Zhou, Guofei; Amable, Lauren; Skarra, Danalea; Honkanen, Richard E.

    2008-01-01

    Ser/Thr protein phosphatase 5 (PP5) regulates several signaling-cascades that suppress growth and/or facilitate apoptosis in response to genomic stress. The expression of PP5 is responsive to hypoxia inducible factor-1 (HIF-1) and estrogen, which have both been linked to the progression of human breast cancer. Still, it is not clear if PP5 plays a role in the development of human cancer. Here, immunostaining of breast cancer tissue-microarrays (TMAs) revealed a positive correlation between PP5 overexpression and ductal carcinoma in situ (DCIS; P value 0.0028), invasive ductal carcinoma (IDC; P value 0.012) and IDC with metastases at the time of diagnosis (P value 0.0001). In a mouse xenograft model, the constitutive overexpression of PP5 was associated with an increase in the rate of tumor growth. In a MCF-7 cell culture model overexpression correlated with both an increase in the rate of proliferation and protection from cell death induced by oxidative stress, UVC-irradiation, adriamycin, and vinblastine. PP5 overexpression had no apparent effect on the sensitivity of MCF-7 cells to taxol or rapamycin. Western analysis of extracts from cells over-expressing PP5 revealed a decrease in the phosphorylation of known substrates for PP5. Together, these studies indicate that elevated levels of PP5 protein occur in human breast cancer and suggest that PP5 overexpression may aid tumor progression. PMID:18280813

  1. Surface modification of paclitaxel-loaded tri-block copolymer PLGA- b-PEG- b-PLGA nanoparticles with protamine for liver cancer therapy

    NASA Astrophysics Data System (ADS)

    Gao, Nansha; Chen, Zhihong; Xiao, Xiaojun; Ruan, Changshun; Mei, Lin; Liu, Zhigang; Zeng, Xiaowei

    2015-08-01

    In order to enhance the therapeutic effect of chemotherapy on liver cancer, a biodegradable formulation of protamine-modified paclitaxel-loaded poly(lactide- co-glycolide)- b-poly(ethylene glycol)- b-poly(lactide- co-glycolide) (PLGA- b-PEG- b-PLGA) nanoparticles (PTX-loaded/protamine NPs) was prepared. Tri-block copolymer PLGA- b-PEG- b-PLGA was synthesized by ring-opening polymerization and characterized by 1H NMR spectroscopy and gel permeation chromatography. PTX-loaded and PTX-loaded/protamine NPs were characterized in terms of size, size distribution, zeta potential, surface morphology, drug encapsulation efficiency, and drug release. Confocal laser scanning microscopy showed that coumarin 6-loaded/protamine NPs were internalized by hepatocellular carcinoma cell line HepG2. The cellular uptake efficiency of NPs was obviously elevated after protamine modification. With commercial formulation Taxol® as the reference, HepG2 cells were also used to study the cytotoxicity of the NPs. PTX-loaded/protamine NPs exhibited significantly higher cytotoxicity than PTX-loaded NPs and Taxol® did. All the results suggested that surface modification of PTX-loaded PLGA- b-PEG- b-PLGA NPs with protamine boosted the therapeutic efficacy on liver cancer.

  2. Evaluating Dual Activity LPA Receptor Pan-Antagonist/Autotaxin Inhibitors as Anti-Cancer Agents in vivo using Engineered Human Tumors

    PubMed Central

    Xu, Xiaoyu; Yang, Guanghui; Zhang, Honglu; Prestwich, Glenn D.

    2009-01-01

    Using an in situ crosslinkable hydrogel that mimics the extracellular matrix (ECM), cancer cells were encapsulated and injected in vivo following a “tumor engineering” strategy for orthotopic xenografts. Specifically, we created several three-dimensional (3-D) human tumor xenografts and evaluated the tumor response to BrP-LPA, a novel dual function LPA antagonist/ATX inhibitor (LPAa/ATXi). First, we describe the model system and the optimization of semi-synthetic ECM (sECM) compositions and injection parameters for engineered xenografts. Second, we summarize a study to compare angiogenesis inhibition in vivo, comparing BrP-LPA to the kinase inhibitor sunitinib maleate (Sutent). Third, we compare treatment of engineered breast tumors with LPAa/ATXi alone with treatment with Taxol. Fourth, using a re-optimized sECM for non-small cell lung cancer cells, we created reproducibly sized subcutaneous lung tumors and evaluated their response to treatment with LPAa/ATXi. Fifth, we summarize the data on the use of LPAa/ATXi to treat a model for colon cancer metastasis to the liver. Taken together, these improved, more realistic xenografts show considerable utility for evaluating the potential of novel anti-metastatic, anti-proliferative, and anti-angiogenic compounds that modify signal transduction through the LPA signaling pathway. PMID:19682598

  3. Beyond taxol: microtubule-based treatment of disease and injury of the nervous system

    PubMed Central

    Ahmad, Fridoon J.

    2013-01-01

    Contemporary research has revealed a great deal of information on the behaviours of microtubules that underlie critical events in the lives of neurons. Microtubules in the neuron undergo dynamic assembly and disassembly, bundling and splaying, severing, and rapid transport as well as integration with other cytoskeletal elements such as actin filaments. These various behaviours are regulated by signalling pathways that affect microtubule-related proteins such as molecular motor proteins and microtubule severing enzymes, as well as a variety of proteins that promote the assembly, stabilization and bundling of microtubules. In recent years, translational neuroscientists have earmarked microtubules as a promising target for therapy of injury and disease of the nervous system. Proof-of-principle has come mainly from studies using taxol and related drugs to pharmacologically stabilize microtubules in animal models of nerve injury and disease. However, concerns persist that the negative consequences of abnormal microtubule stabilization may outweigh the positive effects. Other potential approaches include microtubule-active drugs with somewhat different properties, but also expanding the therapeutic toolkit to include intervention at the level of microtubule regulatory proteins. PMID:23811322

  4. Chemoradiotherapy response in recurrent rectal cancer.

    PubMed

    Yu, Stanley K T; Bhangu, Aneel; Tait, Diana M; Tekkis, Paris; Wotherspoon, Andrew; Brown, Gina

    2014-02-01

    The efficacy of response to preoperative chemoradiotherapy (CRT) in recurrent versus primary rectal cancer has not been investigated. We compared radiological downsizing between primary and recurrent rectal cancers following CRT and determined the optimal size reduction threshold for response validated by survival outcomes. The proportional change in tumor length for primary and recurrent rectal cancers following CRT was compared using the independent sample t-test. Overall survival (OS) was calculated using the Kaplan-Meier product limit method and differences between survival for tumor size reduction thresholds of 30% (response evaluation criteria in solid tumors [RECIST]), 40%, and 50% after CRT in primary and recurrent rectal cancer groups. A total of 385 patients undergoing CRT were analyzed, 99 with recurrent rectal cancer and 286 with primary rectal cancer. The mean proportional reduction in maximum craniocaudal length was significantly higher for primary rectal tumors (33%) compared with recurrent rectal cancer (11%) (P < 0.01). There was no difference in OS for either primary or recurrent rectal cancer when ≤30% or ≤40% definitions were used. However, for both primary and recurrent tumors, significant differences in median 3-year OS were observed when a RECIST cut-off of 50% was used. OS was 99% versus 77% in primary and 100% versus 42% in recurrent rectal cancer (P = 0.002 and P = 0.03, respectively). Only patients that demonstrated >50% size reduction showed a survival benefit. Recurrent rectal cancer appears radioresistant compared with primary tumors for tumor size after CRT. Further investigation into improving/intensifying chemotherapy and radiotherapy for locally recurrent rectal cancer is justified. © 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  5. Immune Response in Thyroid Cancer: Widening the Boundaries

    PubMed Central

    Ward, Laura Sterian

    2014-01-01

    The association between thyroid cancer and thyroid inflammation has been repeatedly reported and highly debated in the literature. In fact, both molecular and epidemiological data suggest that these diseases are closely related and this association reinforces that the immune system is important for thyroid cancer progression. Innate immunity is the first line of defensive response. Unlike innate immune responses, adaptive responses are highly specific to the particular antigen that induced them. Both branches of the immune system may interact in antitumor immune response. Major effector cells of the immune system that directly target thyroid cancer cells include dendritic cells, macrophages, polymorphonuclear leukocytes, mast cells, and lymphocytes. A mixture of immune cells may infiltrate thyroid cancer microenvironment and the balance of protumor and antitumor activity of these cells may be associated with prognosis. Herein, we describe some evidences that immune response may be important for thyroid cancer progression and may help us identify more aggressive tumors, sparing the vast majority of patients from costly unnecessary invasive procedures. The future trend in thyroid cancer is an individualized therapy. PMID:25328756

  6. BYSTANDERS, ADAPTIVE RESPONSES AND GENOMIC INSTABILITY - POTENTIAL MODIFIERS OF LOW-DOSE CANCER RESPONSES.

    EPA Science Inventory

    Bystanders, Adaptive Responses and Genomic Instability -Potential Modifiers ofLow-Dose
    Cancer Responses
    .
    There has been a concerted effort in the field of radiation biology to better understand cellular
    responses that could have an impact on the estin1ation of cancer...

  7. [Clinical efficacy and adverse effects of taxol plus carboplatin or gemcitabine plus carboplatin in patients with advanced non-small-cell lung carcinoma].

    PubMed

    Wang, Xiao-Yun; Zhao, Yu-Liang

    2010-12-21

    To observe the clinical efficacy and adverse effects of taxol plus carboplatin (TP) or gemcitabine plus carboplatin (GP) in patients with advanced non-small-cell lung carcinoma. A total of 86 patients with advanced non-small-cell lung carcinoma with a histologically confirmed diagnosis at our department were treated with at least two cycles of drug therapy according to the WHO standard. There were 43 cases in TP group and 43 cases in GP group. TP group: taxol 150 mg/m(2), d1, carboplatin 300 mg/m(2) in d1; GP group: gemcitabine 1000 mg/m(2), 30 min, d1, 8, carboplatin 300 mg/m(2) in d1, 3 weeks a cycle. The efficacy and side effects were analyzed after two cycles of chemotherapy. When TP and GP groups were compared, the effective rate was 44.2% vs 39.5%; disease control rate (CR + PR + SD): 81.4% vs 74.4%; median time to progress (TTP): 4.6 vs 4.5 months; medium survivals: 8.6 vs 8.8 months; 1-year survival rates: 17.2% vs 18.1%; 2-year survival rates: 8% vs 10%. The statistic analysis showed that the two groups had no significant difference. The main cytotoxicities of GP and TP groups were predominantly thrombocytopenia and leucopenia respectively. The two groups had no significant statistical difference. The incidences of allergen, alopecia and peripheral neurotoxicity were higher in the TP group. The two groups had statistical difference. Tolerance was excellent in both groups. The therapeutic effect and tolerance are excellent for advanced non-small cell lung carcinoma. The efficacy and survival rate of two groups show no statistical difference.

  8. Dinaciclib Induces Anaphase Catastrophe in Lung Cancer Cells via Inhibition of Cyclin-Dependent Kinases 1 and 2.

    PubMed

    Danilov, Alexey V; Hu, Shanhu; Orr, Bernardo; Godek, Kristina; Mustachio, Lisa Maria; Sekula, David; Liu, Xi; Kawakami, Masanori; Johnson, Faye M; Compton, Duane A; Freemantle, Sarah J; Dmitrovsky, Ethan

    2016-11-01

    Despite advances in targeted therapy, lung cancer remains the most common cause of cancer-related mortality in the United States. Chromosomal instability is a prominent feature in lung cancer and, because it rarely occurs in normal cells, it represents a potential therapeutic target. Our prior work discovered that lung cancer cells undergo anaphase catastrophe in response to inhibition of cyclin-dependent kinase 2 (CDK2), followed by apoptosis and reduced growth. In this study, the effects and mechanisms of the multi-CDK inhibitor dinaciclib on lung cancer cells were investigated. We sought to determine the specificity of CDK-dependent induction of anaphase catastrophe. Live cell imaging provided direct evidence that dinaciclib caused multipolar cell divisions resulting in extensive chromosome missegregation. Genetic knockdown of dinaciclib CDK targets revealed that repression of CDK2 and CDK1, but not CDK5 or CDK9, triggered anaphase catastrophe in lung cancer cells. Overexpression of CP110, which is a mediator of CDK2 inhibitor-induced anaphase catastrophe (and a CDK1 and 2 phosphorylation substrate), antagonized anaphase catastrophe and apoptosis following dinaciclib treatment. Consistent with our previous findings, acquisition of activated KRAS sensitized lung cancer cells to dinaciclib-mediated anaphase catastrophe and cell death. Combining dinaciclib with the mitotic inhibitor taxol augmented anaphase catastrophe induction and reduced cell viability of lung cancer cells. Thus, the multi-CDK inhibitor dinaciclib causes anaphase catastrophe in lung cancer cells and should be investigated as a potential therapeutic for wild-type and KRAS-mutant lung cancer, individually or in combination with taxanes. Mol Cancer Ther; 15(11); 2758-66. ©2016 AACR. ©2016 American Association for Cancer Research.

  9. Physical activity and cancer risk: dose-response and cancer, all sites and site-specific.

    PubMed

    Thune, I; Furberg, A S

    2001-06-01

    The association between physical activity and overall and site-specific cancer risk is elaborated in relation to whether any observed dose-response association between physical activity and cancer can be interpreted in terms of how much physical activity (type, intensity, duration, frequency) is needed to influence site- and gender-specific cancer risk. Observational studies were reviewed that have examined the independent effect of the volume of occupational physical activity (OPA) and/or leisure time physical activity (LPA) on overall and site-specific cancer risk. The evidence of cohort and case-control studies suggests that both leisure time and occupational physical activity protect against overall cancer risk, with a graded dose-response association suggested in both sexes. Confounding effects such as diet, body weight, and parity are often included as a covariate in the analyses, with little influence on the observed associations. A crude graded inverse dose-response association was observed between physical activity and colon cancer in 48 studies including 40,674 colon/colorectal cancer cases for both sexes. A dose-response effect of physical activity on colon cancer risk was especially observed, when participation in activities of at least moderate activity (>4.5 MET) and demonstrated by activities expressed as MET-hours per week. An observed inverse association with a dose-response relationship between physical activity and breast cancer was also identified in the majority of the 41 studies including 108,031 breast cancer cases. The dose-response relationship was in particular observed in case-control studies and supported by observations in cohort studies when participation in activities of at least moderate activity (>4.5 MET) and demonstrated by activities expressed by MET-hours per week. This association between physical activity and breast cancer risk is possibly dependent on age at exposure, age at diagnosis, menopausal status and other effect

  10. Recent Advances in Nanoparticle-Based Targeted Drug-Delivery Systems Against Cancer and Role of Tumor Microenvironment.

    PubMed

    Ashfaq, Usman Ali; Riaz, Muhammad; Yasmeen, Erum; Yousaf, Muhammad Zubair

    2017-01-01

    Cancer is one of the major causes of death worldwide. The silent activation of cellular factors responsible for deviation from normal regulatory pathways leads to the development of cancer. Nano-biotechnology is a novel drug-delivery system with high potential of efficacy and accuracy to target lethal cancers. Various biocompatible nanoparticle (NP)-based drug-delivery systems such as liposomes, dendrimers, micelles, silica, quantum dots, and magnetic, gold, and carbon nanotubes have already been reported for successful targeted cancer treatment. NPs are functionalized with different biological molecules, peptides, antibody, and protein ligands for targeted drug delivery. These systems include a hydrophilic central core, a target-oriented biocompatible outer layer, and a middle hydrophobic core where the drug destined to reach target site resides. Most of the NPs have the ability to maintain their structural shape and are constructed according to the cancer microenvironment. The self-assembling and colloidal properties of NPs have caused them to become the best vehicles for targeted drug delivery. The tumor microenvironment (TME) plays a major role in cancer progression, detection, and treatment. Due to its continuous complex behavior, the TME can hinder delivery systems, thus halting cancer treatment. Nonetheless, a successful biophysiological interaction between the NPs and the TME results in targeted release of drugs. Currently, a number of drugs and NP-based delivery systems against cancer are in clinical and preclinical trials and a few have been approved by Food and Drug Administration (FDA); for example: taxol, doxil, cerubidine, and adrucil. This review summarizes topical advances about the drugs being used for cancer treatment, their targeted delivery systems based on NPs, and the role of TME in this connection.

  11. Amino Acid Sensor Kinase Gcn2 Is Required for Conidiation, Secondary Metabolism, and Cell Wall Integrity in the Taxol-Producer Pestalotiopsis microspora

    PubMed Central

    Wang, Dan; Akhberdi, Oren; Hao, Xiaoran; Yu, Xi; Chen, Longfei; Liu, Yanjie; Zhu, Xudong

    2017-01-01

    The canonical Gcn2/Cpc1 kinase in fungi coordinates the expression of target genes in response to amino acid starvation. To investigate its possible role in secondary metabolism, we characterized a gcn2 homolog in the taxol-producing fungus Pestalotiopsis microspora. Deletion of the gene led to severe physiological defects under amino acid starvation, suggesting a conserved function of gcn2 in amino acid sensing. The mutant strain Δgcn2 displayed retardation in vegetative growth. It generated dramatically fewer conidia, suggesting a connection between amino acid metabolism and conidiation in this fungus. Importantly, disruption of the gene altered the production of secondary metabolites by HPLC profiling. For instance, under amino acid starvation, the deletion strain Δgcn2 barely produced secondary metabolites including the known natural product pestalotiollide B. Even more, we showed that gcn2 played critical roles in the tolerance to several stress conditions. Δgcn2 exhibited a hypersensitivity to Calcofluor white and Congo red, implying a role of Gcn2 in maintaining the integrity of the cell wall. This study suggests that Gcn2 kinase is an important global regulator in the growth and development of filamentous fungi and will provide knowledge for the manipulation of secondary metabolism in P. microspora. PMID:29021785

  12. Amino Acid Sensor Kinase Gcn2 Is Required for Conidiation, Secondary Metabolism, and Cell Wall Integrity in the Taxol-Producer Pestalotiopsis microspora.

    PubMed

    Wang, Dan; Akhberdi, Oren; Hao, Xiaoran; Yu, Xi; Chen, Longfei; Liu, Yanjie; Zhu, Xudong

    2017-01-01

    The canonical Gcn2/Cpc1 kinase in fungi coordinates the expression of target genes in response to amino acid starvation. To investigate its possible role in secondary metabolism, we characterized a gcn2 homolog in the taxol-producing fungus Pestalotiopsis microspora . Deletion of the gene led to severe physiological defects under amino acid starvation, suggesting a conserved function of gcn2 in amino acid sensing. The mutant strain Δgcn2 displayed retardation in vegetative growth. It generated dramatically fewer conidia, suggesting a connection between amino acid metabolism and conidiation in this fungus. Importantly, disruption of the gene altered the production of secondary metabolites by HPLC profiling. For instance, under amino acid starvation, the deletion strain Δgcn2 barely produced secondary metabolites including the known natural product pestalotiollide B. Even more, we showed that gcn2 played critical roles in the tolerance to several stress conditions. Δgcn2 exhibited a hypersensitivity to Calcofluor white and Congo red, implying a role of Gcn2 in maintaining the integrity of the cell wall. This study suggests that Gcn2 kinase is an important global regulator in the growth and development of filamentous fungi and will provide knowledge for the manipulation of secondary metabolism in P . microspora .

  13. Responses to advanced cancer: Chinese-Australians.

    PubMed

    Chui, Ying-Yu; Donoghue, Judith; Chenoweth, Lynn

    2005-12-01

    This paper describes a study identifying the impact of key aspects of Chinese culture on the responses of mid-aged Chinese-Australians to their advanced cancer in order to make recommendations about their care within the health system. Studies conducted in the 1960s and 1970s focused on understanding people's psychological responses to their experiences of terminal illness, but the issue of culture was not addressed. In recent years, a few studies have been conducted with Chinese-Australians, but were limited to issues related to their information needs and the disclosure of a cancer diagnosis. There is a lack of understanding of the impact of Chinese culture on the experiences of these patients. A grounded theory approach was used to generate a substantive theory to explain how mid-aged Chinese-Australians respond to advancing cancer. Eleven participants were recruited and data were collected from face-to-face interviews, telephone contacts, observation and researcher field notes. Data generation occurred between 1997 and 1999. Four modes of response to advanced cancer were identified: acute crisis, combat, despondency and waiting for death. This paper deals particularly with the combat mode which incorporated five culturally specific strategies used by participants in their struggle against advanced cancer. These were traditional Chinese medicine, traditional Chinese beliefs on the use of food for health maintenance, qi gong (a form of exercise), feng shui (which involves paying attention to spatial organization) and the worship of ancestors and gods. Deeply entrenched within these responses is the influence of Chinese culture, rooted in the beliefs and practices of traditional Chinese medicine and the philosophy of harmony and balance of yin and yang and qi. Health care professionals need to be aware of the cultural practices and beliefs of the different ethnic groups for whom they care, and of the importance of accommodation to and negotiation about these

  14. Red Maca (Lepidium meyenii) did not affect cell viability despite increased androgen receptor and prostate-specific antigen gene expression in the human prostate cancer cell line LNCaP.

    PubMed

    Díaz, P; Cardenas, H; Orihuela, P A

    2016-10-01

    We examined whether aqueous extract of Lepidium meyenii (red Maca) could inhibit growth, potentiate apoptotic activity of two anticancer drugs Taxol and 2-methoxyestradiol (2ME) or change mRNA expression for the androgen target genes, androgen receptor (Ar) and prostate-specific antigen (Psa) in the human prostate cancer cell line LNCaP. Red Maca aqueous extract at 0, 10, 20, 40 or 80 μg/ml was added to LNCaP cells, and viability was evaluated by the MTS assay at 24 or 48 hr after treatment. Furthermore, LNCaP cells were treated with 80 μg/ml of red Maca plus Taxol or 2ME 5 μM and viability was assessed 48 hr later. Finally, LNCaP cells were treated with red Maca 0, 20, 40 or 80 μg/ml, and 12 hr later, mRNA level for Ar or Psa was assessed by real-time PCR. Treatment with red Maca did not affect viability of LNCaP cells. Apoptotic activity induced by Taxol and 2ME in LNCaP cells was not altered with red Maca treatment. Relative expression of the mRNA for Ar and Psa increased with red Maca 20 and 40 μg/ml, but not at 80 μg/ml. We conclude that red Maca aqueous extract does not have toxic effects, but stimulates androgen signalling in LNCaP cells. © 2016 Blackwell Verlag GmbH.

  15. Nanoscale theranostics for physical stimulus-responsive cancer therapies.

    PubMed

    Chen, Qian; Ke, Hengte; Dai, Zhifei; Liu, Zhuang

    2015-12-01

    Physical stimulus-responsive therapies often employing multifunctional theranostic agents responsive to external physical stimuli such as light, magnetic field, ultra-sound, radiofrequency, X-ray, etc., have been widely explored as novel cancer therapy strategies, showing encouraging results in many pre-clinical animal experiments. Unlike conventional cancer chemotherapy which often accompanies with severe toxic side effects, physical stimulus-responsive agents usually are non-toxic by themselves and would destruct cancer cells only under specific external stimuli, and thus could offer greatly reduced toxicity and enhanced treatment specificity. In addition, physical stimulus-responsive therapies can also be combined with other traditional therapeutics to achieve synergistic anti-tumor effects via a variety of mechanisms. In this review, we will summarize the latest progress in the development of physical stimulus-responsive therapies, and discuss the important roles of nanoscale theranostic agents involved in those non-conventional therapeutic strategies. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Prevention effect of rare ginsenosides against stress-hormone induced MTOC amplification

    PubMed Central

    Lee, Jee-Hyun; Cheong, Kyu Jin; Jung, Youn-Sang; Woo, Tae-Gyun; Yoon, Min-Ho; Oh, Ah-Young; Kang, So-Mi; Lee, Chunghui; Sun, Hokeun; Hwang, Jihwan; Song, Gyu-Yong; Park, Bum-Joon

    2016-01-01

    Stress has been suggested as one of important cause of human cancer without molecular biological evidence. Thus, we test the effect of stress-related hormones on cell viability and mitotic fidelity. Similarly to estrogen, stress hormone cortisol and its relative cortisone increase microtubule organizing center (MTOC) number through elevated expression of γ-tubulin and provide the Taxol resistance to human cancer cell lines. However, these effects are achieved by glucocorticoid hormone receptor (GR) but not by estrogen receptor (ER). Since ginsenosides possess steroid-like structure, we hypothesized that it would block the stress or estrogen-induced MTOC amplification and Taxol resistance. Among tested chemicals, rare ginsenoside, CSH1 (Rg6) shows obvious effect on inhibition of MTOC amplification, γ-tubulin induction and Taxol resistance. Comparing to Fulvestant (FST), ER-α specific inhibitor, this chemical can block the cortisol/cortisone-induced MTOC deregulation as well as ER-α signaling. Our results suggest that stress hormone induced tumorigenesis would be achieved by MTOC amplification, and CSH1 would be useful for prevention of stress-hormone or steroid hormone-induced chromosomal instability. PMID:27147573

  17. Diffusion MRI in early cancer therapeutic response assessment

    PubMed Central

    Galbán, C. J.; Hoff, B. A.; Chenevert, T. L.; Ross, B. D.

    2016-01-01

    Imaging biomarkers for the predictive assessment of treatment response in patients with cancer earlier than standard tumor volumetric metrics would provide new opportunities to individualize therapy. Diffusion-weighted MRI (DW-MRI), highly sensitive to microenvironmental alterations at the cellular level, has been evaluated extensively as a technique for the generation of quantitative and early imaging biomarkers of therapeutic response and clinical outcome. First demonstrated in a rodent tumor model, subsequent studies have shown that DW-MRI can be applied to many different solid tumors for the detection of changes in cellularity as measured indirectly by an increase in the apparent diffusion coefficient (ADC) of water molecules within the lesion. The introduction of quantitative DW-MRI into the treatment management of patients with cancer may aid physicians to individualize therapy, thereby minimizing unnecessary systemic toxicity associated with ineffective therapies, saving valuable time, reducing patient care costs and ultimately improving clinical outcome. This review covers the theoretical basis behind the application of DW-MRI to monitor therapeutic response in cancer, the analytical techniques used and the results obtained from various clinical studies that have demonstrated the efficacy of DW-MRI for the prediction of cancer treatment response. PMID:26773848

  18. Preclinical Pharmacology and Structure-Activity Studies of Epothilones

    NASA Astrophysics Data System (ADS)

    Altmann, Karl-Heinz

    Microtubule inhibitors are an important class of anticancer agents (1), with clinical applications in the treatment of a variety of cancer types, either as single agents or as part of different combination regimens (2, 3). Microtubule-interacting agents can be grouped into two distinct functional classes, namely, compounds that inhibit the assembly of tubulin heterodimers into microtubule polymers (“tubulin polymerization inhibitors”) and those that stabilize microtubules under normally destabilizing conditions (“microtubule stabilizers”) (4). The latter will also promote the assembly of tubulin heterodimers into microtubule polymers and, as will be discussed later, the induction of tubulin polymerization is often used as a biochemical readout for a quantitative assessment of the interaction of microtubule-stabilizing agents with tubulin. Tubulin polymerization inhibitors such as vincristine and vinblastine have been employed in cancer therapy for more than 40 years (vincristine and vinblastine received FDA approval in 1963 and 1965, respectively). In contrast, the clinical history of microtubule-stabilizing agents is significantly shorter and its beginning dates back no more than 15 years. The first microtubule stabilizer to be introduced into clinical practice was the natural product taxol (paclitaxel; Taxol®) in 1993 (Fig. 1), with FDA approval for the semi-synthetic taxol analog docetaxel (Taxotere®) following three years later. Both compounds rapidly became an important part of today’s armamentarium in the battle against cancer,which marks the emergence of microtubule-stabilizing anti-cancer drugs as an important milestone in the development of modern cancer chemotherapy (5).

  19. The Role of Chromosomal Instability in Cancer and Therapeutic Responses

    PubMed Central

    Vargas-Rondón, Natalia

    2017-01-01

    Cancer is one of the leading causes of death, and despite increased research in recent years, control of advanced-stage disease and optimal therapeutic responses remain elusive. Recent technological improvements have increased our understanding of human cancer as a heterogeneous disease. For instance, four hallmarks of cancer have recently been included, which in addition to being involved in cancer development, could be involved in therapeutic responses and resistance. One of these hallmarks is chromosome instability (CIN), a source of genetic variation in either altered chromosome number or structure. CIN has become a hot topic in recent years, not only for its implications in cancer diagnostics and prognostics, but also for its role in therapeutic responses. Chromosomal alterations are mainly used to determine genetic heterogeneity in tumors, but CIN could also reveal treatment efficacy, as many therapies are based on increasing CIN, which causes aberrant cells to undergo apoptosis. However, it should be noted that contradictory findings on the implications of CIN for the therapeutic response have been reported, with some studies associating high CIN with a better therapeutic response and others associating it with therapeutic resistance. Considering these observations, it is necessary to increase our understanding of the role CIN plays not only in tumor development, but also in therapeutic responses. This review focuses on recent studies that suggest possible mechanisms and consequences of CIN in different disease types, with a primary focus on cancer outcomes and therapeutic responses. PMID:29283387

  20. Immune Response Following Photodynamic Therapy For Bladder Cancer

    NASA Astrophysics Data System (ADS)

    Raymond K.

    1989-06-01

    This study was undertaken to determine if photodynamic therapy (PDT) produces an immunologic response in patients treated for bladder cancer. Gamma interferon, interleukin 1-beta, interleukin 2 and tumor necrosis factor-alpha were assayed in the urine of four patients treated with photodynamic therapy for bladder cancer, in seven patients undergoing transurethral procedures, and in five healthy control subjects. Quantifiable concentrations of all cytokines, except gamma interferon, were measured in urine samples from the PDT patients treated with the highest light energies, while no urinary cytokines were found in the PDT patient who received the lowest light energy or in the control subjects. These findings suggest that a local immunologic response may occur following PDT for bladder cancer. Such an immunologic response activated by PDT may be an additional mechanism involved in bladder tumor destruction.

  1. Inferences of drug responses in cancer cells from cancer genomic features and compound chemical and therapeutic properties

    PubMed Central

    Wang, Yongcui; Fang, Jianwen; Chen, Shilong

    2016-01-01

    Accurately predicting the response of a cancer patient to a therapeutic agent is a core goal of precision medicine. Existing approaches were mainly relied primarily on genomic alterations in cancer cells that have been treated with different drugs. Here we focus on predicting drug response based on integration of the heterogeneously pharmacogenomics data from both cell and drug sides. Through a systematical approach, named as PDRCC (Predict Drug Response in Cancer Cells), the cancer genomic alterations and compound chemical and therapeutic properties were incorporated to determine the chemotherapeutic response in cancer patients. Using the Cancer Cell Line Encyclopedia (CCLE) study as the benchmark dataset, all pharmacogenomics data exhibited their roles in inferring the relationships between cancer cells and drugs. When integrating both genomic resources and compound information, the prediction coverage was significantly increased. The validity of PDRCC was also supported by its effective in uncovering the unknown cell-drug associations with database and literature evidences. It set the stage for clinical testing of novel therapeutic strategies, such as the sensitive association between cancer cell ‘A549_LUNG’ and compound ‘Topotecan’. In conclusion, PDRCC offers the possibility for faster, safer, and cheaper the development of novel anti-cancer therapeutics in the early-stage clinical trails. PMID:27645580

  2. Inferences of drug responses in cancer cells from cancer genomic features and compound chemical and therapeutic properties

    NASA Astrophysics Data System (ADS)

    Wang, Yongcui; Fang, Jianwen; Chen, Shilong

    2016-09-01

    Accurately predicting the response of a cancer patient to a therapeutic agent is a core goal of precision medicine. Existing approaches were mainly relied primarily on genomic alterations in cancer cells that have been treated with different drugs. Here we focus on predicting drug response based on integration of the heterogeneously pharmacogenomics data from both cell and drug sides. Through a systematical approach, named as PDRCC (Predict Drug Response in Cancer Cells), the cancer genomic alterations and compound chemical and therapeutic properties were incorporated to determine the chemotherapeutic response in cancer patients. Using the Cancer Cell Line Encyclopedia (CCLE) study as the benchmark dataset, all pharmacogenomics data exhibited their roles in inferring the relationships between cancer cells and drugs. When integrating both genomic resources and compound information, the prediction coverage was significantly increased. The validity of PDRCC was also supported by its effective in uncovering the unknown cell-drug associations with database and literature evidences. It set the stage for clinical testing of novel therapeutic strategies, such as the sensitive association between cancer cell ‘A549_LUNG’ and compound ‘Topotecan’. In conclusion, PDRCC offers the possibility for faster, safer, and cheaper the development of novel anti-cancer therapeutics in the early-stage clinical trails.

  3. Inferences of drug responses in cancer cells from cancer genomic features and compound chemical and therapeutic properties.

    PubMed

    Wang, Yongcui; Fang, Jianwen; Chen, Shilong

    2016-09-20

    Accurately predicting the response of a cancer patient to a therapeutic agent is a core goal of precision medicine. Existing approaches were mainly relied primarily on genomic alterations in cancer cells that have been treated with different drugs. Here we focus on predicting drug response based on integration of the heterogeneously pharmacogenomics data from both cell and drug sides. Through a systematical approach, named as PDRCC (Predict Drug Response in Cancer Cells), the cancer genomic alterations and compound chemical and therapeutic properties were incorporated to determine the chemotherapeutic response in cancer patients. Using the Cancer Cell Line Encyclopedia (CCLE) study as the benchmark dataset, all pharmacogenomics data exhibited their roles in inferring the relationships between cancer cells and drugs. When integrating both genomic resources and compound information, the prediction coverage was significantly increased. The validity of PDRCC was also supported by its effective in uncovering the unknown cell-drug associations with database and literature evidences. It set the stage for clinical testing of novel therapeutic strategies, such as the sensitive association between cancer cell 'A549_LUNG' and compound 'Topotecan'. In conclusion, PDRCC offers the possibility for faster, safer, and cheaper the development of novel anti-cancer therapeutics in the early-stage clinical trails.

  4. Responsibilities in cancer preventive care in Greece. A physicians' survey.

    PubMed

    Zacharias, Georgios; Xilomenos, Apostolos; Koukourakis, Georgios; Kamposioras, Konstantinos; Mauri, Davide; Chasioti, Dimitra; Bristianou, Magdalini; Ferentinos, Georgios; Levantakis, Ioannis; Tsali, Lamprini; Valachis, Antonis; Karampoiki, Vassiliki

    2008-04-01

    Colorectal cancer is the second leading cause of cancer death in European countries. Differences in screening implementation may explain USA vs. European survival differences. The proportion of European primary care physicians advising colorectal screening has been reported to be inconsistent. We therefore hypothesised the presence of a belief-related bias among European physicians regarding who is responsible for cancer screening delivery. To index beliefs in cancer screening implementation among a wide sample of Greek physicians. Study design Cross-sectional survey. Three hundred and sixty-six physicians involved in primary care activities in 15 provinces answered a questionnaire about responsibility in cancer screening delivery. Results 22.4% and 7.6% of physicians declared that the health system and the patients, respectively, have the main responsibility for cancer screening implementation, while 70 % advocated patient-health system co-responsibility. Beliefs were statistically correlated to age (p=0.039) and specialisation category (p=0.002). Patients' will was mainly indicated by internists, trainee internists and physicians older than 30, while GPs, trainee GPs and house officers were mainly health system-oriented. Worryingly, when physicians were asked about which specialty should inform the population, 81% indicated family doctor (for-fee-service) while the involvement of free-from-fee specialities was inconsistent. A considerable disorientation about responsibilities in cancer screening delivery was observed in our study sample. Continual medical education and clear redefinition of primary care physicians' activities are required.

  5. Mutation drivers of immunological responses to cancer

    PubMed Central

    Porta-Pardo, Eduard; Godzik, Adam

    2016-01-01

    In cancer immunology, somatic missense mutations have been mostly studied regarding their role in the generation of neoantigens. However, growing evidence suggests that mutations in certain genes, such as CASP8 or TP53, influence the immune response against a tumor by other mechanisms. Identifying these genes and mechanisms is important because, just as the identification of cancer driver genes led to the development of personalized cancer therapies, a comprehensive catalog of such cancer immunity drivers will aid in the development of therapies aimed at restoring antitumor immunity. Here we present an algorithm, domainXplorer, that can be used to identify potential cancer immunity drivers. To demonstrate its potential, we used it to analyze a dataset of 5,164 tumor samples from TCGA and to identify protein domains whose mutation status correlates with the presence of immune cells in cancer tissue (immune infiltrate). We identified 122 such protein regions including several that belong to proteins with known roles in immune response, such as C2, CD163L1, or FCγR2A. In several cases we show that mutations within the same protein can be associated with more or less immune cell infiltration, depending on the specific domain mutated. These results expand the catalog of potential cancer immunity drivers and highlight the importance of taking into account the structural context of somatic mutations when analyzing their potential association with immune phenotypes. PMID:27401919

  6. Future Directions for Monitoring Treatment Response in Colorectal Cancer

    PubMed Central

    Walker, Avery S.; Zwintscher, Nathan P.; Johnson, Eric K.; Maykel, Justin A.; Stojadinovic, Alexander; Nissan, Aviram; Avital, Itzhak; Brücher, Björn LDM; Steele, Scott R.

    2014-01-01

    Treatment of advanced colon and rectal cancer has significantly evolved with the introduction of neoadjuvant chemoradiation therapy so much that, along with more effective chemotherapy regimens, surgery has been considered unnecessary among some institutions for select patients. The tumor response to these treatments has also improved and ultimately has been shown to have a direct effect on prognosis. Yet, the best way to monitor that response, whether clinically, radiologically, or with laboratory findings, remains controversial. The authors' aim is to briefly review the options available and, more importantly, examine emerging and future options to assist in monitoring treatment response in cases of locally advanced rectal cancer and metastatic colon cancer. PMID:24396497

  7. Tumor Suppression and Sensitization to Taxol Induces Apoptosis of EIA in Breast Cancer Cells

    DTIC Science & Technology

    2005-06-01

    participated in the regulation of apoptosis induced by ceramide, mistletoe lectin, and 4-hydroxynonenal, an aldehyde product of mem- brane lipid peroxidation... Mistletoe lectin induces apoptosis and telomerase inhibition in hu- man A253 cancer cells through dephosphorylation of Akt. Arch Pharm Res 2004; 27:68-76...participated subunit of protein phosphatase 2A [PP2A (PP2A/C)l enhanced the activity in the regulation of apoptosis induced by ceramide, mistletoe lectin, of

  8. Low doses of Paclitaxel repress breast cancer invasion through DJ-1/KLF17 signalling pathway.

    PubMed

    Ismail, Ismail Ahmed; El-Sokkary, Gamal H; Saber, Saber H

    2018-04-27

    Paclitaxel (taxol) is an important agent against many tumours, including breast cancer. Ample data documents that paclitaxel inhibits breast cancer metastasis while others prove that paclitaxel enhances breast cancer metastasis. The mechanisms by which paclitaxel exerts its action are not well established. This study focuses on the effect of paclitaxel, particularly the low doses on breast cancer metastasis and the mechanisms that regulate it. Current results show that, paclitaxel exerts significant cytotoxicity even at low doses in both MCF-7 and MDA-MB-231 cells. Interestingly, paclitaxel significantly inhibits cell invasion and migration, decreases Snail and increases E-cadherin mRNA expression levels at the indicated low doses. Furthermore, paclitaxel-inhibiting breast cancer metastasis is associated with down-regulation of DJ-1 and ID-1 mRNA expression level with a concurrent increase in KLF17 expression. Under the same experimental conditions, paclitaxel induces KLF17 and concurrently represses ID-1 protein levels. Our results show for the first time that paclitaxel inhibits breast cancer metastasis through regulating DJ-1/KLF17/ID-1 signalling pathway; repressed DJ-1 and ID-1 and enhanced KLF17 expression. © 2018 John Wiley & Sons Australia, Ltd.

  9. Mcl-1 dynamics influence mitotic slippage and death in mitosis.

    PubMed

    Sloss, Olivia; Topham, Caroline; Diez, Maria; Taylor, Stephen

    2016-02-02

    Microtubule-binding drugs such as taxol are frontline treatments for a variety of cancers but exactly how they yield patient benefit is unclear. In cell culture, inhibiting microtubule dynamics prevents spindle assembly, leading to mitotic arrest followed by either apoptosis in mitosis or slippage, whereby a cell returns to interphase without dividing. Myeloid cell leukaemia-1 (Mcl-1), a pro-survival member of the Bcl-2 family central to the intrinsic apoptosis pathway, is degraded during a prolonged mitotic arrest and may therefore act as a mitotic death timer. Consistently, we show that blocking proteasome-mediated degradation inhibits taxol-induced mitotic apoptosis in a Mcl-1-dependent manner. However, this degradation does not require the activity of either APC/C-Cdc20, FBW7 or MULE, three separate E3 ubiquitin ligases implicated in targeting Mcl-1 for degradation. This therefore challenges the notion that Mcl-1 undergoes regulated degradation during mitosis. We also show that Mcl-1 is continuously synthesized during mitosis and that blocking protein synthesis accelerates taxol induced death-in-mitosis. Modulating Mcl-1 levels also influences slippage; overexpressing Mcl-1 extends the time from mitotic entry to mitotic exit in the presence of taxol, while inhibiting Mcl-1 accelerates it. We suggest that Mcl-1 competes with Cyclin B1 for binding to components of the proteolysis machinery, thereby slowing down the slow degradation of Cyclin B1 responsible for slippage. Thus, modulating Mcl-1 dynamics influences both death-in-mitosis and slippage. However, because mitotic degradation of Mcl-1 appears not to be under the control of an E3 ligase, we suggest that the notion of network crosstalk is used with caution.

  10. Characterizing and Targeting Replication Stress Response Defects in Breast Cancer

    DTIC Science & Technology

    2015-08-01

    1 AD_________________ Award Number: W81XWH-10-1-0558 TITLE: Characterizing and Targeting Replication Stress Response Defects in Breast Cancer ...PRINCIPAL INVESTIGATOR: Shiaw-Yih Lin, Ph.D. CONTRACTING ORGANIZATION: University of Texas M. D. Anderson Cancer Center Houston, TX 77030 REPORT...Response Defects in Breast Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Betty Diamond 5d. PROJECT NUMBER Chun-Jen Lin, Hui Dai

  11. Species differences in tumour responses to cancer chemotherapy

    PubMed Central

    Lawrence, Jessica; Cameron, David; Argyle, David

    2015-01-01

    Despite advances in chemotherapy, radiotherapy and targeted drug development, cancer remains a disease of high morbidity and mortality. The treatment of human cancer patients with chemotherapy has become commonplace and accepted over the past 100 years. In recent years, and with a similar incidence of cancer to people, the use of cancer chemotherapy drugs in veterinary patients such as the dog has also become accepted clinical practice. The poor predictability of tumour responses to cancer chemotherapy drugs in rodent models means that the standard drug development pathway is costly, both in terms of money and time, leading to many drugs failing in Phase I and II clinical trials. This has led to the suggestion that naturally occurring cancers in pet dogs may offer an alternative model system to inform rational drug development in human oncology. In this review, we will explore the species variation in tumour responses to conventional chemotherapy and highlight our understanding of the differences in pharmacodynamics, pharmacokinetics and pharmacogenomics between humans and dogs. Finally, we explore the potential hurdles that need to be overcome to gain the greatest value from comparative oncology studies. PMID:26056373

  12. Slick Nanoparticles and Other Gleanings from Nature

    NASA Astrophysics Data System (ADS)

    Heinhorst, Sabine; Cannon, Gordon C.

    1997-09-01

    The total synthesis of a new class of compounds that promise to be cancer chemotherapeutic agents at least as effective as taxol was presented in the May 15 issue (Vol. 387, pp 238-239) as a "News and Views" article. Although structurally unrelated, epothilones, like taxol, target the microtubules of the cytoskeleton and inhibit cancer cell growth by polymerizing these subcellular structures. Future research will have to determine which derivatives of natural epothilones are effective and which functional groups hold the key to the compounds' biological activity. An article by Deshpande and Danishefsky (May 8 issue of Vol. 387, pp 164-166) details the successful chemical synthesis of an oligosaccharide that is frequently found on the surface of colon adenocarcinomas. While the small quantities of this cancer antigen that can be purified from natural sources preclude its usefulness as an immunological tool, the synthetic compound and an analog that can be linked to a carrier molecule for biological delivery have potential as vaccines for several human cancers.

  13. Integrative Tumor Board: a Case Report and Discussion from Dana-Farber Cancer Institute

    PubMed Central

    Lu, Weidong; Ott, Mary Jane; Kennedy, Stacy; Mathay, Maria B.; Doherty-Gilman, Anne M.; Dean-Clower, Elizabeth; Hayes, Carolyn M.; Rosenthal, David S.

    2010-01-01

    A 34-year-old female carrying a BRCA1 gene and a significant family history was diagnosed with T1c, N1 breast cancer. The tumor was estrogen receptor, progesterone receptor and HER-2/Neu negative. The patient received dose-dense chemotherapy with Adriamycin and Cytoxan followed by Taxol, and left breast irradiation. Later, a bilateral S-GAP flap reconstruction with right prophylactic mastectomy and left mastectomy were performed. During her treatment, the patient had an integrative medicine consultation and was seen by a team of healthcare providers specializing in integrative therapies including integrative nutrition, therapeutic massage, acupuncture, and yoga. Each modality contributed unique benefit in her care that led to a satisfactory outcome of the patient. A detailed discussion regarding her care from each modality is presented. The case elucidates the need of integrative approaches for cancer patients in a conventional medical setting. PMID:19815593

  14. Paclitaxel Nano-Delivery Systems: A Comprehensive Review

    PubMed Central

    Ma, Ping; Mumper, Russell J.

    2013-01-01

    Paclitaxel is one of the most effective chemotherapeutic drugs ever developed and is active against a broad range of cancers, such as lung, ovarian, and breast cancers. Due to its low water solubility, paclitaxel is formulated in a mixture of Cremophor EL and dehydrated ethanol (50:50, v/v) a combination known as Taxol. However, Taxol has some severe side effects related to Cremophor EL and ethanol. Therefore, there is an urgent need for the development of alternative Taxol formulations. The encapsulation of paclitaxel in biodegradable and non-toxic nano-delivery systems can protect the drug from degradation during circulation and in-turn protect the body from toxic side effects of the drug thereby lowering its toxicity, increasing its circulation half-life, exhibiting improved pharmacokinetic profiles, and demonstrating better patient compliance. Also, nanoparticle-based delivery systems can take advantage of the enhanced permeability and retention (EPR) effect for passive tumor targeting, therefore, they are promising carriers to improve the therapeutic index and decrease the side effects of paclitaxel. To date, paclitaxel albumin-bound nanoparticles (Abraxane®) have been approved by the FDA for the treatment of metastatic breast cancer and non-small cell lung cancer (NSCLC). In addition, there are a number of novel paclitaxel nanoparticle formulations in clinical trials. In this comprehensive review, several types of developed paclitaxel nano-delivery systems will be covered and discussed, such as polymeric nanoparticles, lipid-based formulations, polymer conjugates, inorganic nanoparticles, carbon nanotubes, nanocrystals, and cyclodextrin nanoparticles. PMID:24163786

  15. Paclitaxel and carboplatin in early phase studies: Roswell Park Cancer Institute experience in the subset of patients with lung cancer.

    PubMed

    Creaven, P J; Raghavan, D; Pendyala, L; Loewen, G; Kindler, H L; Berghorn, E J

    1997-08-01

    The combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given by 3-hour infusion followed by carboplatin infused over 30 minutes has been evaluated in a series of phase I studies and is currently being explored in a phase II study in patients with limited- and extensive-stage small cell lung cancer. Pharmacokinetic measurements were performed at all dose levels in the phase I studies, in which the use of granulocyte colony-stimulating factor in previously treated patients enabled more than twice the dose of paclitaxel to be given with low to moderate doses of carboplatin (dosed to a target area under the concentration-time curve of 4.0 mg x min x mL[-1]). Treatment-naive patients tolerated high paclitaxel doses (270 mg/m2) with carboplatin (dosed to a target area under the curve of 4.5 mg x min x mL[-1]) without granulocyte colony-stimulating factor support. Twenty-three patients (including previously treated and untreated) with non-small cell lung cancer were entered at a variety of paclitaxel doses in the phase I studies. At 100 to 205 mg/m2 paclitaxel, none of nine treated patients responded; at 230 to 290 mg/m2, four (29%) of 14 responded. In the phase II study of paclitaxel 250 mg/m2 in previously untreated patients with small cell lung cancer, two of five evaluable patients with extensive-stage disease have shown a partial response. In a preliminary analysis of the pharmacodynamics of paclitaxel in relation to neurotoxicity (dose limiting in two of three phase I studies), neurotoxicity correlated with the total dose of paclitaxel, the area under the curve, and the peak paclitaxel concentration, but not with the length of time plasma paclitaxel levels remained above 0.05 micromol/L. These correlations were not strong, however, and analysis of these data is ongoing.

  16. The battle of "nano" paclitaxel.

    PubMed

    Sofias, Alexandros Marios; Dunne, Michael; Storm, Gert; Allen, Christine

    2017-12-01

    Paclitaxel (PTX) is one of the three most widely used chemotherapeutic agents, together with doxorubicin and cisplatin, and is first or second line treatment for several types of cancers. In 2000, Taxol, the conventional formulation of PTX, became the best-selling cancer drug of all time with annual sales of 1.6 billion. In 2005, the introduction of the albumin-based formulation of PTX, known as Abraxane, ended Taxol's monopoly of the PTX market. Abraxane's ability to push the Taxol innovator and generic formulations aside attracted fierce competition amongst competitors worldwide to develop their own unique, new and improved formulation of PTX. At this time there are at least 18 companies focused on pre-clinical and/or clinical development of nano-formulations of PTX. These pharmaceutical companies are investing substantial capital to capture a share of the lucrative global PTX market. It is hoped that any formulation that dominates the market will result in tangible benefits to patients in terms of both survival and quality of life. Given all of this activity, here we address the question: Who is going to win the battle of "nano" paclitaxel? Copyright © 2017 Elsevier B.V. All rights reserved.

  17. The Chemical Synthesis of Discodermolide

    NASA Astrophysics Data System (ADS)

    Paterson, I.; Florence, G. J.

    The marine sponge-derived polyketide discodermolide is a potent antimitotic agent that represents a promising natural product lead structure in the treatment of cancer. Discodermolide shares the same microtubule-stabilising mechanism of action as Taxol®, inhibits the growth of solid tumours in animal models and shows synergy with Taxol. The pronounced cytotoxicity of discodermolide, which is maintained against cancer cell lines that display resistance to Taxol and other drugs, combined with its scarce availability from its natural source, has fuelled significant academic and industrial interest in devising a practical total synthesis as a means of ensuring a sustainable supply for drug development. This chapter surveys the various total syntheses of discodermolide that have been completed over the period 1993-2007, focusing on the strategies employed for introduction of the multiple stereocentres and achieving control over the alkene geometry, along with the various methods used for realising the pivotal fragment couplings to assemble progressively the full carbon skeleton. This dedicated synthetic effort has triumphed in removing the supply problem for discodermolide, providing sufficient material for extensive biological studies and enabling its early stage clinical development, as well as facilitating SAR studies for lead optimisation.

  18. Current Approaches, Challenges and Future Directions for Monitoring Treatment Response in Prostate Cancer

    PubMed Central

    Wallace, T.J.; Torre, T.; Grob, M.; Yu, J.; Avital, I.; Brücher, BLDM; Stojadinovic, A.; Man, Y.G.

    2014-01-01

    Prostate cancer is the most commonly diagnosed non-cutaneous neoplasm in men in the United States and the second leading cause of cancer mortality. One in 7 men will be diagnosed with prostate cancer during their lifetime. As a result, monitoring treatment response is of vital importance. The cornerstone of current approaches in monitoring treatment response remains the prostate-specific antigen (PSA). However, with the limitations of PSA come challenges in our ability to monitor treatment success. Defining PSA response is different depending on the individual treatment rendered potentially making it difficult for those not trained in urologic oncology to understand. Furthermore, standard treatment response criteria do not apply to prostate cancer further complicating the issue of treatment response. Historically, prostate cancer has been difficult to image and no single modality has been consistently relied upon to measure treatment response. However, with newer imaging modalities and advances in our understanding and utilization of specific biomarkers, the future for monitoring treatment response in prostate cancer looks bright. PMID:24396494

  19. Overcoming heterologous protein interdependency to optimize P450-mediated Taxol precursor synthesis in Escherichia coli

    PubMed Central

    Biggs, Bradley Walters; Lim, Chin Giaw; Sagliani, Kristen; Shankar, Smriti; Stephanopoulos, Gregory; Ajikumar, Parayil Kumaran

    2016-01-01

    Recent advances in metabolic engineering have demonstrated the potential to exploit biological chemistry for the synthesis of complex molecules. Much of the progress to date has leveraged increasingly precise genetic tools to control the transcription and translation of enzymes for superior biosynthetic pathway performance. However, applying these approaches and principles to the synthesis of more complex natural products will require a new set of tools for enabling various classes of metabolic chemistries (i.e., cyclization, oxygenation, glycosylation, and halogenation) in vivo. Of these diverse chemistries, oxygenation is one of the most challenging and pivotal for the synthesis of complex natural products. Here, using Taxol as a model system, we use nature’s favored oxygenase, the cytochrome P450, to perform high-level oxygenation chemistry in Escherichia coli. An unexpected coupling of P450 expression and the expression of upstream pathway enzymes was discovered and identified as a key obstacle for functional oxidative chemistry. By optimizing P450 expression, reductase partner interactions, and N-terminal modifications, we achieved the highest reported titer of oxygenated taxanes (∼570 ± 45 mg/L) in E. coli. Altogether, this study establishes E. coli as a tractable host for P450 chemistry, highlights the potential magnitude of protein interdependency in the context of synthetic biology and metabolic engineering, and points to a promising future for the microbial synthesis of complex chemical entities. PMID:26951651

  20. Overcoming heterologous protein interdependency to optimize P450-mediated Taxol precursor synthesis in Escherichia coli.

    PubMed

    Biggs, Bradley Walters; Lim, Chin Giaw; Sagliani, Kristen; Shankar, Smriti; Stephanopoulos, Gregory; De Mey, Marjan; Ajikumar, Parayil Kumaran

    2016-03-22

    Recent advances in metabolic engineering have demonstrated the potential to exploit biological chemistry for the synthesis of complex molecules. Much of the progress to date has leveraged increasingly precise genetic tools to control the transcription and translation of enzymes for superior biosynthetic pathway performance. However, applying these approaches and principles to the synthesis of more complex natural products will require a new set of tools for enabling various classes of metabolic chemistries (i.e., cyclization, oxygenation, glycosylation, and halogenation) in vivo. Of these diverse chemistries, oxygenation is one of the most challenging and pivotal for the synthesis of complex natural products. Here, using Taxol as a model system, we use nature's favored oxygenase, the cytochrome P450, to perform high-level oxygenation chemistry in Escherichia coli. An unexpected coupling of P450 expression and the expression of upstream pathway enzymes was discovered and identified as a key obstacle for functional oxidative chemistry. By optimizing P450 expression, reductase partner interactions, and N-terminal modifications, we achieved the highest reported titer of oxygenated taxanes (∼570 ± 45 mg/L) in E. coli. Altogether, this study establishes E. coli as a tractable host for P450 chemistry, highlights the potential magnitude of protein interdependency in the context of synthetic biology and metabolic engineering, and points to a promising future for the microbial synthesis of complex chemical entities.

  1. A Biophysico-computational Perspective of Breast Cancer Pathogenesis and Treatment Response

    DTIC Science & Technology

    2006-03-01

    of Breast Cancer Pathogenesis and Treatment Response PRINCIPAL INVESTIGATOR: Valerie M. Weaver Ph.D. CONTRACTING...burden for this collection of information is estimated to average 1 hour per response , including the time for reviewing instructions, searching existing...Biophysico-computational Perspective of Breast Cancer Pathogenesis and 5a. CONTRACT NUMBER Treatment Response 5b. GRANT NUMBER W81XWH-05-1-0330 5c

  2. Prediction of anti-cancer drug response by kernelized multi-task learning.

    PubMed

    Tan, Mehmet

    2016-10-01

    Chemotherapy or targeted therapy are two of the main treatment options for many types of cancer. Due to the heterogeneous nature of cancer, the success of the therapeutic agents differs among patients. In this sense, determination of chemotherapeutic response of the malign cells is essential for establishing a personalized treatment protocol and designing new drugs. With the recent technological advances in producing large amounts of pharmacogenomic data, in silico methods have become important tools to achieve this aim. Data produced by using cancer cell lines provide a test bed for machine learning algorithms that try to predict the response of cancer cells to different agents. The potential use of these algorithms in drug discovery/repositioning and personalized treatments motivated us in this study to work on predicting drug response by exploiting the recent pharmacogenomic databases. We aim to improve the prediction of drug response of cancer cell lines. We propose to use a method that employs multi-task learning to improve learning by transfer, and kernels to extract non-linear relationships to predict drug response. The method outperforms three state-of-the-art algorithms on three anti-cancer drug screen datasets. We achieved a mean squared error of 3.305 and 0.501 on two different large scale screen data sets. On a recent challenge dataset, we obtained an error of 0.556. We report the methodological comparison results as well as the performance of the proposed algorithm on each single drug. The results show that the proposed method is a strong candidate to predict drug response of cancer cell lines in silico for pre-clinical studies. The source code of the algorithm and data used can be obtained from http://mtan.etu.edu.tr/Supplementary/kMTrace/. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. 2’-Behenoyl-Paclitaxel Conjugate Containing Lipid Nanoparticles for the Treatment of Metastatic Breast Cancer

    PubMed Central

    Ma, Ping; Benhabbour, S. Rahima; Feng, Lan; Mumper, Russell J

    2012-01-01

    The aim of these studies was to develop a novel 2’-behenoyl-paclitaxel (C22-PX) conjugate nanoparticle (NP) formulation for the treatment of metastatic breast cancer. A lipophilic paclitaxel derivative C22-PX was synthesized and incorporated into lipid-based NPs. Free C22-PX and its NP formulation were evaluated in a series of in-vitro and in-vivo studies. The results demonstrated that C22-PX NPs were much better tolerated and had significantly higher plasma and tumor AUCs compared to Taxol at the maximum tolerated dose (MTD) in a subcutaneous 4T1 mouse mammary carcinoma model. These benefits resulted in significantly improved antitumor efficacy with the NP-based formulation. PMID:22902506

  4. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy.

    PubMed

    Montero, Joan; Sarosiek, Kristopher A; DeAngelo, Joseph D; Maertens, Ophélia; Ryan, Jeremy; Ercan, Dalia; Piao, Huiying; Horowitz, Neil S; Berkowitz, Ross S; Matulonis, Ursula; Jänne, Pasi A; Amrein, Philip C; Cichowski, Karen; Drapkin, Ronny; Letai, Anthony

    2015-02-26

    There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient's living cancer cell with the drug(s) in question. To satisfy this unmet need, we developed the Dynamic BH3 Profiling technique to measure early changes in net pro-apoptotic signaling at the mitochondrion ("priming") induced by chemotherapeutic agents in cancer cells, not requiring prolonged ex vivo culture. We find in cell line and clinical experiments that early drug-induced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies. We propose that Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chemotherapeutics in vivo. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Difference of protein 53 expression based on radiation therapy response in cervical cancer

    NASA Astrophysics Data System (ADS)

    Pasaribu, H. P.; Lubis, L. I.; Dina, S.; Simanjuntak, R. Y.; Siregar, H. S.; Rivany, R.

    2018-03-01

    Cervical cancer is one of most common gynecological cancer in women and the leading cause of death in developing countries. An analytic study with the case-control design was conducted to determine the difference of p53 expression based on radiation therapy response in cervical cancer. The study was performed in Obstetric and Gynecology Department and Pathology Department of Adam Malik General Hospital Medan from January to February 2017. 15 paraffin blocks of acervical cancer patient with incomplete response were obtained as study samples, and 15 paraffin blocks of acervical cancer patient with complete response were obtained as control samples, The samples were collected by consecutive sampling, andan immunohistochemical assessment of p53 expression was done to assessapoptosis count and radiation response. Data were analyzed using Kruskal-Wallis with confidence interval 83.5% and p<0.05 was considered statistically significant. The study found that an increase of p53 expressionin samples with abundant apoptosis (≥5 apoptosis cells/5 HPF), p=0.033, and in incomplete response group, p=0.046. It means that p53 expression before radiation therapy can be used as an early marker for radiation therapy response in cervical cancer.

  6. Novobiocin and additional inhibitors of the Hsp90 C-terminal nucleotide-binding pocket.

    PubMed

    Donnelly, Alison; Blagg, Brian S J

    2008-01-01

    proteins. Unlike the N-terminal ATP binding site, there is no reported co-crystal structure of Hsp90 C-terminus bound to any inhibitor. The Hsp90 C-terminal domain, however, is known to contain a conserved pentapeptide sequence (MEEVD) which is recognized by co-chaperones. Cisplatin is a platinum-containing chemotherapeutic used to treat various types of cancers, including testicular, ovarian, bladder, and small cell lung cancer. Most notably, cisplatin coordinates to DNA bases, resulting in cross-linked DNA, which prohibits rapidly dividing cells from duplicating DNA for mitosis. Itoh and co-workers reported that cisplatin decreases the chaperone activity of Hsp90. This group applied bovine brain cytosol to a cisplatin affinity column, eluted with cisplatin and detected Hsp90 in the eluent. Subsequent experiments indicated that cisplatin exhibits high affinity for Hsp90. Moreover Csermely and co-workers determined that the cisplatin binding site is located proximal to the C-terminal ATP binding site. EGCG is one of the active ingredients found in green tea. EGCG is known to inhibit the activity of many Hsp90-dependent client proteins, including telomerase, several kinases, and the aryl hydrocarbon receptor (AhR). Recently Gasiewicz and co-workers reported that EGCG manifests its antagonistic activity against AhR through binding Hsp90. Similar to novobiocin, EGCG was shown to bind the C-terminus of Hsp90. Unlike previously identified N-terminal Hsp90 inhibitors, EGCG does not appear to prevent Hsp90 from forming multiprotein complexes. Studies are currently underway to determine whether EGCG competes with novobiocin or cisplatin binding. Taxol, a well-known drug for the treatment of cancer, is responsible for the stabilization of microtubules and the inhibition of mitosis. Previous studies have shown that taxol induces the activation of kinases and transcription factors, and mimics the effect of bacterial lipopolysaccharide (LPS), an attribute unrelated to its tubulin

  7. POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer.

    PubMed

    van Gool, Inge C; Eggink, Florine A; Freeman-Mills, Luke; Stelloo, Ellen; Marchi, Emanuele; de Bruyn, Marco; Palles, Claire; Nout, Remi A; de Kroon, Cor D; Osse, Elisabeth M; Klenerman, Paul; Creutzberg, Carien L; Tomlinson, Ian Pm; Smit, Vincent Thbm; Nijman, Hans W; Bosse, Tjalling; Church, David N

    2015-07-15

    Recent studies have shown that 7% to 12% of endometrial cancers are ultramutated due to somatic mutation in the proofreading exonuclease domain of the DNA replicase POLE. Interestingly, these tumors have an excellent prognosis. In view of the emerging data linking mutation burden, immune response, and clinical outcome in cancer, we investigated whether POLE-mutant endometrial cancers showed evidence of increased immunogenicity. We examined immune infiltration and activation according to tumor POLE proofreading mutation in a molecularly defined endometrial cancer cohort including 47 POLE-mutant tumors. We sought to confirm our results by analysis of RNAseq data from the TCGA endometrial cancer series and used the same series to examine whether differences in immune infiltration could be explained by an enrichment of immunogenic neoepitopes in POLE-mutant endometrial cancers. Compared with other endometrial cancers, POLE mutants displayed an enhanced cytotoxic T-cell response, evidenced by increased numbers of CD8(+) tumor-infiltrating lymphocytes and CD8A expression, enrichment for a tumor-infiltrating T-cell gene signature, and strong upregulation of the T-cell cytotoxic differentiation and effector markers T-bet, Eomes, IFNG, PRF, and granzyme B. This was accompanied by upregulation of T-cell exhaustion markers, consistent with chronic antigen exposure. In silico analysis confirmed that POLE-mutant cancers are predicted to display more antigenic neoepitopes than other endometrial cancers, providing a potential explanation for our findings. Ultramutated POLE proofreading-mutant endometrial cancers are characterized by a robust intratumoral T-cell response, which correlates with, and may be caused by an enrichment of antigenic neopeptides. Our study provides a plausible mechanism for the excellent prognosis of these cancers. ©2015 American Association for Cancer Research.

  8. Brain Tumor Genetic Modification Yields Increased Resistance to Paclitaxel in Physical Confinement

    PubMed Central

    Bui, Loan; Hendricks, Alissa; Wright, Jamie; Chuong, Cheng-Jen; Davé, Digant; Bachoo, Robert; Kim, Young-tae

    2016-01-01

    Brain tumor cells remain highly resistant to radiation and chemotherapy, particularly malignant and secondary cancers. In this study, we utilized microchannel devices to examine the effect of a confined environment on the viability and drug resistance of the following brain cancer cell lines: primary cancers (glioblastoma multiforme and neuroblastoma), human brain cancer cell lines (D54 and D54-EGFRvIII), and genetically modified mouse astrocytes (wild type, p53−/−, p53−/− PTEN−/−, p53−/− Braf, and p53−/− PTEN−/− Braf). We found that loss of PTEN combined with Braf activation resulted in higher viability in narrow microchannels. In addition, Braf conferred increased resistance to the microtubule-stabilizing drug Taxol in narrow confinement. Similarly, survival of D54-EGFRvIII cells was unaffected following treatment with Taxol, whereas the viability of D54 cells was reduced by 75% under these conditions. Taken together, our data suggests key targets for anticancer drugs based on cellular genotypes and their specific survival phenotypes during confined migration. PMID:27184621

  9. Acquired immune response to oncogenic human papillomavirus associated with prophylactic cervical cancer vaccines.

    PubMed

    Einstein, Mark H

    2008-04-01

    Human papillomavirus (HPV) is a common infection among women and a necessary cause of cervical cancer. Oncogenic HPV types infecting the anogenital tract have the potential to induce natural immunity, but at present we do not clearly understand the natural history of infection in humans and the mechanisms by which the virus can evade the host immune response. Natural acquired immune responses against HPV may be involved in the clearance of infection, but persistent infection with oncogenic virus types leads to the development of precancerous lesions and cancer. B cell responses are important for viral neutralization, but antibody responses in patients with cervical cancer are poor. Prophylactic vaccines targeting oncogenic virus types associated with cervical cancer have the potential to prevent up to 80% of cervical cancers by targeting HPV types 16 and 18. Clinical data show that prophylactic vaccines are effective in inducing antibody responses and in preventing persistent infection with HPV, as well as the subsequent development of high-grade cervical intraepithelial neoplasia. This article reviews the known data regarding natural immune responses to HPV and those developed by prophylactic vaccination.

  10. Inflammatory responses to psychological stress in fatigued breast cancer survivors: relationship to glucocorticoids.

    PubMed

    Bower, Julienne E; Ganz, Patricia A; Aziz, Najib; Olmstead, Richard; Irwin, Michael R; Cole, Steve W

    2007-03-01

    Fatigue is a common problem following cancer treatment and our previous studies suggest that a chronic inflammatory process might contribute to cancer-related fatigue. However, immune responses to challenge have not yet been evaluated among individuals with cancer-related fatigue, and it is not known what mechanisms drive increased levels of inflammatory markers in fatigued cancer survivors. We have previously reported that fatigued breast cancer survivors show a blunted cortisol response to an experimental psychological stressor. In this report, we focus on inflammatory responses to this stressor and their relationship to circulating glucocorticoids and cellular sensitivity to glucocorticoid inhibition. Relative to non-fatigued control survivors, participants experiencing persistent fatigue showed significantly greater increases in LPS-stimulated production of IL-1beta and IL-6 following the stressor (Group x Time interaction: p<.05). Fatigued participants did not show any difference in cellular sensitivity to cortisol inhibition of cytokine production, but they did show significantly less salivary cortisol increase in the aftermath of the stressor. Moreover, blunted cortisol responses were associated with significantly increased production of IL-6 in response to LPS stimulation (p<.05). These data provide further evidence of enhanced inflammatory processes in fatigued breast cancer survivors and suggest that these processes may stem in part from decreased glucocorticoid response to stress.

  11. Effects of chemotherapy on immune responses in dogs with cancer.

    PubMed

    Walter, Claudia U; Biller, Barbara J; Lana, Susan E; Bachand, Annette M; Dow, Steven W

    2006-01-01

    Chemotherapy is assumed to be immunosuppressive; yet to the authors' knowledge, the effects of common chemotherapy protocols on adaptive immune responses in dogs with cancer have not been fully evaluated. Therefore, a study was conducted to evaluate the effects of 2 common chemotherapy protocols on T- and B-cell numbers and humoral immune responses to de novo vaccination in dogs with cancer. Twenty-one dogs with cancer (12 with lymphoma, 9 with osteosarcoma) were enrolled in a prospective study to assess effects of doxorubicin versus multi-drug chemotherapy on adaptive immunity. Numbers of circulating T and B cells were assessed by flow cytometry, and antibody responses to de novo vaccination were assessed before, during, and after chemotherapy. The T- and B-cell numbers before treatment also were compared with those of healthy, age-matched, control dogs. Prior to treatment, dogs with cancer had significantly fewer (P < .05) CD4+ T cells and CD8+ T cells than did healthy dogs. Doxorubicin treatment did not cause a significant decrease in T- or B-cell numbers, whereas treatment with combination chemotherapy caused a significant and persistent decrease in B-cell numbers. Antibody titers after vaccination were not significantly different between control and chemotherapy-treated dogs. These findings suggest that chemotherapy may have less impact on T-cell numbers and ability to mount antibody responses in dogs with cancer than was previously anticipated, though dogs with lymphoma or osteosarcoma appear to be relatively T-cell deficient before initiation of chemotherapy.

  12. Cancer Survivors’ Responses to Daily Stressors: Implications for Quality of Life

    PubMed Central

    Costanzo, Erin S.; Stawski, Robert S.; Ryff, Carol D.; Coe, Christopher L.; Almeida, David M.

    2012-01-01

    Objective This study examined cancer survivors’ experience of and responses to challenges and stressors associated with every-day living. The impact of daily stressors on quality of life concerns and cortisol patterns was also investigated. Design Participants were 111 cancer survivors who participated in a national telephone diary study of daily experiences (NSDE). Their responses were compared with those of 111 sociodemographically-matched participants with no cancer history using a multilevel modeling approach. Main Outcome Measures Over an 8-day period, participants completed a daily inventory of the occurrence and impact of stressful events, affect, and physical symptoms. Salivary cortisol was sampled 4 times per day, and indices of awakening response (CAR), diurnal slope, and overall output (AUC) were examined. Results Cancer survivors experienced similar numbers and types of stressful events as the comparison group. While appraisals were largely comparable, cancer survivors showed a modest tendency to perceive stressors as more severe and disruptive, particularly those involving interpersonal tensions. The occurrence of stressors was associated with increased negative affect, decreased positive affect, and increased physical symptoms, but little change in cortisol. Relative to the comparison group, cancer survivors showed less pronounced changes in positive affect and cortisol output when stressors occurred, but a greater increase in negative affect in response to interpersonal conflicts. Conclusions Findings indicate that cancer survivors show a resilient ability to respond to day-to-day stressors and challenges. However, daily stressors can have a significant impact on survivors’ mood and physical symptoms and therefore may be an important intervention target. PMID:22268712

  13. Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer.

    PubMed

    Janjigian, Yelena Y; Sanchez-Vega, Francisco; Jonsson, Philip; Chatila, Walid K; Hechtman, Jaclyn F; Ku, Geoffrey Y; Riches, Jamie C; Tuvy, Yaelle; Kundra, Ritika; Bouvier, Nancy; Vakiani, Efsevia; Gao, Jianjiong; Heins, Zachary J; Gross, Benjamin E; Kelsen, David P; Zhang, Liying; Strong, Vivian E; Schattner, Mark; Gerdes, Hans; Coit, Daniel G; Bains, Manjit; Stadler, Zsofia K; Rusch, Valerie W; Jones, David R; Molena, Daniela; Shia, Jinru; Robson, Mark E; Capanu, Marinela; Middha, Sumit; Zehir, Ahmet; Hyman, David M; Scaltriti, Maurizio; Ladanyi, Marc; Rosen, Neal; Ilson, David H; Berger, Michael F; Tang, Laura; Taylor, Barry S; Solit, David B; Schultz, Nikolaus

    2018-01-01

    The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability-high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein-Barr virus-positive patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance. Significance: Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers. Cancer Discov; 8(1); 49-58. ©2017 AACR. See related commentary by Sundar and Tan, p. 14 See related article by Pectasides et al., p. 37 This article is highlighted in the In This Issue feature, p. 1 . ©2017 American Association for Cancer Research.

  14. Distinct metabolic responses of an ovarian cancer stem cell line.

    PubMed

    Vermeersch, Kathleen A; Wang, Lijuan; McDonald, John F; Styczynski, Mark P

    2014-12-18

    Cancer metabolism is emerging as an important focus area in cancer research. However, the in vitro cell culture conditions under which much cellular metabolism research is performed differ drastically from in vivo tumor conditions, which are characterized by variations in the levels of oxygen, nutrients like glucose, and other molecules like chemotherapeutics. Moreover, it is important to know how the diverse cell types in a tumor, including cancer stem cells that are believed to be a major cause of cancer recurrence, respond to these variations. Here, in vitro environmental perturbations designed to mimic different aspects of the in vivo environment were used to characterize how an ovarian cancer cell line and its derived, isogenic cancer stem cells metabolically respond to environmental cues. Mass spectrometry was used to profile metabolite levels in response to in vitro environmental perturbations. Docetaxel, the chemotherapeutic used for this experiment, caused significant metabolic changes in amino acid and carbohydrate metabolism in ovarian cancer cells, but had virtually no metabolic effect on isogenic ovarian cancer stem cells. Glucose deprivation, hypoxia, and the combination thereof altered ovarian cancer cell and cancer stem cell metabolism to varying extents for the two cell types. Hypoxia had a much larger effect on ovarian cancer cell metabolism, while glucose deprivation had a greater effect on ovarian cancer stem cell metabolism. Core metabolites and pathways affected by these perturbations were identified, along with pathways that were unique to cell types or perturbations. The metabolic responses of an ovarian cancer cell line and its derived isogenic cancer stem cells differ greatly under most conditions, suggesting that these two cell types may behave quite differently in an in vivo tumor microenvironment. While cancer metabolism and cancer stem cells are each promising potential therapeutic targets, such varied behaviors in vivo would need to

  15. Responsiveness of a Brief Measure of Lung Cancer Screening Knowledge.

    PubMed

    Housten, Ashley J; Lowenstein, Lisa M; Leal, Viola B; Volk, Robert J

    2016-12-14

    Our aim was to examine the responsiveness of a lung cancer screening brief knowledge measure (LCS-12). Eligible participants were aged 55-80 years, current smokers or had quit within 15 years, and English speaking. They completed a baseline pretest survey, viewed a lung cancer screening video-based patient decision aid, and then filled out a follow-up posttest survey. We performed a paired samples t-test, calculated effect size, and calculated absolute and relative percent improvement for each item. Participants (n = 30) were primarily White (63%) with less than a college degree (63%), and half were female (50%). Mean age was 61.5 years (standard deviation [SD] = 4.67) and average smoking history was 30.4 pack-years (range = 4.6-90.0). Mean score on the 12-item measure increased from 47.3% correct on the pretest to 80.3% correct on the posttest (mean pretest score = 5.67 vs. mean posttest score = 9.63; mean score difference = 3.97, SD = 2.87, 95% CI = 2.90, 5.04). Total knowledge scores improved significantly and were responsive to the decision aid intervention (paired samples t-test = 7.57, p < .001; Cohen's effect size = 1.59; standard response mean [SRM] = 1.38). All individual items were responsive, yet two items had lower absolute responsiveness than the others (item 8: "Without screening, is lung cancer often found at a later stage when cure is less likely?" pretest correct = 83.3% vs. posttest = 96.7%, responsiveness = 13.4%; and item 10: "Can a CT scan find lung disease that is not cancer?" pretest correct = 80.0% vs. posttest = 93.3%, responsiveness = 13.3%). The LCS-12 knowledge measure may be a useful outcome measure of shared decision making for lung cancer screening.

  16. Autoimmune response to PARP and BRCA1/BRCA2 in cancer

    PubMed Central

    Zhu, Qing; Han, Su-Xia; Zhou, Cong-Ya; Cai, Meng-Jiao; Dai, Li-Ping; Zhang, Jian-Ying

    2015-01-01

    Purpose To determine the role of autoantibodies to PARP1 and BRCA1/BRCA2 which were involved in the synthetic lethal interaction in cancer. Methods Enzyme-Linked Immunosorbent Assay (ELISA) was used to detect autoantibodies to PARP1 and BRCA1/BRCA2 in 618 serum samples including 131 from breast cancer, 94 from lung cancer, 34 from ovarian cancer, 107 from prostate cancer, 76 from liver cancer, 41 from pancreatic cancer and 135 from normal individuals. The positive sera with ELISA were confirmed by Western blot. Immunohistochemistry was used to examine the expression of PARP1 and BRCA1/BRCA2 in breast cancer. Results Autoantibody frequency to PARP1, BRCA1, and BRCA2 in cancer varied from 0% to 50%. When the sera from cancer patients were tested for the presence of autoantibodies to PARP1 and BRCA1/BRCA2, the autoantibody responses slightly decreased and the positive autoantibody reactions varied from 0% to 50.0%. This was significantly higher autoantibody responses to PARP1 and BRCA1/BRCA2 (especially to PARP1 and BRCA1) in ovarian cancer and breast cancer compared to normal control sera (P < 0.001 and P < 0.01). Immunohistochemistry indicated that Pathology Grade at diagnosis to PARP1 expression in breast cancer was different (P < 0.05). Conclusions Different cancers have different profiles of autoantibodies. The autoantibodies to proteins involving the synthetic lethal interactions would be novel serological biomarker in some selective cancers. PMID:25865228

  17. Stimuli-responsive Smart Liposomes in Cancer Targeting.

    PubMed

    Jain, Ankit; Jain, Sanjay K

    2018-02-08

    Liposomes are vesicular carriers which possess aqueous core entrapped within the lipid bilayer. These are carriers of choice because of biocompatible and biodegradable features in addition to flexibility of surface modifications at surface and lipid compositions of lipid bilayers. Liposomes have been reported well for cancer treatment using both passive and active targeting approaches however tumor microenvironment is still the biggest hurdle for safe and effective delivery of anticancer agents. To overcome this problem, stimuli-responsive smart liposomes have emerged as promising cargoes pioneered to anomalous tumor milieu in response to pH, temperature, and enzymes etc. as internal triggers, and magnetic field, ultrasound, and redox potential as external guides for enhancement of drug delivery to tumors. This review focuses on all such stimuli-responsive approaches using fabrication potentiality of liposomes in combination to various ligands, linkers, and PEGylation etc. Scientists engaged in cancer targeting approaches can get benefited greatly with this knowledgeable assemblage of advances in liposomal nanovectors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Utilization of rapid response resources and outcomes in a comprehensive cancer center*.

    PubMed

    Austin, Charles A; Hanzaker, Chris; Stafford, Renae; Mayer, Celeste; Culp, Loc; Lin, Feng-Chang; Chang, Lydia

    2014-04-01

    To compare the differences in characteristics and outcomes of cancer center patients with other subspecialty medical patients reviewed by rapid response teams. A retrospective cohort study of hospitalized general medicine patients, subspecialty medicine patients, and oncology patients requiring rapid response team activation over a 2-year period from September 2009 to August 2011. Five hundred fifty-seven subspecialty medical patients required rapid response team intervention. A single academic medical center in the southeastern United States (800+ bed) with a dedicated 50-bed inpatient comprehensive cancer care center. Data abstraction from computerized medical records and a hospital quality improvement rapid response database. Of the 557 patients, 135 were cancer center patients. Cancer center patients had a significantly higher Charlson Comorbidity Score (4.4 vs 2.9, < 0.001). Cancer center patients had a significantly longer hospitalization period prior to rapid response team activation (11.4 vs 6.1 d, p < 0.001). There was no significant difference between proportions of patients requiring ICU transfer between the two groups (odds ratio, 1.2; 95% CI, 0.8-1.8). Cancer center patients had a significantly higher in-hospital mortality compared with the other subspecialty medical patients (33% vs 18%; odds ratio, 2.2; 95% CI, 1.50-3.5). If the rapid response team event required an ICU transfer, this finding was more pronounced (56% vs 23%; odds ratio, 4.0; 95% CI, 2.0-7.8). The utilization of rapid response team resources during the 2-year period studied was also much higher for the oncology patients with 37.34 activations per 1,000 patient discharges compared with 20.86 per 1,000 patient discharges for the general medical patients. Oncology patients requiring rapid response team activation have a significantly higher in-hospital mortality rate, particularly if the rapid response team requires ICU transfer. Oncology patients also utilize rapid response team

  19. Subtype and pathway specific responses to anticancer compounds in breast cancer.

    PubMed

    Heiser, Laura M; Sadanandam, Anguraj; Kuo, Wen-Lin; Benz, Stephen C; Goldstein, Theodore C; Ng, Sam; Gibb, William J; Wang, Nicholas J; Ziyad, Safiyyah; Tong, Frances; Bayani, Nora; Hu, Zhi; Billig, Jessica I; Dueregger, Andrea; Lewis, Sophia; Jakkula, Lakshmi; Korkola, James E; Durinck, Steffen; Pepin, François; Guan, Yinghui; Purdom, Elizabeth; Neuvial, Pierre; Bengtsson, Henrik; Wood, Kenneth W; Smith, Peter G; Vassilev, Lyubomir T; Hennessy, Bryan T; Greshock, Joel; Bachman, Kurtis E; Hardwicke, Mary Ann; Park, John W; Marton, Laurence J; Wolf, Denise M; Collisson, Eric A; Neve, Richard M; Mills, Gordon B; Speed, Terence P; Feiler, Heidi S; Wooster, Richard F; Haussler, David; Stuart, Joshua M; Gray, Joe W; Spellman, Paul T

    2012-02-21

    Breast cancers are comprised of molecularly distinct subtypes that may respond differently to pathway-targeted therapies now under development. Collections of breast cancer cell lines mirror many of the molecular subtypes and pathways found in tumors, suggesting that treatment of cell lines with candidate therapeutic compounds can guide identification of associations between molecular subtypes, pathways, and drug response. In a test of 77 therapeutic compounds, nearly all drugs showed differential responses across these cell lines, and approximately one third showed subtype-, pathway-, and/or genomic aberration-specific responses. These observations suggest mechanisms of response and resistance and may inform efforts to develop molecular assays that predict clinical response.

  20. Measuring response to a cancer information telephone facility: Can-Dial.

    PubMed Central

    Wilkinson, G S; Mirand, E A; Graham, S

    1976-01-01

    In an attempt to meet the need for increasing public knowledge about cancer, a system providing free information by telephone has been developed. The system is comprised of 36 pre-recorded taped lectures containing information about various aspects of cancer. Interested individuals call a toll-free number, indicate a topic of interest, and listen to the pre-recorded lecture over the phone. An operator handles incoming calls and obtains information from callers used in evaluating the program. During the first year of operation, over 30,000 calls were processed. Topics most frequently requested included those concerning smoking, breast and cervical cancer, and general information. Female response exceeded male response in all age categories. Older people responded less frequently than younger. Urban utilization greatly exceeded suburban and rural utilization. Considerable fluctuation in response related to promotional activities was found. Printed advertisements elicited far greater response than radio and television. Promotional efforts in an experimental group of low-utilizing townships greatly increased utilization while no change was observed in a control group. PMID:1267080

  1. Radiation, Inflammation, and Immune Responses in Cancer

    PubMed Central

    Multhoff, Gabriele; Radons, Jürgen

    2012-01-01

    Chronic inflammation has emerged as one of the hallmarks of cancer. Inflammation also plays a pivotal role in modulating radiation responsiveness of tumors. As discussed in this review, ionizing radiation (IR) leads to activation of several transcription factors modulating the expression of numerous mediators in tumor cells and cells of the microenvironment promoting cancer development. Novel therapeutic approaches thus aim to interfere with the activity or expression of these factors, either in single-agent or combinatorial treatment or as supplements of the existing therapeutic concepts. Among them, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. A great variety of classical or novel drugs including nutraceuticals such as plant phytochemicals have the capacity to interfere with the inflammatory network in cancer and are considered as putative radiosensitizers. Thus, targeting the inflammatory signaling pathways induced by IR offers the opportunity to improve the clinical outcome of radiation therapy by enhancing radiosensitivity and decreasing putative metabolic effects. Since inflammation and sex steroids also impact tumorigenesis, a therapeutic approach targeting glucocorticoid receptors and radiation-induced production of tumorigenic factors might be effective in sensitizing certain tumors to IR. PMID:22675673

  2. Durable remission of leptomeningeal metastases from hormone-responsive prostate cancer.

    PubMed

    Zhang, Meng; Mahta, Ali; Kim, Ryan Y; Akar, Serra; Kesari, Santosh

    2012-06-01

    Prostate cancer is rarely associated with leptomeningeal metastasis. An 87-year-old man with a history of prostate cancer presented with leptomeningeal metastasis. He received hormonal therapy with leuprolide. Subsequently, he achieved an impressive response, indicated by a constant fall in his PSA levels and by the stabilization of leptomeningeal disease and clinical improvement. Hormonal therapy may be effective in inducing remission in hormone-sensitive prostate cancer with leptomeningeal metastasis.

  3. State of the Art: Response Assessment in Lung Cancer in the Era of Genomic Medicine

    PubMed Central

    Hatabu, Hiroto; Johnson, Bruce E.; McLoud, Theresa C.

    2014-01-01

    Tumor response assessment has been a foundation for advances in cancer therapy. Recent discoveries of effective targeted therapy for specific genomic abnormalities in lung cancer and their clinical application have brought revolutionary advances in lung cancer therapy and transformed the oncologist’s approach to patients with lung cancer. Because imaging is a major method of response assessment in lung cancer both in clinical trials and practice, radiologists must understand the genomic alterations in lung cancer and the rapidly evolving therapeutic approaches to effectively communicate with oncology colleagues and maintain the key role in lung cancer care. This article describes the origin and importance of tumor response assessment, presents the recent genomic discoveries in lung cancer and therapies directed against these genomic changes, and describes how these discoveries affect the radiology community. The authors then summarize the conventional Response Evaluation Criteria in Solid Tumors and World Health Organization guidelines, which continue to be the major determinants of trial endpoints, and describe their limitations particularly in an era of genomic-based therapy. More advanced imaging techniques for lung cancer response assessment are presented, including computed tomography tumor volume and perfusion, dynamic contrast material–enhanced and diffusion-weighted magnetic resonance imaging, and positron emission tomography with fluorine 18 fluorodeoxyglucose and novel tracers. State-of-art knowledge of lung cancer biology, treatment, and imaging will help the radiology community to remain effective contributors to the personalized care of lung cancer patients. © RSNA, 2014 PMID:24661292

  4. Applications of Light-Responsive Systems for Cancer Theranostics.

    PubMed

    Chen, Hongzhong; Zhao, Yanli

    2018-06-27

    Achieving controlled and targeted delivery of chemotherapeutic drugs and other therapeutic agents to tumor sites is challenging. Among many stimulus strategies, light as a mode of action shows various advantages such as high spatiotemporal selectivity, minimal invasiveness and easy operation. Thus, drug delivery systems (DDSs) have been designed with the incorporation of various functionalities responsive to light as an exogenous stimulus. Early development has focused on guiding chemotherapeutic drugs to designated location, followed by the utilization of UV irradiation for controlled drug release. Because of the disadvantages of UV light such as phototoxicity and limited tissue penetration depth, scientists have moved the research focus onto developing nanoparticle systems responsive to light in the visible region (400-700 nm), aiming to reduce the phototoxicity. In order to enhance the tissue penetration depth, near-infrared light triggered DDSs become increasingly important. In addition, light-based advanced systems for fluorescent and photoacoustic imaging, as well as photodynamic and photothermal therapy have also been reported. Herein, we highlight some of recent developments by applying light-responsive systems in cancer theranostics, including light activated drug release, photodynamic and photothermal therapy, and bioimaging techniques such as fluorescent and photoacoustic imaging. Future prospect of light-mediated cancer treatment is discussed at the end of the review. This Spotlights on Applications article aims to provide up-to-date information about the rapidly developing field of light-based cancer theranostics.

  5. Peptide-targeted, stimuli-responsive polymersomes for delivering a cancer stemness inhibitor to cancer stem cell microtumors.

    PubMed

    Karandish, Fataneh; Froberg, James; Borowicz, Pawel; Wilkinson, John C; Choi, Yongki; Mallik, Sanku

    2018-03-01

    Often cancer relapses after an initial response to chemotherapy because of the tumor's heterogeneity and the presence of progenitor stem cells, which can renew. To overcome drug resistance, metastasis, and relapse in cancer, a promising approach is the inhibition of cancer stemness. In this study, the expression of the neuropilin-1 receptor in both pancreatic and prostate cancer stem cells was identified and targeted with a stimuli-responsive, polymeric nanocarrier to deliver a stemness inhibitor (napabucasin) to cancer stem cells. Reduction-sensitive amphiphilic block copolymers PEG 1900 -S-S-PLA 6000 and the N 3 -PEG 1900 -PLA 6000 were synthesized. The tumor penetrating iRGD peptide-hexynoic acid conjugate was linked to the N 3 -PEG 1900 -PLA 6000 polymer via a Cu 2+ catalyzed "Click" reaction. Subsequently, this peptide-polymer conjugate was incorporated into polymersomes for tumor targeting and tissue penetration. We prepared polymersomes containing 85% PEG 1900 -S-S-PLA 6000 , 10% iRGD-polymer conjugate, and 5% DPPE-lissamine rhodamine dye. The iRGD targeted polymersomes encapsulating the cancer stemness inhibitor napabucasin were internalized in both prostate and pancreatic cancer stem cells. The napabucasin encapsulated polymersomes significantly (p < .05) reduced the viability of both prostate and pancreatic cancer stem cells and decreased the stemness protein expression notch-1 and nanog compared to the control and vesicles without any drug. The napabucasin encapsulated polymersome formulations have the potential to lead to a new direction in prostate and pancreatic cancer therapy by penetrating deeply into the tumors, releasing the encapsulated stemness inhibitor, and killing cancer stem cells. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Antibody Responses to Prostate-Associated Antigens in Patients with Prostatitis and Prostate Cancer

    PubMed Central

    Maricque, Brett B.; Eickhoff, Jens C.; McNeel, Douglas G.

    2010-01-01

    Background An important focus of tumor immunotherapy has been the identification of appropriate antigenic targets. Serum-based screening approaches have led to the discovery of hundreds of tumor-associated antigens recognized by IgG. Our efforts to identify immunologically recognized proteins in prostate cancer have yielded a multitude of antigens, however prioritizing these antigens as targets for evaluation in immunotherapies has been challenging. In this report, we set out to determine whether the evaluation of multiple antigenic targets would allow the identification of a subset of antigens that are common immunologic targets in patients with prostate cancer. Methods Using a phage immunoblot approach, we evaluated IgG responses in patients with prostate cancer (n=126), patients with chronic prostatitis (n=45), and men without prostate disease (n=53). Results We found that patients with prostate cancer or prostatitis have IgG specific for multiple common antigens. A subset of 23 proteins was identified to which IgG were detected in 38% of patients with prostate cancer and 33% patients with prostatitis versus 6% of controls (p<0.001 and p=0.003, respectively). Responses to multiple members were not higher in patients with advanced disease, suggesting antibody immune responses occur early in the natural history of cancer progression. Conclusions These findings suggest an association between inflammatory conditions of the prostate and prostate cancer, and suggest that IgG responses to a panel of commonly recognized prostate antigens could be potentially used in the identification of patients at risk for prostate cancer or as a tool to identify immune responses elicited to prostate tissue. PMID:20632317

  7. Immune Response Augmentation in Metastasized Breast Cancer by Localized Therapy Utilizing Biocompatible Magnetic Fluids

    DTIC Science & Technology

    2008-08-01

    SUBJECT TERMS Cancer therapy by localized immune response, Magneto -rehological Fluids 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT...Metastasized Breast Cancer by Localized Therapy utilizing Biocompatible Magnetic Fluids PRINCIPAL INVESTIGATOR: Cahit Evrensel...2008 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Immune Response Augmentation in Metastasized Breast Cancer by Localized Therapy utilizing

  8. Reirradiation on recurrent cervical cancer case: Treatment response and side effects

    NASA Astrophysics Data System (ADS)

    Siregar, M. F.; Supriana, N.; Nuranna, L.; Prihartono, J.

    2017-08-01

    Management of recurrent cervical cancer by reirradiation after radiation treatment remains controversial. In Indonesia, there is currently no data about reirradiation tumor response and side effects. This study aims to assess the tumor response to and side effects of reirradiation, the effect of time interval between first radiation treatment and cancer recurrence on the tumor response and side effects, and the effect of tumor size on tumor response. A cohort retrospective study with no comparison was done with the Radiotherapy Department at Cipto Mangunkusumo General Hospital, Jakarta. Participants were recurrent cervical cancer patients undergoing reirradiation. Data was collected from patients’ medical records and follow-up phone calls. Twenty-two patients participated in this study. Nine patients (40.9%) had complete responses, 10 patients (45.5%) had partial responses, 1 patient (4.5%) had a stable response, and 2 patients (9.1%) had tumor progressions. In general, 15 patients (68.2%) had no to light side effects (grade 0-2 RTOG) and 7 patients (31.8%) had severe side effects (grade 3-4 RTOG). Four patients (18.1%) had severe gastrointestinal acute side effects, 6 patients (27.3%) had severe gastrointestinal late side effects, 2 patients (9.1%) had severe urogenital side effects, and there were no patients had severe urogenital late side effects. There was no significant difference in tumor response between patients with time interval between first radiation treatment and recurrence of <12 months vs. ≥12 months. There was no significant difference in tumor response between patients with tumor size ≤4 cm vs. >4 cm. Reirradiation can be considered as a modality in recurrent cervical cancer management since good tumor response was achieved and the majority of patients had no to light side effects (grade 0-2 RTOG). This study found no correlation between tumor response, side effects, and time gap between first radiation treatment and recurrence of <12 months

  9. Employee response to a company-sponsored program of colorectal and prostate cancer screening.

    PubMed

    Myers, R E; Vernon, S W; Carpenter, A V; Balshem, A M; Lewis, P G; Wolf, T A; Hilbert, J; DeFonso, L R; Ross, E A

    1997-01-01

    Studies done in the mid-1970s documented increased risk for respiratory cancer and leukemia among employees in a chemical company manufacturing plant where chloromethyl ethers were used in production from 1948 to 1971. In the late 1980s, the company informed current and former employees about the results of follow-up studies which showed a moderation of risk of respiratory cancer and leukemia. New data showing elevated rates of mortality from colorectal, prostate, bladder, and pancreatic cancer in the population were also reported. Via mailed correspondence, the company made a no-cost program of colorectal and prostate cancer screening available to employees upon request; and information about bladder and pancreatic cancer was made available. Thirteen percent of employees in the population indicated interest in colorectal and prostate cancer screening (response). Thirty-one percent of these responders were screened (adherence). Multivariate analyses showed that education and length of employment in the plant were positively associated with response. Being white was positively associated with response for younger workers; while among older workers being male was positively associated with response. In terms of adherence, we found that older, more highly educated workers were more likely to have a screening examination. Findings indicate that employee participation in workplace-sponsored colorectal and prostate cancer screening can vary according to worker sociodemographic factors and length of employment in areas of potential exposure.

  10. Monoclonal antibody to a cancer-specific and drug-responsive hydroquinone (NADH) oxidase from the sera of cancer patients

    NASA Technical Reports Server (NTRS)

    Cho, NaMi; Chueh, Pin-Ju; Kim, Chinpal; Caldwell, Sara; Morre, Dorothy M.; Morre, D. James

    2002-01-01

    Monoclonal antibodies were generated in mice to a 34-kDa circulating form of a drug-responsive hydroquinone (NADH) oxidase with a protein disulfide-thiol interchange activity specific to the surface of cancer cells and the sera of cancer patients. Screening used Western blots with purified 34-kDa tNOX from HeLa cells and the sera of cancer patients. Epitopes were sought that inhibited the drug-responsive oxidation of NADH with the sera of cancer patients, but which had no effect on NADH oxidation with the sera of healthy volunteers. Two such antisera were generated. One, designated monoclonal antibody (mAb) 12.1, was characterized extensively. The NADH oxidase activity inhibited by mAb 12.1 also was inhibited by the quinone site inhibitor capsaicin (8-methyl- N-vanillyl-6-noneamide). The inhibition was competitive for the drug-responsive protein disulfide-thiol interchange activity assayed either by restoration of activity to scrambled RNase or by cleavage of a dithiodipyridine substrate, and was uncompetitive for NADH oxidation. Both the mAb 12.1 and the postimmune antisera immunoprecipitated drug-responsive NOX activity and identified the same 34-kDa tNOX protein in the sera of cancer patients that was absent from sera of healthy volunteers, and was utilized as immunogen. Preimmune sera from the same mouse as the postimmune antisera was without effect. Both mouse ascites containing mAb 12.1 and postimmune sera (but not preimmune sera) slowed the growth of human cancer cell lines in culture, but did not affect the growth of non-cancerous cell lines. Immunocytochemical and histochemical findings showed that mAb 12.1 reacted with the surface membranes of human carcinoma cells and tissues.

  11. The Glasgow Prognostic Score Predicts Response to Chemotherapy in Patients with Metastatic Breast Cancer.

    PubMed

    Wang, Dexing; Duan, Li; Tu, Zhiquan; Yan, Fei; Zhang, Cuicui; Li, Xu; Cao, Yuzhu; Wen, Hongsheng

    2016-01-01

    Breast cancer is one of the most common causes of cancer death in women worldwide. The Glasgow Prognostic Score (GPS), a cumulative prognostic score based on C-reactive protein and albumin, indicates the presence of a systemic inflammatory response. The GPS has been adopted as a powerful prognostic tool for patients with various types of malignant tumors, including breast cancer. The aim of this study was to assess the value of the GPS in predicting the response and toxicity in breast cancer patients treated with chemotherapy. Patients with metastatic breast cancers in a progressive stage for consideration of chemotherapy were eligible. The clinical characteristics and demographics were recorded. The GPS was calculated before the onset of chemotherapy. Data on the response to chemotherapy and progression-free survival (PFS) were also collected. Objective tumor responses were evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST). Toxicities were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC) version 3.0 throughout therapy. In total, 106 breast cancer patients were recruited. The GPS was associated with the response rate (p = 0.05), the clinical benefit rate (p = 0.03), and PFS (p = 0.005). The GPS was the only independent predictor of PFS (p = 0.005). The GPS was significantly associated with neutropenia, thrombocytopenia, anorexia, nausea and vomiting, fatigue, and mucositis (p = 0.05-0.001). Our data demonstrate that GPS assessment is associated with poor clinical outcomes and severe chemotherapy-related toxicities in patients with metastatic breast cancer who have undergone chemotherapy, without any specific indication regarding the type of chemotherapy applied. © 2016 S. Karger AG, Basel.

  12. The Replication Stress Response in Pancreatic Cancer

    DTIC Science & Technology

    2013-10-01

    network that recognizes challenges to DNA replication and mobilizes diverse activities to maintain genome integrity. The RSR is critical for the...pancreatic cancer cells. We further validated positive hits be deconvolution of individual siRNAs and began work on determining their activities in DNA replication and DNA damage responses.

  13. Recombinant Peptides as Biomarkers for Metastatic Breast Cancer Response

    DTIC Science & Technology

    2007-10-01

    could be specific to breast cancer tumor models has just been concluded. In vivo biopanning wsa conducted with a T7 phage -based random peptide library...peptides selected from phage -displayed libraries. 15. SUBJECT TERMS Breast cancer, phage display, molecular imaging, personalized medicine 16...recombinant peptides from phage -displayed peptide libraries can be selected that bind to receptors activated in response to therapy. These peptides in turn

  14. p53 in breast cancer subtypes and new insights into response to chemotherapy.

    PubMed

    Bertheau, Philippe; Lehmann-Che, Jacqueline; Varna, Mariana; Dumay, Anne; Poirot, Brigitte; Porcher, Raphaël; Turpin, Elisabeth; Plassa, Louis-François; de Roquancourt, Anne; Bourstyn, Edwige; de Cremoux, Patricia; Janin, Anne; Giacchetti, Sylvie; Espié, Marc; de Thé, Hugues

    2013-08-01

    Despite an obvious central role of p53 in the hallmarks of cancer, TP53 status is not yet used for the management of breast cancer. Recent findings may lead to reconsider the role of p53 in breast cancer. TP53 mutations are the most frequent genetic alterations in breast cancer, observed in 30% of breast carcinomas. Their distribution is highly linked to molecular tumor subtypes found in 26% of luminal tumors (17% of luminal A, 41% of luminal B), in 50% of HER2 amplified tumors, in 69% of molecular apocrine breast carcinomas and in 88% of basal-like carcinomas. The type of mutation is linked to the tumor subtype with higher frequency of base-pair substitutions in luminal tumors, whereas molecular apocrine and basal-like tumors present much higher frequency of complex mutations (deletions/insertions). The timing of TP53 mutation also depends on the tumor subtype, being the first important event in luminal tumors but occurring after PTEN loss in basal-like tumors. Regarding response to cytotoxic chemotherapy, the situation is far from the p53-dependent apoptosis paradigm with subsequent clinical response. We reported that TP53 mutated non inflammatory locally advanced breast carcinomas had a high rate of complete pathological response to dose-dense doxorubicin-cyclophosphamide chemotherapy, while TP53 wild-type (WT) tumors never achieved complete response. Using human breast cancer xenograft models, we suggested that this could be due to the induction of senescence in TP53 WT tumor cells. A recent work confirmed these findings in MMTV-Wnt1 mammary tumors, showing that growth arrest and senescent phenotype, not apoptosis, were induced in TP53 WT tumors following doxorubicin treatment, while lack of arrest in mutant tumors resulted in aberrant mitoses, cell death and a superior clinical response. Furthermore, in ER positive (ER(+)) breast tumors, it has been recently reported that ER represses the p53-mediated apoptotic response induced by DNA damage. Taken together

  15. DNA Damage Response Genes and the Development of Cancer Metastasis

    PubMed Central

    Broustas, Constantinos G.; Lieberman, Howard B.

    2014-01-01

    DNA damage response genes play vital roles in the maintenance of a healthy genome. Defects in cell cycle checkpoint and DNA repair genes, especially mutation or aberrant downregulation, are associated with a wide spectrum of human disease, including a predisposition to the development of neurodegenerative conditions and cancer. On the other hand, upregulation of DNA damage response and repair genes can also cause cancer, as well as increase resistance of cancer cells to DNA damaging therapy. In recent years, it has become evident that many of the genes involved in DNA damage repair have additional roles in tumorigenesis, most prominently by acting as transcriptional (co-) factors. Although defects in these genes are causally connected to tumor initiation, their role in tumor progression is more controversial and it seems to depend on tumor type. In some tumors like melanoma, cell cycle checkpoint/DNA repair gene upregulation is associated with tumor metastasis, whereas in a number of other cancers the opposite has been observed. Several genes that participate in the DNA damage response, such as RAD9, PARP1, BRCA1, ATM and TP53 have been associated with metastasis by a number of in vitro biochemical and cellular assays, by examining human tumor specimens by immunohistochemistry or by DNA genomewide gene expression profiling. Many of these genes act as transcriptional effectors to regulate other genes implicated in the pathogenesis of cancer. Furthermore, they are aberrantly expressed in numerous human tumors and are causally related to tumorigenesis. However, whether the DNA damage repair function of these genes is required to promote metastasis or another activity is responsible (e.g., transcription control) has not been determined. Importantly, despite some compelling in vitro evidence, investigations are still needed to demonstrate the role of cell cycle checkpoint and DNA repair genes in regulating metastatic phenotypes in vivo. PMID:24397478

  16. Prediction of chemo-response in serous ovarian cancer.

    PubMed

    Gonzalez Bosquet, Jesus; Newtson, Andreea M; Chung, Rebecca K; Thiel, Kristina W; Ginader, Timothy; Goodheart, Michael J; Leslie, Kimberly K; Smith, Brian J

    2016-10-19

    Nearly one-third of serous ovarian cancer (OVCA) patients will not respond to initial treatment with surgery and chemotherapy and die within one year of diagnosis. If patients who are unlikely to respond to current standard therapy can be identified up front, enhanced tumor analyses and treatment regimens could potentially be offered. Using the Cancer Genome Atlas (TCGA) serous OVCA database, we previously identified a robust molecular signature of 422-genes associated with chemo-response. Our objective was to test whether this signature is an accurate and sensitive predictor of chemo-response in serous OVCA. We first constructed prediction models to predict chemo-response using our previously described 422-gene signature that was associated with response to treatment in serous OVCA. Performance of all prediction models were measured with area under the curves (AUCs, a measure of the model's accuracy) and their respective confidence intervals (CIs). To optimize the prediction process, we determined which elements of the signature most contributed to chemo-response prediction. All prediction models were replicated and validated using six publicly available independent gene expression datasets. The 422-gene signature prediction models predicted chemo-response with AUCs of ~70 %. Optimization of prediction models identified the 34 most important genes in chemo-response prediction. These 34-gene models had improved performance, with AUCs approaching 80 %. Both 422-gene and 34-gene prediction models were replicated and validated in six independent datasets. These prediction models serve as the foundation for the future development and implementation of a diagnostic tool to predict response to chemotherapy for serous OVCA patients.

  17. Differential pathway dependency discovery associated with drug response across cancer cell lines* | Office of Cancer Genomics

    Cancer.gov

    The effort to personalize treatment plans for cancer patients involves the identification of drug treatments that can effectively target the disease while minimizing the likelihood of adverse reactions. In this study, the gene-expression profile of 810 cancer cell lines and their response data to 368 small molecules from the Cancer Therapeutics Research Portal (CTRP) are analyzed to identify pathways with significant rewiring between genes, or differential gene dependency, between sensitive and non-sensitive cell lines.

  18. In vivo investigation of hybrid Paclitaxel nanocrystals with dual fluorescent probes for cancer theranostics.

    PubMed

    Hollis, Christin P; Weiss, Heidi L; Evers, B Mark; Gemeinhart, Richard A; Li, Tonglei

    2014-06-01

    To develop novel hybrid paclitaxel (PTX) nanocrystals, in which bioactivatable (MMPSense® 750 FAST) and near infrared (Flamma Fluor® FPR-648) fluorophores are physically incorporated, and to evaluate their anticancer efficacy and diagnostic properties in breast cancer xenograft murine model. The pure and hybrid paclitaxel nanocrystals were prepared by an anti-solvent method, and their physical properties were characterized. The tumor volume change and body weight change were evaluated to assess the treatment efficacy and toxicity. Bioimaging of treated mice was obtained non-invasively in vivo. The released MMPSense molecules from the hybrid nanocrystals were activated by matrix metalloproteinases (MMPs) in vivo, similarly to the free MMPSense, demonstrating its ability to monitor cancer progression. Concurrently, the entrapped FPR-648 was imaged at a different wavelength. Furthermore, when administered at 20 mg/kg, the nanocrystal formulations exerted comparable efficacy as Taxol®, but with decreased toxicity. Hybrid nanocrystals that physically integrated two fluorophores were successfully prepared from solution. Hybrid nanocrystals were shown not only exerting antitumor activity, but also demonstrating the potential of multi-modular bioimaging for diagnostics.

  19. Production of taxadiene by engineering of mevalonate pathway in Escherichia coli and endophytic fungus Alternaria alternata TPF6.

    PubMed

    Bian, Guangkai; Yuan, Yujie; Tao, Hui; Shi, Xiaofei; Zhong, Xiaofang; Han, Yichao; Fu, Shuai; Fang, Chengxiang; Deng, Zixin; Liu, Tiangang

    2017-04-01

    Taxol (paclitaxel) is a diterpenoid compound with significant and extensive applications in the treatment of cancer. The production of Taxol and relevant intermediates by engineered microbes is an attractive alternative to the semichemical synthesis of Taxol. In this study, based on a previously developed platform, the authors first established taxadiene production in mutant E. coli T2 and T4 by engineering of the mevalonate (MVA) pathway. The authors then developed an Agrobacterium tumefaciens-mediated transformation (ATMT) method and verified the strength of heterologous promoters in Alternaria alternata TPF6. The authors next transformed the taxadiene-producing platform into A. alternata TPF6, and the MVA pathway was engineered, with introduction of the plant taxadiene-forming gene. Notably, by co-overexpression of isopentenyl diphosphate isomerase (Idi), a truncated version of 3-hydroxy-3-methylglutaryl-CoA reductase (tHMG1), and taxadiene synthase (TS), the authors could detect 61.9 ± 6.3 μg/L taxadiene in the engineered strain GB127. This is the first demonstration of taxadiene production in filamentous fungi, and the approach presented in this study provides a new method for microbial production of Taxol. The well-established ATMT method and the known promoter strengths facilitated further engineering of taxaenes in this fungus. Copyright © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. The microtubule cytoskeleton does not integrate auxin transport and gravitropism in maize roots

    NASA Technical Reports Server (NTRS)

    Hasenstein, K. H.; Blancaflor, E. B.; Lee, J. S.

    1999-01-01

    The Cholodny-Went hypothesis of gravitropism suggests that the graviresponse is controlled by the distribution of auxin. However, the mechanism of auxin transport during the graviresponse of roots is still unresolved. To determine whether the microtubule (MT) cytoskeleton is participating in auxin transport, the cytoskeleton was examined and the movement of 3H-IAA measured in intact and excised taxol, oryzalin, and naphthylphthalamic acid (NPA)-treated roots of Zea mays cv. Merit. Taxol and oryzalin did not inhibit the graviresponse of roots but the auxin transport inhibitor NPA greatly inhibited both auxin transport and graviresponse. NPA had no effect on MT organization in vertical roots, but caused MT reorientation in horizontally placed roots. Regardless of treatment, the organization of MTs in intact roots differed from that in root segments. The MT inhibitors, taxol and oryzalin had opposite effects on the MTs, namely, depolymerization (oryzalin) and stabilization and thickening (taxol), but both treatments caused swelling of the roots. The data indicate that the MT cytoskeleton does not directly interfere with auxin transport or auxin-mediated growth responses in maize roots.

  1. Noninvasive Subharmonic Pressure Estimation for Monitoring Breast Cancer Response to Neoadjuvant Therapy

    DTIC Science & Technology

    2011-09-01

    predict disease free survival for cervix cancer (34% disease free survival (DFS) if IFP > 19 mmHg, 68% DFS if IFP < 19 mmHg (p = 0.002)) [11]. Thus, the...pressure predicts survival in patients with cervix cancer independent of clinical prognostic factors and tumor oxygen measurements. Cancer Res...Estimation for Monitoring Breast Cancer Response to Neoadjuvant Therapy PRINCIPAL INVESTIGATOR: Flemming Forsberg, Ph.D

  2. Cytokinetic study of MCF-7 cells treated with commercial and recombinant bromelain.

    PubMed

    Fouz, Nour; Amid, Azura; Hashim, Yumi Zuhanis Has-Yun

    2014-01-01

    Breast cancer is a leading cause of death in women. The available chemotherapy drugs have been associated with many side effects. Bromelain has novel medicinal qualities including anti-inflammatory, anti-thrombotic, fibrinolytic and anti-cancer functions. Commercially available bromelain is obtained through tedious methods; therefore, recombinant bromelain may provide a cheaper and simpler choice with similar quality. This study aimed to assess the effects of commercial and recombinant bromelain on the cytokinetic behavior of MCF-7 breast cancer cells and their potential as therapeutic alternatives in cancer treatment. Cytotoxic activities of commercial and recombinant bromelain were determined using (sulforhodamine) SRB assay. Next, cell viability assays were conducted to determine effects of commercial and recombinant bromelain on MCF-7 cell cytokinetic behavior. Finally, the established growth kinetic data were used to modify a model that predicts the effects of commercial and recombinant bromelain on MCF-7 cells. Commercial and recombinant bromelain exerted strong effects towards decreasing the cell viability of MCF-7 cells with IC50 values of 5.13 μg/mL and 6.25 μg/mL, respectively, compared to taxol with an IC50 value of 0.063 μg/mL. The present results indicate that commercial and recombinant bromelain both have anti-proliferative activity, reduced the number of cell generations from 3.92 to 2.81 for commercial bromelain and to 2.86 for recombinant bromelain, while with taxol reduction was to 3.12. Microscopic observation of bromelain-treated MCF-7 cells demonstrated detachment. Inhibition activity was verified with growth rates decreased dynamically from 0.009 h-1 to 0.0059 h-1 for commercial bromelain and to 0.0063 h-1 for recombinant bromelain. Commercial and recombinant bromelain both affect cytokinetics of MCF-7 cells by decreasing cell viability, demonstrating similar strength to taxol.

  3. Inulin based glutathione-responsive delivery system for colon cancer treatment.

    PubMed

    Wang, Dongdong; Sun, Feifei; Lu, Chunbo; Chen, Peng; Wang, Zhaojie; Qiu, Yuanhao; Mu, Haibo; Miao, Zehong; Duan, Jinyou

    2018-05-01

    Colorectal cancer is one of the most common types of tumor in the world. Here we developed a lipoic acid esterified polysaccharide (inulin) delivery system for tanshinone IIA to treat colorectal cancer in vitro. The release of tanshinone IIA in the system was highly responsive to glutathione, which is commonly abundant in cancer cells. In addition, this drug delivery system was proliferative to Bifidobacterium longum, the common inhabitant of human intestine. Thus, this strategy might be useful to improve colon cancer therapy efficacy of anticancer drugs and meanwhile promote the growth of beneficial commensal flora in the gut. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. Responses to fertility treatment among patients with cancer: a retrospective cohort study.

    PubMed

    Dolinko, A V; Farland, L V; Missmer, S A; Srouji, S S; Racowsky, C; Ginsburg, E S

    2018-01-01

    Cancer treatments have significant negative impacts on female fertility, but the impact of cancer itself on fertility remains to be clarified. While some studies have shown that compared with healthy women, those with cancer require higher doses of gonadotropins resulting in decreased oocyte yields, others have shown comparable oocyte yields between the two groups. The purpose of this study is to evaluate whether there is an association between any cancer and/or type of cancer, and response to ovarian stimulation for egg and embryo banking. In this retrospective cohort study, ovarian stimulation cycles performed from June 2007 through October 2014 at a single academic medical center were reviewed to identify those undertaken for women with cancer undergoing fertility preservation ( n  = 147) or women with no cancer undergoing their first cycle due to male factor infertility ( n  = 664). Of the 147 women undergoing fertility preservation, 105 had local cancer (Stage I-III solid malignancies) and 42 had systemic cancer (hematologic or Stage IV solid malignancies). Response to ovarian stimulation was compared among these two groups and women with no cancer. Adjusting for age and BMI, women with systemic cancer had lower baseline antral follicle counts (AFC) than women with no cancer or local cancer. Women with systemic cancer required higher doses of FSH than women with no cancer or local cancer, and they had higher oocyte to AFC ratios than women with no cancer or local cancer, but greater odds of cycle cancellation as compared to women with no cancer or local cancer. No significant differences were observed among the three groups for duration of stimulation, number of oocytes and mature oocytes retrieved, or number of embryos created. Women with cancer achieve similar oocyte and embryo yields as women with no cancer, although those with systemic cancer require higher FSH doses and are at greater risk of cycle cancellation.

  5. Ganoderma tsugae Extract Inhibits Growth of HER2-Overexpressing Cancer Cells via Modulation of HER2/PI3K/Akt Signaling Pathway

    PubMed Central

    Kuo, Han-Peng; Hsu, Shih-Chung; Li, Jhy-Wei; Tseng, Hsiu-Hsueh; Chuang, Tzu-Chao; Liu, Jah-Yao; Chen, Shih-Jung; Su, Muh-Hwan; Cheng, Yung-Chi; Chou, Wei-Yuan; Kao, Ming-Ching

    2013-01-01

    Ganoderma, also known as Lingzhi or Reishi, has been used for medicinal purposes in Asian countries for centuries. It is a medicinal fungus with a variety of biological properties including immunomodulatory and antitumor activities. In this study, we investigated the molecular mechanisms by which Ganoderma tsugae (GT), one of the most common species of Ganoderma, inhibits the proliferation of HER2-overexpressing cancer cells. Here, we show that a quality assured extract of GT (GTE) inhibited the growth of HER2-overexpressing cancer cells in vitro and in vivo and enhanced the growth-inhibitory effect of antitumor drugs (e.g., taxol and cisplatin) in these cells. We also demonstrate that GTE induced cell cycle arrest by interfering with the HER2/PI3K/Akt signaling pathway. Furthermore, GTE curtailed the expression of the HER2 protein by modulating the transcriptional activity of the HER2 gene and the stability/degradation of the HER2 protein. In conclusion, this study suggests that GTE may be a useful adjuvant therapeutic agent in the treatment of cancer cells that highly express HER2. PMID:23662119

  6. 4-Nitroquinoline-1-oxide effects human lung adenocarcinoma A549 cells by regulating the expression of POLD4

    PubMed Central

    HUANG, QIN-MIAO; ZENG, YI-MING; ZHANG, HUA-PING; LV, LIANG-CHAO; YANG, DONG-YONG; LIN, HUI-HUANG

    2016-01-01

    The aim of the present study was to explore the expression of POLD4 in human lung adenocarcinoma A549 cells under 4-nitroquinoline-1-oxide (4NQO) stimulation to investigate the role of POLD4 in smoking-induced lung cancer. The lung cancer A549 cell line was treated with 4NQO, with or without MG132 (an inhibitor of proteasome activity), and subsequently the POLD4 level was determined by western blot analysis. Secondly, the cell sensitivity to 4NQO and Taxol was determined when the POLD4 expression level was downregulated by siRNA. The POLD4 protein levels in the A549 cells decreased following treatment with 4NQO; however, MG132 could reverse this phenotype. Downregulation of the POLD4 expression by siRNA enhanced A549 cell sensitivity to 4NQO, but not to Taxol. In conclusion, 4NQO affects human lung adenocarcinoma A549 cells by regulating the expression of POLD4. PMID:26998273

  7. Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer.

    PubMed

    Dayde, Delphine; Tanaka, Ichidai; Jain, Rekha; Tai, Mei Chee; Taguchi, Ayumu

    2017-03-07

    The standard of care in locally advanced rectal cancer is neoadjuvant chemoradiation (nCRT) followed by radical surgery. Response to nCRT varies among patients and pathological complete response is associated with better outcome. However, there is a lack of effective methods to select rectal cancer patients who would or would not have a benefit from nCRT. The utility of clinicopathological and radiological features are limited due to lack of adequate sensitivity and specificity. Molecular biomarkers have the potential to predict response to nCRT at an early time point, but none have currently reached the clinic. Integration of diverse types of biomarkers including clinicopathological and imaging features, identification of mechanistic link to tumor biology, and rigorous validation using samples which represent disease heterogeneity, will allow to develop a sensitive and cost-effective molecular biomarker panel for precision medicine in rectal cancer. Here, we aim to review the recent advance in tissue- and blood-based molecular biomarker research and illustrate their potential in predicting nCRT response in rectal cancer.

  8. DNA Mismatch Repair Deficiency in Rectal Cancer: Benchmarking Its Impact on Prognosis, Neoadjuvant Response Prediction, and Clinical Cancer Genetics.

    PubMed

    de Rosa, Nicole; Rodriguez-Bigas, Miguel A; Chang, George J; Veerapong, Jula; Borras, Ester; Krishnan, Sunil; Bednarski, Brian; Messick, Craig A; Skibber, John M; Feig, Barry W; Lynch, Patrick M; Vilar, Eduardo; You, Y Nancy

    2016-09-01

    DNA mismatch repair deficiency (dMMR) hallmarks consensus molecular subtype 1 of colorectal cancer. It is being routinely tested, but little is known about dMMR rectal cancers. The efficacy of novel treatment strategies cannot be established without benchmarking the outcomes of dMMR rectal cancer with current therapy. We aimed to delineate the impact of dMMR on prognosis, the predicted response to fluoropyrimidine-based neoadjuvant therapy, and implications of germline alterations in the MMR genes in rectal cancer. Between 1992 and 2012, 62 patients with dMMR rectal cancers underwent multimodality therapy. Oncologic treatment and outcomes as well as clinical genetics work-up were examined. Overall and rectal cancer-specific survival were calculated by the Kaplan-Meier method. The median age at diagnosis was 41 years. MMR deficiency was most commonly due to alterations in MSH2 (53%) or MSH6 (23%). After a median follow-up of 6.8 years, the 5-year rectal cancer-specific survival was 100% for stage I and II, 85.1% for stage III, and 60.0% for stage IV disease. Fluoropyrimidine-based neoadjuvant chemoradiation was associated with a complete pathologic response rate of 27.6%. The extent of surgical resection was influenced by synchronous colonic disease at presentation, tumor height, clinical stage, and pelvic radiation. An informed decision for a limited resection focusing on proctectomy did not compromise overall survival. Five of the 11 (45.5%) deaths during follow-up were due to extracolorectal malignancies. dMMR rectal cancer had excellent prognosis and pathologic response with current multimodality therapy including an individualized surgical treatment plan. Identification of a dMMR rectal cancer should trigger germline testing, followed by lifelong surveillance for both colorectal and extracolorectal malignancies. We herein provide genotype-specific outcome benchmarks for comparison with novel interventions. © 2016 by American Society of Clinical Oncology.

  9. Personal responsibility, regret, and medical stigma among individuals living with lung cancer.

    PubMed

    Criswell, Kevin R; Owen, Jason E; Thornton, Andrea A; Stanton, Annette L

    2016-04-01

    Understanding the degree to which adults with lung cancer perceive personal responsibility for their disease, personal regret for actions that may have contributed to lung cancer, and potential stigmatization from others is important, because these perceptions and experiences may be linked with treatment nonadherence, feelings of isolation, avoidance of healthcare providers, and poor quality of life. The purpose of this study was to evaluate rates and intensity of these types of experiences and to characterize the extent to which they are linked with smoking status and psychological adjustment in those living with lung cancer. Adults with lung cancer (N = 213) were recruited from two major cancer centers to complete a mail survey. Perceived responsibility was frequent in those who had ever smoked (74-80%), whereas regret and feelings of stigmatization were less frequent. When present, however, personal regret and stigmatization were associated with adverse psychological outcomes, particularly for never smokers. These results are consistent with the theory of stereotype threat and have clinical implications for management of people with lung cancer.

  10. Discovering novel pharmacogenomic biomarkers by imputing drug response in cancer patients from large genomics studies.

    PubMed

    Geeleher, Paul; Zhang, Zhenyu; Wang, Fan; Gruener, Robert F; Nath, Aritro; Morrison, Gladys; Bhutra, Steven; Grossman, Robert L; Huang, R Stephanie

    2017-10-01

    Obtaining accurate drug response data in large cohorts of cancer patients is very challenging; thus, most cancer pharmacogenomics discovery is conducted in preclinical studies, typically using cell lines and mouse models. However, these platforms suffer from serious limitations, including small sample sizes. Here, we have developed a novel computational method that allows us to impute drug response in very large clinical cancer genomics data sets, such as The Cancer Genome Atlas (TCGA). The approach works by creating statistical models relating gene expression to drug response in large panels of cancer cell lines and applying these models to tumor gene expression data in the clinical data sets (e.g., TCGA). This yields an imputed drug response for every drug in each patient. These imputed drug response data are then associated with somatic genetic variants measured in the clinical cohort, such as copy number changes or mutations in protein coding genes. These analyses recapitulated drug associations for known clinically actionable somatic genetic alterations and identified new predictive biomarkers for existing drugs. © 2017 Geeleher et al.; Published by Cold Spring Harbor Laboratory Press.

  11. Therapeutic cure against human tumor xenografts in nude mice by a microtubule stabilization agent, fludelone, via parenteral or oral route.

    PubMed

    Chou, Ting-Chao; Dong, Huajin; Zhang, Xiuguo; Tong, William P; Danishefsky, Samuel J

    2005-10-15

    Epothilones, 16-membered macrolides isolated from a myxobacterium in soil, exert their antitumor effect, like Taxol, by induction of microtubule polymerization and microtubule stabilization. They are effective against tumor cells that are resistant to Taxol or vinblastine. We recently designed, via molecular editing and total synthesis, a new class of epothilones represented by 26-trifluoro-(E)-9,10-dehydro-12,13-desoxy-epothilone B (Fludelone), which has emerged as a lead candidate for clinical development. Treatment of nude mice bearing MX-1 human mammary carcinoma xenografts (as large as 3.4% body weight) with Fludelone (6-hour i.v. infusion, 25 mg/kg, q3d x 5, q3d x 4) led to complete disappearance and de facto "cure" (i.e., remission without a relapse for over 15% of the average life span of 2 years). The toxicities induced by bolus i.v. injection could be avoided through prolonged i.v. infusion, which allowed for a 10-fold increase in maximal tolerated dose. Complete remission of MX-1 xenografts was achieved with only one third of this maximal tolerated dose. Parallel studies with Taxol and Fludelone [20 mg/kg, 6-hour i.v. infusion (q2d x 4) x3] against HCT-116 human colon carcinoma xenografts revealed that both drugs achieved tumor remission; however, all Taxol-treated mice relapsed in approximately 1.3 months, whereas the Fludelone-treated mice were cured without any relapse for over 7 months. Furthermore, tumor remission was achieved by Fludelone against SK-OV-3 (ovary), PC-3 (prostate), and the Taxol-resistant CCRF-CEM/Taxol (leukemia) xenograft tumors. Most remarkably, p.o. administration of Fludelone (30 mg/kg, q2d x 7, q2d x 9, q2d x 5) against MX-1 xenografts achieved a nonrelapsing cure for as long as 8.4 months. The above results indicate that Fludelone is a highly promising compound for cancer chemotherapeutics.

  12. Novobiocin and Additional Inhibitors of the Hsp90 C-Terminal Nucleotide-binding Pocket

    PubMed Central

    Donnelly, Alison; Blagg, Brian S. J.

    2009-01-01

    N-terminal ATP binding site, there is no reported co-crystal structure of Hsp90 C-terminus bound to any inhibitor. The Hsp90 C-terminal domain, however, is known to contain a conserved pentapeptide sequence (MEEVD) which is recognized by co-chaperones. Cisplatin is a platinum-containing chemotherapeutic used to treat various types of cancers, including testicular, ovarian, bladder, and small cell lung cancer. Most notably, cisplatin coordinates to DNA bases, resulting in cross-linked DNA, which prohibits rapidly dividing cells from duplicating DNA for mitosis. Itoh and co-workers reported that cisplatin decreases the chaperone activity of Hsp90. This group applied bovine brain cytosol to a cisplatin affinity column, eluted with cisplatin and detected Hsp90 in the eluent. Subsequent experiments indicated that cisplatin exhibits high affinity for Hsp90. Moreover Csermely and co-workers determined that the cisplatin binding site is located proximal to the C-terminal ATP binding site. EGCG is one of the active ingredients found in green tea EGCG is known to inhibit the activity of many Hsp90-dependent client proteins, including telomerase, several kinases, and the aryl hydrocarbon receptor (AhR). Recently Gasiewicz and co-workers reported that EGCG manifests its antagonistic activity against AhR through binding Hsp90. Similar to novobiocin, EGCG was shown to bind the C-terminus of Hsp90. Unlike previously identified N-terminal Hsp90 inhibitors, EGCG does not appear to prevent Hsp90 from forming multiprotein complexes. Studies are currently underway to determine whether EGCG competes with novobiocin or cisplatin binding. Taxol, a well-known drug for the treatment of cancer, is responsible for the stabilization of microtubules and the inhibition of mitosis. Previous studies have shown that taxol induces the activation of kinases and transcription factors, and mimies the effect of bacterial lipopolysaccharide (LPS), an attribute unrelated to its tubulin-binding properties

  13. Cell death and immunity in cancer: From danger signals to mimicry of pathogen defense responses.

    PubMed

    Garg, Abhishek D; Agostinis, Patrizia

    2017-11-01

    The immunogenicity of cancer cells is an emerging determinant of anti-cancer immunotherapy. Beyond developing immunostimulatory regimens like dendritic cell-based vaccines, immune-checkpoint blockers, and adoptive T-cell transfer, investigators are beginning to focus on the immunobiology of dying cancer cells and its relevance for the success of anticancer immunotherapies. It is currently accepted that cancer cells may die in response to anti-cancer therapies through regulated cell death programs, which may either repress or increase their immunogenic potential. In particular, the induction of immunogenic cancer cell death (ICD), which is hallmarked by the emission of damage-associated molecular patterns (DAMPs); molecules analogous to pathogen-associated molecular patterns (PAMPs) acting as danger signals/alarmins, is of great relevance in cancer therapy. These ICD-associated danger signals favor immunomodulatory responses that lead to tumor-associated antigens (TAAs)-directed T-cell immunity, which paves way for the removal of residual, treatment-resistant cancer cells. It is also emerging that cancer cells succumbing to ICD can orchestrate "altered-self mimicry" i.e. mimicry of pathogen defense responses, on the levels of nucleic acids and/or chemokines (resulting in type I interferon/IFN responses or pathogen response-like neutrophil activity). In this review, we exhaustively describe the main molecular, immunological, preclinical, and clinical aspects of immunosuppressive cell death or ICD (with respect to apoptosis, necrosis and necroptosis). We also provide an extensive historical background of these fields, with special attention to the self/non-self and danger models, which have shaped the field of cell death immunology. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. MicroRNA-133b targets glutathione S-transferase π expression to increase ovarian cancer cell sensitivity to chemotherapy drugs.

    PubMed

    Chen, Shuo; Jiao, Jin-Wen; Sun, Kai-Xuan; Zong, Zhi-Hong; Zhao, Yang

    2015-01-01

    Accumulating studies reveal that aberrant microRNA (miRNA) expression can affect the development of chemotherapy drug resistance by modulating the expression of relevant target proteins. The aim of this study was to investigate the role of miR-133b in the development of drug resistance in ovarian cancer cells. We examined the levels of miR-133b expression in ovarian carcinoma tissues and the human ovarian carcinoma cell lines (A2780, A2780/DDP and A2780/Taxol, respectively). We determined the cell viability of these cell lines treated with cisplatin or paclitaxel in the presence or absence of miR-133b or anti-miR-133b transfection using the MTT assay. Reverse transcription polymerase chain reaction and Western blotting were used to assess the mRNA and protein expression levels of two drug-resistance-related genes: glutathione S-transferase (GST)-π and multidrug resistance protein 1 (MDR1). The dual-luciferase reporter assay was used to detect the promoter activity of GST-π in the presence and absence of miR-133b. The expression of miR-133b was significantly lower in primary resistant ovarian carcinomas than in the chemotherapy-sensitive carcinomas (P<0.05), and the same results were found in primary resistant ovarian cell lines (A2780/Taxol and A2780/DDP) compared to the chemotherapy-sensitive cell line (A2780; P<0.05). Following miR-133b transfection, four cell lines showed increased sensitivity to paclitaxel and cisplatin, while anti-miR-133b transfection reduced cell sensitivity to paclitaxel and cisplatin. Dual-luciferase reporter assay showed that miR-133b interacted with the 3'-untranslated region of GST-π. Compared to controls, the mRNA and protein levels of MDR1 and GST-π were downregulated after miR-133b transfection and upregulated after anti-miR-133b transfection. MicroRNA-133b may reduce ovarian cancer drug resistance by silencing the expression of the drug-resistance-related proteins, GST-π and MDR1. In future, the combination of miR-133b with

  15. Physicochemical properties and biocompatibility of a polymer-paclitaxel conjugate for cancer treatment.

    PubMed

    Yang, Danbo; Van, Sang; Liu, Jian; Wang, Jing; Jiang, Xinguo; Wang, Yiting; Yu, Lei

    2011-01-01

    Poly(L-γ-glutamylglutamine) paclitaxel (PGG-PTX) conjugate is a non-diblock polymeric drug nanoparticle intended to improve the therapeutic index of paclitaxel. The purpose of the present study was to elucidate further the physicochemical properties of PGG-PTX in order to proceed with its clinical development. PGG-PTX was designed by integration of a hydrophobic paclitaxel conjugate through an added hydrophilic glutamic acid onto poly(L-glutamic acid). The addition of a flexible glutamic linker between PGA and paclitaxel resulted in spontaneous self-assembly of a PGG-PTX conjugate into nanoparticles. The PGG-PTX conjugate was stable as a lyophilized solid form. An in vitro viability experiment showed that PGG-PTX was effective after a longer incubation period, the same trend as Taxol. In vitro studies using NCI-H460 and B16F0 cancer cells demonstrated significantly high cellular uptake after 30 minutes of incubation. The in vivo biocompatibility of PGG-PTX conjugate was evaluated in the NCI-H460 tumor model, the assessment of tissue seemed to be normal after 21 days of treatment. These results are encouraging for further development of non-block polymeric paclitaxel nanoparticles for treatment of cancer.

  16. Stimuli-responsive cross-linked micelles for on-demand drug delivery against cancers

    PubMed Central

    Li, Yuanpei; Xiao, Kai; Zhu, Wei; Deng, Wenbin; Lam, Kit S.

    2013-01-01

    Stimuli-responsive cross-linked micelles (SCMs) represent an ideal nanocarrier system for drug delivery against cancers. SCMs exhibit superior structural stability compared to their non-crosslinked counterpart. Therefore, these nanocarriers are able to minimize the premature drug release during blood circulation. The introduction of environmentally sensitive crosslinkers or assembly units makes SCMs responsive to single or multiple stimuli present in tumor local microenvironment or exogenously applied stimuli. In these instances, the payload drug is released almost exclusively in cancerous tissue or cancer cells upon accumulation via enhanced permeability and retention effect or receptor mediated endocytosis. In this review, we highlight recent advances in the development of SCMs for cancer therapy. We also introduce the latest biophysical techniques, such as electron paramagnetic resonance (EPR) spectroscopy and fluorescence resonance energy transfer (FRET), for the characterization of the interactions between SCMs and blood proteins. PMID:24060922

  17. Post-sampling mortality and non-response patterns in the English Cancer Patient Experience Survey: Implications for epidemiological studies based on surveys of cancer patients.

    PubMed

    Abel, Gary A; Saunders, Catherine L; Lyratzopoulos, Georgios

    2016-04-01

    Surveys of the experience of cancer patients are increasingly being introduced in different countries and used in cancer epidemiology research. Sampling processes, post-sampling mortality and survey non-response can influence the representativeness of cancer patient surveys. We examined predictors of post-sampling mortality and non-response among patients initially included in the sampling frame of the English Cancer Patient Experience Survey. We also compared the respondents' diagnostic case-mix to other relevant populations of cancer patients, including incident and prevalent cases. Of 109,477 initially sampled cancer patients, 6273 (5.7%) died between sampling and survey mail-out. Older age and diagnosis of brain, lung and pancreatic cancer were associated with higher risk of post-sampling mortality. The overall response rate was 67% (67,713 respondents), being >70% for the most affluent patients and those diagnosed with colon or breast cancer and <50% for Asian or Black patients, those under 35 and those diagnosed with brain cancer. The diagnostic case-mix of respondents varied substantially from incident or prevalent cancer cases. Respondents to the English Cancer Patient Experience Survey represent a population of recently treated cancer survivors. Although patient survey data can provide unique insights for improving cancer care quality, features of survey populations need to be acknowledged when analysing and interpreting findings from studies using such data. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Observers' response to facial disfigurement from head and neck cancer.

    PubMed

    Cho, Joowon; Fingeret, Michelle Cororve; Huang, Sheng-Cheng; Liu, Jun; Reece, Gregory P; Markey, Mia K

    2018-05-30

    Our long-term goal is to develop a normative feedback intervention to support head and neck cancer patients in forming realistic expectations about how other people in non-social group settings will respond to their appearance. This study aimed to evaluate the relationship between observer ratings of facial disfigurement and observer ratings of emotional response when viewing photographs of faces of head and neck cancer patients. Seventy-five (75) observers rated their emotional response to each of 144 facial photographs of head and neck cancer patients using the Self-Assessment-Manikin and rated severity of facial disfigurement on a 9-point scale. Body image investment of the observers was measured using the Appearance Schemas Inventory-Revised. A standardized multiple regression model was used to assess the relationship between observer ratings of facial disfigurement and observer ratings of emotional response, taking into consideration the age and sex of the patient depicted in the stimulus photograph, as well as the age, sex, and body image investment of the observer. Observers who had a strong emotional response to a patient's facial photograph tended to rate the patient's facial disfigurement as more severe (standardized regression coefficient β = 0.328, P < 0.001). Sex and age of the observer had more influence on the rating of facial disfigurement than did the patient's demographic characteristics. Observers more invested in their own body image tended to rate the facial disfigurement as more severe. This study lays the groundwork for a normative database of emotional response to facial disfigurement. Copyright © 2018 John Wiley & Sons, Ltd.

  19. Radiation-Related New Primary Solid Cancers in the Childhood Cancer Survivor Study: Comparative Radiation Dose Response and Modification of Treatment Effects

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Inskip, Peter D., E-mail: inskippeter@gmail.com; Sigurdson, Alice J.; Veiga, Lene

    Objectives: The majority of childhood cancer patients now achieve long-term survival, but the treatments that cured their malignancy often put them at risk of adverse health outcomes years later. New cancers are among the most serious of these late effects. The aims of this review are to compare and contrast radiation dose–response relationships for new solid cancers in a large cohort of childhood cancer survivors and to discuss interactions among treatment and host factors. Methods: This review is based on previously published site-specific analyses for subsequent primary cancers of the brain, breast, thyroid gland, bone and soft tissue, salivary glands,more » and skin among 12,268 5-year childhood cancer survivors in the Childhood Cancer Survivor Study. Analyses included tumor site–specific, individual radiation dose reconstruction based on radiation therapy records. Radiation-related second cancer risks were estimated using conditional logistic or Poisson regression models for excess relative risk (ERR). Results: Linear dose–response relationships over a wide range of radiation dose (0-50 Gy) were seen for all cancer sites except the thyroid gland. The steepest slopes occurred for sarcoma, meningioma, and nonmelanoma skin cancer (ERR/Gy > 1.00), with glioma and cancers of the breast and salivary glands forming a second group (ERR/Gy = 0.27-0.36). The relative risk for thyroid cancer increased up to 15-20 Gy and then decreased with increasing dose. The risk of thyroid cancer also was positively associated with chemotherapy, but the chemotherapy effect was not seen among those who also received very high doses of radiation to the thyroid. The excess risk of radiation-related breast cancer was sharply reduced among women who received 5 Gy or more to the ovaries. Conclusions: The results suggest that the effect of high-dose irradiation is consistent with a linear dose–response for most organs, but they also reveal important organ-specific and host

  20. Molecular predictors of therapeutic response to specific anti-cancer agents

    DOEpatents

    Spellman, Paul T.; Gray, Joe W.; Sadanandam, Anguraj; Heiser, Laura M.; Gibb, William J.; Kuo, Wen-lin; Wang, Nicholas J.

    2016-11-29

    Herein is described the use of a collection of 50 breast cancer cell lines to match responses to 77 conventional and experimental therapeutic agents with transcriptional, proteomic and genomic subtypes found in primary tumors. Almost all compounds produced strong differential responses across the cell lines produced responses that were associated with transcriptional and proteomic subtypes and produced responses that were associated with recurrent genome copy number abnormalities. These associations can now be incorporated into clinical trials that test subtype markers and clinical responses simultaneously.

  1. Paclitaxel (3-hour infusion) followed by carboplatin (24 hours after paclitaxel): a phase II study in advanced non-small cell lung cancer.

    PubMed

    Roychowdhury, D F; Desai, P; Zhu, Y W

    1997-08-01

    This phase II study was performed to investigate the efficacy of a 3-hour 225 mg/m2 paclitaxel infusion (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) followed 24 hours later by a 30-minute infusion of carboplatin (dosed to an area under the concentration-time curve of 6) in patients with stage IIIA, IIIB, or IV non-small cell lung cancer. Patients received chemotherapy and were monitored for toxicity, response, quality of life, and survival. Paclitaxel and carboplatin pharmacokinetics were also determined with the first cycle of chemotherapy. Eleven men have been treated to date. Eight were white and three black, with a median age of 65 years. All patients had a performance status of 0 or 1. The regimen was well tolerated, with no deaths or grade 4 toxicities noted. The most common grade 3 toxicity was neutropenia, thrombocytopenia, and parasthesias (observed in <10% of cycles). The overall response rate was 57% (14% complete and 43% partial responses). Quality of life improved in most patients. Physical and emotional well-being improved in 57%, functional well-being in 43%, and social/family well-being in 14% of patients. Pharmacokinetic data are being analyzed by limited sampling technique to predict the paclitaxel area under the concentration-time curve. This unique schedule of paclitaxel and carboplatin is well tolerated and active, and is associated with improvements in various aspects of quality of life.

  2. Time-dependent micromechanical responses of breast cancer cells and adjacent fibroblasts to electric treatment.

    PubMed

    Yizraeli, Maayan Lia; Weihs, Daphne

    2011-12-01

    Direct-current, low-intensity, electric fields were suggested as a minimally invasive treatment for various cancers. The tumor microenvironment may affect treatment efficacy, albeit it has not generally been considered when evaluating novel anti-cancer treatments. We evaluate the effects of electric treatment on epithelial, breast-cancer cells, co-cultured with non-cancerous fibroblasts, a simplified model for the tumor-microenvironment. We evaluate changes in morphology, cytoskeleton, and focus on dynamic intracellular structure and mechanics. Multiple-particle tracking was used within living cells to quantify time-dependent structural and mechanical changes. Cancer cells suffer severe cell death and exhibit transient rounding and changes in internal structural and mechanics. Interestingly, treating cancer cells in co-culture with fibroblasts delays and reduces their responses to treatment. Our particle-tracking data indicates a mechanism relating the observed changes in intracellular transport to transient changes in the microtubule network and its motors. In contrast, fibroblasts are only minimally affected by treatment, separately or in co-culture. To conclude, intracellular mechanics reveal time-dependent responses after treatment, unavailable by bulk measurements. This time-dependence could provide a window of opportunity for continued treatment. We demonstrate the importance of evaluating anti-cancer treatments within their microenvironment, which can affect response magnitude and time-course.

  3. Synthesis of Taxol-Like Prostate Cancer Chemotherapeutic Agents

    DTIC Science & Technology

    2007-11-01

    in Scheme 5, conventional condition utilizing n- BuLi as a base was not successful in the preparation of the desired Diels-Alder substrate 19 as only...unsuccessful. The only product obtained was n- BuLi addition to aldehyde 21. Thus, deprotonation conditions of terminal alkyne 17 or 20 are now being

  4. Response shift in quality of life assessment among cancer patients: A study from Iran

    PubMed Central

    Hosseini, Bayan; Nedjat, Saharnaz; Zendehdel, Kazem; Majdzadeh, Reza; Nourmohammadi, Azam; Montazer, Ali

    2017-01-01

    Background: During the course of disease, particularly of chronic diseases, changes in internal standards cause certain changes in the estimation of quality of life (QOL). These changes indicate the phenomenon of ‘response shift’. The present study aimed at assessing response shift in different scales of QOL in Iranian cancer patients. Methods: To assess response shift through the ‘then test’ approach, we asked 211 cancer patients to complete the EORTC QLQ-C30 questionnaire at pretest (at the beginning of the study), posttest (3 months later), and then test (administered immediately after the posttest). Paired t test and Cohen’s effect size were used for comparison. Results: Response shift was significant in all 4 scales under study, i.e. fatigue, pain, emotional functioning, and general QOL (p<0.001). Fatigue, pain, and global QOL have deteriorated significantly with then test approach and emotional function was significantly improved. Conclusion: We observed a response shift in Iranian cancer patients in our study. Thus, in light of the multifactorial nature of QOL and the effect of the response shift bias on different aspects of QOL changes, it is of utmost importance to keep this bias in mind when interpreting the results and managing cancer patients’ treatment regimens. PMID:29951421

  5. Distinct Roles of Velvet Complex in the Development, Stress Tolerance, and Secondary Metabolism in Pestalotiopsis microspora, a Taxol Producer

    PubMed Central

    Akhberdi, Oren; Zhang, Qian; Wang, Dan; Wang, Haichuan; Hao, Xiaoran; Liu, Yanjie; Wei, Dongsheng; Zhu, Xudong

    2018-01-01

    The velvet family proteins have been shown to play critical roles in fungal secondary metabolism and development. However, variations of the roles have been observed in different fungi. We report here the observation on the role of three velvet complex components VeA, VelB, and LaeA in Pestalotiopsis microspora, a formerly reported taxol-producing fungus. Deletion of individual members led to the retardation of vegetative growth and sporulation and pigmentation, suggesting critical roles in these processes. The mutant strain △velB appeared hypersensitive to osmotic stress and the dye Congo red, whereas △veA and △laeA were little affected by the pressures, suggesting only velB was required for the integrity of the cell wall. Importantly, we found that the genes played distinct roles in the biosynthesis of secondary metabolites in P. microspora. For instance, the production of pestalotiollide B, a previously characterized polyketide, required velB and laeA. In contrast, the veA gene appeared to inhibit the pestalotiollide B (PB) role in its biosynthesis. This study suggests that the three components of the velvet complex are important global regulators, but with distinct roles in hyphal growth, asexual production, and secondary metabolism in P. microspora. This work provides information for further understanding the biosynthesis of secondary metabolism in the fungus. PMID:29538316

  6. Roles of phospholipid methyltransferases in pycnidia development, stress tolerance and secondary metabolism in the taxol-producing fungus Pestalotiopsis microspore.

    PubMed

    Akhberdi, Oren; Zhang, Qian; Wang, Haichuan; Li, Yingying; Chen, Longfei; Wang, Dan; Yu, Xi; Wei, Dongsheng; Zhu, Xudong

    2018-05-01

    Phosphatidylcholine (PC) is an important membrane component of the eukaryotic cell. In yeast fungi, two phospholipid methyltransferases catalyze consecutive steps of methylation in the formation of phosphatidylcholine from phosphatidylethanolamine. However, roles of phospholipid methyltransferases in filamentous fungi remains less investigated. We report here the characterization of two genes, choA and choC, that putatively encoded phospholipid methyltransferases in the taxol-producing fungus Pestalotiopsis microspora. Deletion of choC resulted in defects in PC production, vegetative growth and development of asexual structure. The mutant strains exhibited multiple morphological abnormalities, e.g. swollen hyphal tips and enhanced hyphal branching, and even mycelial autolysis. Some novel roles for the genes were also revealed, for instance, the deletion of either choC or choA impaired the development of pycnidia and conidia, the cell wall integrity. The mutant strains displayed a hypersensitivity to stress conditions, e.g. osmotic stress, cold and metal ions. The osmotic hypersensitivity indicates a crosstalk of PC pathways to other signaling pathways, such as the HOG pathway. Still more, choA, but not choC, was required for the production of secondary metabolites, e.g. pestalotiollide B, suggesting distinct roles of the two genes. This work would contribute to better understanding the function of phospholipid methyltransferases in fungi. Copyright © 2018 Elsevier GmbH. All rights reserved.

  7. Distinct Roles of Velvet Complex in the Development, Stress Tolerance, and Secondary Metabolism in Pestalotiopsis microspora, a Taxol Producer.

    PubMed

    Akhberdi, Oren; Zhang, Qian; Wang, Dan; Wang, Haichuan; Hao, Xiaoran; Liu, Yanjie; Wei, Dongsheng; Zhu, Xudong

    2018-03-14

    The velvet family proteins have been shown to play critical roles in fungal secondary metabolism and development. However, variations of the roles have been observed in different fungi. We report here the observation on the role of three velvet complex components VeA, VelB, and LaeA in Pestalotiopsis microspora , a formerly reported taxol-producing fungus. Deletion of individual members led to the retardation of vegetative growth and sporulation and pigmentation, suggesting critical roles in these processes. The mutant strain △velB appeared hypersensitive to osmotic stress and the dye Congo red, whereas △veA and △laeA were little affected by the pressures, suggesting only velB was required for the integrity of the cell wall. Importantly, we found that the genes played distinct roles in the biosynthesis of secondary metabolites in P. microspora . For instance, the production of pestalotiollide B, a previously characterized polyketide, required velB and laeA . In contrast, the veA gene appeared to inhibit the pestalotiollide B (PB) role in its biosynthesis. This study suggests that the three components of the velvet complex are important global regulators, but with distinct roles in hyphal growth, asexual production, and secondary metabolism in P. microspora . This work provides information for further understanding the biosynthesis of secondary metabolism in the fungus.

  8. Pretubulysin: a new option for the treatment of metastatic cancer

    PubMed Central

    Braig, S; Wiedmann, R M; Liebl, J; Singer, M; Kubisch, R; Schreiner, L; Abhari, B A; Wagner, E; Kazmaier, U; Fulda, S; Vollmar, A M

    2014-01-01

    Tubulin-binding agents such as taxol, vincristine or vinblastine are well-established drugs in clinical treatment of metastatic cancer. However, because of their highly complex chemical structures, the synthesis and hence the supply issues are still quite challenging. Here we set on stage pretubulysin, a chemically accessible precursor of tubulysin that was identified as a potent microtubule-binding agent produced by myxobacteria. Although much simpler in chemical structure, pretubulysin abrogates proliferation and long-term survival as well as anchorage-independent growth, and also induces anoikis and apoptosis in invasive tumor cells equally potent to tubulysin. Moreover, pretubulysin posseses in vivo efficacy shown in a chicken chorioallantoic membrane (CAM) model with T24 bladder tumor cells, in a mouse xenograft model using MDA-MB-231 mammary cancer cells and finally in a model of lung metastasis induced by 4T1 mouse breast cancer cells. Pretubulysin induces cell death via the intrinsic apoptosis pathway by abrogating the expression of pivotal antiapoptotic proteins, namely Mcl-1 and Bcl-xL, and shows distinct chemosensitizing properties in combination with TRAIL in two- and three-dimensional cell culture models. Unraveling the underlying signaling pathways provides novel information: pretubulysin induces proteasomal degradation of Mcl-1 by activation of mitogen-activated protein kinase (especially JNK (c-Jun N-terminal kinase)) and phosphorylation of Mcl-1, which is then targeted by the SCFFbw7 E3 ubiquitin ligase complex for ubiquitination and degradation. In sum, we designate the microtubule-destabilizing compound pretubulysin as a highly promising novel agent for mono treatment and combinatory treatment of invasive cancer. PMID:24434509

  9. Prediction of response to neoadjuvant chemotherapy in breast cancer: a radiomic study

    NASA Astrophysics Data System (ADS)

    Wu, Guolin; Fan, Ming; Zhang, Juan; Zheng, Bin; Li, Lihua

    2017-03-01

    Breast cancer is one of the most malignancies among women in worldwide. Neoadjuvant Chemotherapy (NACT) has gained interest and is increasingly used in treatment of breast cancer in recent years. Therefore, it is necessary to find a reliable non-invasive assessment and prediction method which can evaluate and predict the response of NACT. Recent studies have highlighted the use of MRI for predicting response to NACT. In addition, molecular subtype could also effectively identify patients who are likely have better prognosis in breast cancer. In this study, a radiomic analysis were performed, by extracting features from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and immunohistochemistry (IHC) to determine subtypes. A dataset with fifty-seven breast cancer patients were included, all of them received preoperative MRI examination. Among them, 47 patients had complete response (CR) or partial response (PR) and 10 had stable disease (SD) to chemotherapy based on the RECIST criterion. A total of 216 imaging features including statistical characteristics, morphology, texture and dynamic enhancement were extracted from DCE-MRI. In multivariate analysis, the proposed imaging predictors achieved an AUC of 0.923 (P = 0.0002) in leave-one-out crossvalidation. The performance of the classifier increased to 0.960, 0.950 and 0.936 when status of HER2, Luminal A and Luminal B subtypes were added into the statistic model, respectively. The results of this study demonstrated that IHC determined molecular status combined with radiomic features from DCE-MRI could be used as clinical marker that is associated with response to NACT.

  10. TFF3 is a valuable predictive biomarker of endocrine response in metastatic breast cancer

    PubMed Central

    May, Felicity E B; Westley, Bruce R

    2015-01-01

    The stratification of breast cancer patients for endocrine therapies by oestrogen or progesterone receptor expression is effective but imperfect. The present study aims were to validate microarray studies that demonstrate TFF3 regulation by oestrogen and its association with oestrogen receptors in breast cancer, to evaluate TFF3 as a biomarker of endocrine response, and to investigate TFF3 function. Microarray data were validated by quantitative RT-PCR and northern and western transfer analyses. TFF3 was induced by oestrogen, and its induction was inhibited by antioestrogens, tamoxifen, 4-hydroxytamoxifen and fulvestrant in oestrogen-responsive breast cancer cells. The expression of TFF3 mRNA was associated with oestrogen receptor mRNA in breast tumours (Pearson's coefficient=0.762, P=0.000). Monoclonal antibodies raised against the TFF3 protein detected TFF3 by immunohistochemistry in oesophageal submucosal glands, intestinal goblet and neuroendocrine cells, Barrett's metaplasia and intestinal metaplasia. TFF3 protein expression was associated with oestrogen receptor, progesterone receptor and TFF1 expression in malignant breast cells. TFF3 is a specific and sensitive predictive biomarker of response to endocrine therapy, degree of response and duration of response in unstratified metastatic breast cancer patients (P=0.000, P=0.002 and P=0.002 respectively). Multivariate binary logistic regression analysis demonstrated that TFF3 is an independent biomarker of endocrine response and degree of response, and this was confirmed in a validation cohort. TFF3 stimulated migration and invasion of breast cancer cells. In conclusion, TFF3 expression is associated with response to endocrine therapy, and outperforms oestrogen receptor, progesterone receptor and TFF1 as an independent biomarker, possibly because it mediates the malign effects of oestrogen on invasion and metastasis. PMID:25900183

  11. Evidence of drug-response heterogeneity rapidly generated from a single cancer cell.

    PubMed

    Wang, Rong; Jin, Chengmeng; Hu, Xun

    2017-06-20

    One cancer cell line is believed to be composed of numerous clones with different drug sensitivity. We sought to investigate the difference of drug-response pattern in clones from a cell line or from a single cell. We showed that 22 clones derived from 4T1 cells were drastically different from each other with respect to drug-response pattern against 11 anticancer drugs and expression profile of 19 genes associated with drug resistance or sensitivity. Similar results were obtained using daughter clones derived from a single 4T1 cell. Each daughter clone showed distinct drug-response pattern and gene expression profile. Similar results were also obtained using Bcap37 cells. We conclude that a single cancer cell can rapidly produce a population of cells with high heterogeneity of drug response and the acquisition of drug-response heterogeneity is random.

  12. Utilization of the cellular stress response to sensitize cancer cells to TRAIL-mediated apoptosis.

    PubMed

    Siegelin, Markus David

    2012-08-01

    Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising death ligand who has received significant attention due to its specific anti-cancer activity. Recently, a number of clinical trials involving either recombinant soluble TRAIL or agonistic death receptor (DR) antibodies have even been initiated. One major caveat in TRAIL-based anti-cancer therapies is that a considerable number of cancer cells are notorious resistant to apoptosis induction by TRAIL. Overcoming this primary or secondary evolved resistance is an utmost important goal of present cancer research. The current literature suggests that TRAIL resistance is mediated by a number of endogenous factors. According to recent research, stress-related transcription factors have acquired a pivotal role in the sensitization of highly resistant cancer cells, for example, pancreatic cancer and glioblastoma cells, to TRAIL-mediated cell death. Out of this transcription factor family, C/EBP-homologous protein (CHOP) is linked to the control of DR-mediated apoptosis by modulation of several apoptotic and anti-apoptotic factors. Stress responses in certain organelles, such as endoplasmic reticulum (ER) and mitochondria, are potent inductors of CHOP expression. This report focuses on the influence of stress responses on endogenous or acquired resistance to extrinsic apoptosis in tumor cells and summarizes recent findings and results. The Medline and ClinicalTrials database with key words were used for this review. A potential novel treatment strategy for highly treatment-resistant tumors is the induction of a cellular stress response in cancer cells. The induction of an organelle-related stress response, such as nuclear, ER and mitochondrial stress, leads to a dramatic sensitization of a broad variety of cancer cells of different tumor entities to the apoptotic ligand, TRAIL. Importantly, non-neoplastic cells are not sensitized to TRAIL-mediated cell death through the unfolded protein response in

  13. The intensity of radiotherapy-elicited immune response is associated with esophageal cancer clearance.

    PubMed

    Ma, Jin-lu; Jin, Long; Li, Yao-Dong; He, Chen-chen; Guo, Xi-jing; Liu, Rui; Yang, Yun-Yi; Han, Su-xia

    2014-01-01

    Radiation therapy is one of the standard therapeutic modalities for esophageal cancer, achieving its main antitumor efficacy through DNA damage. However, accumulating evidence shows that radiotherapy can substantially alter the tumor microenvironment, particularly with respect to its effects on immune cells. We hypothesized that the immune response elicited by radiotherapy may be as important as the radiation itself for successful treatment. More specifically, immunomodulatory cytokines may enhance the effectiveness of radiotherapy. To investigate this hypothesis, we measured changes in the serum interferon-gamma (IFN- γ ) and interleukin-2 (IL-2) concentrations during radiotherapy and compared these modifications with outcomes. We found that serum concentrations of IL-2 and IFN- γ were positively associated with local response to radiotherapy in esophageal cancer. More generally, the intensity of the radiotherapy-elicited immune response was positively associated with local response to radiotherapy in esophageal cancer. Changes in serum IL-2 and IFN- γ concentrations were further associated with increased risks of acute hematologic toxicity and acute organ toxicity of the esophagus, lung, and skin. These results suggest that deciphering the mechanisms of radiotherapy-elicited immune response may help in the development of therapeutic interventions that would enhance the efficacy of radiotherapy and convert some ineffective responses to effective responses.

  14. DNA Mismatch Repair Deficiency in Rectal Cancer: Benchmarking Its Impact on Prognosis, Neoadjuvant Response Prediction, and Clinical Cancer Genetics

    PubMed Central

    de Rosa, Nicole; Rodriguez-Bigas, Miguel A.; Chang, George J.; Veerapong, Jula; Borras, Ester; Krishnan, Sunil; Bednarski, Brian; Messick, Craig A.; Skibber, John M.; Feig, Barry W.; Lynch, Patrick M.; Vilar, Eduardo

    2016-01-01

    Purpose DNA mismatch repair deficiency (dMMR) hallmarks consensus molecular subtype 1 of colorectal cancer. It is being routinely tested, but little is known about dMMR rectal cancers. The efficacy of novel treatment strategies cannot be established without benchmarking the outcomes of dMMR rectal cancer with current therapy. We aimed to delineate the impact of dMMR on prognosis, the predicted response to fluoropyrimidine-based neoadjuvant therapy, and implications of germline alterations in the MMR genes in rectal cancer. Methods Between 1992 and 2012, 62 patients with dMMR rectal cancers underwent multimodality therapy. Oncologic treatment and outcomes as well as clinical genetics work-up were examined. Overall and rectal cancer–specific survival were calculated by the Kaplan-Meier method. Results The median age at diagnosis was 41 years. MMR deficiency was most commonly due to alterations in MSH2 (53%) or MSH6 (23%). After a median follow-up of 6.8 years, the 5-year rectal cancer–specific survival was 100% for stage I and II, 85.1% for stage III, and 60.0% for stage IV disease. Fluoropyrimidine-based neoadjuvant chemoradiation was associated with a complete pathologic response rate of 27.6%. The extent of surgical resection was influenced by synchronous colonic disease at presentation, tumor height, clinical stage, and pelvic radiation. An informed decision for a limited resection focusing on proctectomy did not compromise overall survival. Five of the 11 (45.5%) deaths during follow-up were due to extracolorectal malignancies. Conclusion dMMR rectal cancer had excellent prognosis and pathologic response with current multimodality therapy including an individualized surgical treatment plan. Identification of a dMMR rectal cancer should trigger germline testing, followed by lifelong surveillance for both colorectal and extracolorectal malignancies. We herein provide genotype-specific outcome benchmarks for comparison with novel interventions. PMID:27432916

  15. Altered Blood Flow Response to Small Muscle Mass Exercise in Cancer Survivors Treated With Adjuvant Therapy.

    PubMed

    Didier, Kaylin D; Ederer, Austin K; Reiter, Landon K; Brown, Michael; Hardy, Rachel; Caldwell, Jacob; Black, Christopher; Bemben, Michael G; Ade, Carl J

    2017-02-07

    Adjuvant cancer treatments have been shown to decrease cardiac function. In addition to changes in cardiovascular risk, there are several additional functional consequences including decreases in exercise capacity and increased incidence of cancer-related fatigue. However, the effects of adjuvant cancer treatment on peripheral vascular function during exercise in cancer survivors have not been well documented. We investigated the vascular responses to exercise in cancer survivors previously treated with adjuvant cancer therapies. Peripheral vascular responses were investigated in 11 cancer survivors previously treated with adjuvant cancer therapies (age 58±6 years, 34±30 months from diagnosis) and 9 healthy controls group matched for age, sex, and maximal voluntary contraction. A dynamic handgrip exercise test at 20% maximal voluntary contraction was performed with simultaneous measurements of forearm blood flow and mean arterial pressure. Forearm vascular conductance was calculated from forearm blood flow and mean arterial pressure. Left ventricular ejection time index (LVETi) was derived from the arterial pressure wave form. Forearm blood flow was attenuated in cancer therapies compared to control at 20% maximal voluntary contraction (189.8±53.8 vs 247.9±80.3 mL·min -1 , respectively). Forearm vascular conductance was not different between groups at rest or during exercise. Mean arterial pressure response to exercise was attenuated in cancer therapies compared to controls (107.8±10.8 vs 119.2±16.2 mm Hg). LEVTi was lower in cancer therapies compared to controls. These data suggest an attenuated exercise blood flow response in cancer survivors ≈34 months following adjuvant cancer therapy that may be attributed to an attenuated increase in mean arterial pressure. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  16. Presence of early stage cancer does not impair the early protein metabolic response to major surgery

    PubMed Central

    Klimberg, V. Suzanne; Allasia, Arianna; Deutz, Nicolaas EP

    2017-01-01

    Abstract Background Combined bilateral mastectomy and reconstruction is a common major surgical procedure in women with breast cancer and in those with a family history of breast cancer. As this large surgical procedure induces muscle protein loss, a preserved anabolic response to nutrition is warranted for optimal recovery. It is unclear whether the presence of early stage cancer negatively affects the protein metabolic response to major surgery as this would mandate perioperative nutritional support. Methods In nine women with early stage (Stage II) breast malignancy and nine healthy women with a genetic predisposition to breast cancer undergoing the same large surgical procedure, we examined whether surgery influences the catabolic response to overnight fasting and the anabolic response to nutrition differently. Prior to and within 24 h after combined bilateral mastectomy and reconstruction surgery, whole body protein synthesis and breakdown rates were assessed after overnight fasting and after meal intake by stable isotope methodology to enable the calculation of net protein catabolism in the post‐absorptive state and net protein anabolic response to a meal. Results Major surgery resulted in an up‐regulation of post‐absorptive protein synthesis and breakdown rates (P < 0.001) and lower net protein catabolism (P < 0.05) and was associated with insulin resistance and increased systemic inflammation (P < 0.01). Net anabolic response to the meal was reduced after surgery (P < 0.05) but higher in cancer (P < 0.05) indicative of a more preserved meal efficiency. The significant relationship between net protein anabolism and the amount of amino acids available in the circulation (R 2 = 0.85, P < 0.001) was independent of the presence of non‐cachectic early stage breast cancer or surgery. Conclusions The presence of early stage breast cancer does not enhance the normal catabolic response to major surgery or further attenuates the

  17. Presence of early stage cancer does not impair the early protein metabolic response to major surgery.

    PubMed

    Engelen, Mariëlle P K J; Klimberg, V Suzanne; Allasia, Arianna; Deutz, Nicolaas Ep

    2017-06-01

    Combined bilateral mastectomy and reconstruction is a common major surgical procedure in women with breast cancer and in those with a family history of breast cancer. As this large surgical procedure induces muscle protein loss, a preserved anabolic response to nutrition is warranted for optimal recovery. It is unclear whether the presence of early stage cancer negatively affects the protein metabolic response to major surgery as this would mandate perioperative nutritional support. In nine women with early stage (Stage II) breast malignancy and nine healthy women with a genetic predisposition to breast cancer undergoing the same large surgical procedure, we examined whether surgery influences the catabolic response to overnight fasting and the anabolic response to nutrition differently. Prior to and within 24 h after combined bilateral mastectomy and reconstruction surgery, whole body protein synthesis and breakdown rates were assessed after overnight fasting and after meal intake by stable isotope methodology to enable the calculation of net protein catabolism in the post-absorptive state and net protein anabolic response to a meal. Major surgery resulted in an up-regulation of post-absorptive protein synthesis and breakdown rates (P < 0.001) and lower net protein catabolism (P < 0.05) and was associated with insulin resistance and increased systemic inflammation (P < 0.01). Net anabolic response to the meal was reduced after surgery (P < 0.05) but higher in cancer (P < 0.05) indicative of a more preserved meal efficiency. The significant relationship between net protein anabolism and the amount of amino acids available in the circulation (R 2  = 0.85, P < 0.001) was independent of the presence of non-cachectic early stage breast cancer or surgery. The presence of early stage breast cancer does not enhance the normal catabolic response to major surgery or further attenuates the anabolic response to meal intake within 24 h after

  18. Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents

    PubMed Central

    Cragg, Gordon M.; Pezzuto, John M.

    2016-01-01

    Throughout history, natural products have played a dominant role in the treatment of human ailments. For example, the legendary discovery of penicillin transformed global existence. Presently, natural products comprise a large portion of current-day pharmaceutical agents, most notably in the area of cancer therapy. Examples include Taxol, vinblastine, and camptothecin. These structurally unique agents function by novel mechanisms of action; isolation from natural sources is the only plausible method that could have led to their discovery. In addition to terrestrial plants as sources for starting materials, the marine environment (e.g., ecteinascidin 743, halichondrin B, and dolastatins), microbes (e.g., bleomycin, doxorubicin, and staurosporin), and slime molds (e.g., epothilone B) have yielded remarkable cancer chemotherapeutic agents. Irrespective of these advances, cancer remains a leading cause of death worldwide. Undoubtedly, the prevention of human cancer is highly preferable to treatment. Cancer chemoprevention, the use of vaccines or pharmaceutical agents to inhibit, retard, or reverse the process of carcinogenesis, is another important approach for easing this formidable public health burden. Similar to cancer chemotherapeutic agents, natural products play an important role in this field. There are many examples, including dietary phytochemicals such as sulforaphane and phenethyl isothiocyanate (cruciferous vegetables) and resveratrol (grapes and grape products). Overall, natural product research is a powerful approach for discovering biologically active compounds with unique structures and mechanisms of action. Given the unfathomable diversity of nature, it is reasonable to suggest that chemical leads can be generated that are capable of interacting with most or possibly all therapeutic targets. PMID:26679767

  19. Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response.

    PubMed

    Beltran, Himisha; Eng, Kenneth; Mosquera, Juan Miguel; Sigaras, Alexandros; Romanel, Alessandro; Rennert, Hanna; Kossai, Myriam; Pauli, Chantal; Faltas, Bishoy; Fontugne, Jacqueline; Park, Kyung; Banfelder, Jason; Prandi, Davide; Madhukar, Neel; Zhang, Tuo; Padilla, Jessica; Greco, Noah; McNary, Terra J; Herrscher, Erick; Wilkes, David; MacDonald, Theresa Y; Xue, Hui; Vacic, Vladimir; Emde, Anne-Katrin; Oschwald, Dayna; Tan, Adrian Y; Chen, Zhengming; Collins, Colin; Gleave, Martin E; Wang, Yuzhuo; Chakravarty, Dimple; Schiffman, Marc; Kim, Robert; Campagne, Fabien; Robinson, Brian D; Nanus, David M; Tagawa, Scott T; Xiang, Jenny Z; Smogorzewska, Agata; Demichelis, Francesca; Rickman, David S; Sboner, Andrea; Elemento, Olivier; Rubin, Mark A

    2015-07-01

    Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low-frequency mutations. We describe a whole-exome sequencing (WES) precision medicine trial focused on patients with advanced cancer. To understand how WES data affect therapeutic decision making in patients with advanced cancer and to identify novel biomarkers of response. Patients with metastatic and treatment-resistant cancer were prospectively enrolled at a single academic center for paired metastatic tumor and normal tissue WES during a 19-month period (February 2013 through September 2014). A comprehensive computational pipeline was used to detect point mutations, indels, and copy number alterations. Mutations were categorized as category 1, 2, or 3 on the basis of actionability; clinical reports were generated and discussed in precision tumor board. Patients were observed for 7 to 25 months for correlation of molecular information with clinical response. Feasibility, use of WES for decision making, and identification of novel biomarkers. A total of 154 tumor-normal pairs from 97 patients with a range of metastatic cancers were sequenced, with a mean coverage of 95X and 16 somatic alterations detected per patient. In total, 16 mutations were category 1 (targeted therapy available), 98 were category 2 (biologically relevant), and 1474 were category 3 (unknown significance). Overall, WES provided informative results in 91 cases (94%), including alterations for which there is an approved drug, there are therapies in clinical or preclinical development, or they are considered drivers and potentially actionable (category 1-2); however, treatment was guided in only 5 patients (5%) on the basis of these recommendations because of access to clinical trials and/or off-label use of drugs. Among unexpected findings, a patient with prostate cancer with exceptional response to treatment was

  20. Breast cancer-specific intrusions are associated with increased cortisol responses to daily life stressors in healthy women without personal or family histories of breast cancer.

    PubMed

    Dettenborn, Lucia; James, Gary D; Valdimarsdottir, Heiddis B; Montgomery, Guy H; Bovbjerg, Dana H

    2006-10-01

    Studies indicate that women fear breast cancer more than any other disease and that women's levels of breast cancer-specific intrusions are related to their perceived risk of breast cancer. Here, we explore possible biological consequences of higher breast cancer risk perceptions and intrusions in healthy women without personal or family histories of the disease. We hypothesized that women with higher perceived risk would have more intrusions about breast cancer, which would constitute a background stressor sufficient to increase hypothalamus-pituitary-adrenal axis (HPA) responsivity to daily stress. HPA responses to an ordinary life stressor (work) were assessed in 141 employed women (age = 37.2+/-9.2) without personal or family histories of breast cancer. Urinary cortisol excretion rates were assessed with timed sample collections at work, home, and during sleep. Repeated measures ANOVA revealed a significant Group by Time interaction with higher work cortisol levels in women with breast cancer-specific intrusions compared to women without intrusions (p < 0.02). Regression analyses revealed a significant association between risk perceptions and intrusions (p < 0.001). Regression analysis with intrusions and risk perceptions predicting work cortisol indicated a significant contribution of intrusions (p < 0.04), but not risk perceptions (p = 0.53). Overestimation of breast cancer risk is associated with higher levels of breast cancer-specific intrusions that can result in increased cortisol responsivity to daily stressors. This heightened responsivity could have long-term negative health implications.

  1. Integration of Network Biology and Imaging to Study Cancer Phenotypes and Responses.

    PubMed

    Tian, Ye; Wang, Sean S; Zhang, Zhen; Rodriguez, Olga C; Petricoin, Emanuel; Shih, Ie-Ming; Chan, Daniel; Avantaggiati, Maria; Yu, Guoqiang; Ye, Shaozhen; Clarke, Robert; Wang, Chao; Zhang, Bai; Wang, Yue; Albanese, Chris

    2014-01-01

    Ever growing "omics" data and continuously accumulated biological knowledge provide an unprecedented opportunity to identify molecular biomarkers and their interactions that are responsible for cancer phenotypes that can be accurately defined by clinical measurements such as in vivo imaging. Since signaling or regulatory networks are dynamic and context-specific, systematic efforts to characterize such structural alterations must effectively distinguish significant network rewiring from random background fluctuations. Here we introduced a novel integration of network biology and imaging to study cancer phenotypes and responses to treatments at the molecular systems level. Specifically, Differential Dependence Network (DDN) analysis was used to detect statistically significant topological rewiring in molecular networks between two phenotypic conditions, and in vivo Magnetic Resonance Imaging (MRI) was used to more accurately define phenotypic sample groups for such differential analysis. We applied DDN to analyze two distinct phenotypic groups of breast cancer and study how genomic instability affects the molecular network topologies in high-grade ovarian cancer. Further, FDA-approved arsenic trioxide (ATO) and the ND2-SmoA1 mouse model of Medulloblastoma (MB) were used to extend our analyses of combined MRI and Reverse Phase Protein Microarray (RPMA) data to assess tumor responses to ATO and to uncover the complexity of therapeutic molecular biology.

  2. Coffee Consumption and Risk of Biliary Tract Cancers and Liver Cancer: A Dose-Response Meta-Analysis of Prospective Cohort Studies.

    PubMed

    Godos, Justyna; Micek, Agnieszka; Marranzano, Marina; Salomone, Federico; Rio, Daniele Del; Ray, Sumantra

    2017-08-28

    A meta-analysis was conducted to summarize the evidence from prospective cohort and case-control studies regarding the association between coffee intake and biliary tract cancer (BTC) and liver cancer risk. Eligible studies were identified by searches of PubMed and EMBASE databases from the earliest available online indexing year to March 2017. The dose-response relationship was assessed by a restricted cubic spline model and multivariate random-effect meta-regression. A stratified and subgroup analysis by smoking status and hepatitis was performed to identify potential confounding factors. We identified five studies on BTC risk and 13 on liver cancer risk eligible for meta-analysis. A linear dose-response meta-analysis did not show a significant association between coffee consumption and BTC risk. However, there was evidence of inverse correlation between coffee consumption and liver cancer risk. The association was consistent throughout the various potential confounding factors explored including smoking status, hepatitis, etc. Increasing coffee consumption by one cup per day was associated with a 15% reduction in liver cancer risk (RR 0.85; 95% CI 0.82 to 0.88). The findings suggest that increased coffee consumption is associated with decreased risk of liver cancer, but not BTC.

  3. Response to DNA damage of CHEK2 missense mutations in familial breast cancer

    PubMed Central

    Roeb, Wendy; Higgins, Jake; King, Mary-Claire

    2012-01-01

    Comprehensive sequencing of tumor suppressor genes to evaluate inherited predisposition to cancer yields many individually rare missense alleles of unknown functional and clinical consequence. To address this problem for CHEK2 missense alleles, we developed a yeast-based assay to assess in vivo CHEK2-mediated response to DNA damage. Of 25 germline CHEK2 missense alleles detected in familial breast cancer patients, 12 alleles had complete loss of DNA damage response, 8 had partial loss and 5 exhibited a DNA damage response equivalent to that mediated by wild-type CHEK2. Variants exhibiting reduced response to DNA damage were found in all domains of the CHEK2 protein. Assay results were in agreement with epidemiologic assessments of breast cancer risk for those variants sufficiently common for case–control studies to have been undertaken. Assay results were largely concordant with consensus predictions of in silico tools, particularly for damaging alleles in the kinase domain. However, of the 25 variants, 6 were not consistently classifiable by in silico tools. An in vivo assay of cellular response to DNA damage by mutant CHEK2 alleles may complement and extend epidemiologic and genetic assessment of their clinical consequences. PMID:22419737

  4. Response to DNA damage of CHEK2 missense mutations in familial breast cancer.

    PubMed

    Roeb, Wendy; Higgins, Jake; King, Mary-Claire

    2012-06-15

    Comprehensive sequencing of tumor suppressor genes to evaluate inherited predisposition to cancer yields many individually rare missense alleles of unknown functional and clinical consequence. To address this problem for CHEK2 missense alleles, we developed a yeast-based assay to assess in vivo CHEK2-mediated response to DNA damage. Of 25 germline CHEK2 missense alleles detected in familial breast cancer patients, 12 alleles had complete loss of DNA damage response, 8 had partial loss and 5 exhibited a DNA damage response equivalent to that mediated by wild-type CHEK2. Variants exhibiting reduced response to DNA damage were found in all domains of the CHEK2 protein. Assay results were in agreement with epidemiologic assessments of breast cancer risk for those variants sufficiently common for case-control studies to have been undertaken. Assay results were largely concordant with consensus predictions of in silico tools, particularly for damaging alleles in the kinase domain. However, of the 25 variants, 6 were not consistently classifiable by in silico tools. An in vivo assay of cellular response to DNA damage by mutant CHEK2 alleles may complement and extend epidemiologic and genetic assessment of their clinical consequences.

  5. Health responsibility and workplace health promotion among women: early detection of cancer.

    PubMed

    Kushnir, T; Rabinowitz, S; Melamed, S; Weisberg, E; Ribak, J

    1995-01-01

    The importance of health responsibility as one aspect of a health-promoting lifestyle has been emphasized repeatedly. Yet there are only a few empirical studies of its role in preventive behavior. We examined the relationship between health responsibility and early-detection practices for breast and cervical cancer. A group of 253 women employees of a large industrial company participated in a cancer screening program subsidized by the employer. They completed questionnaires assessing health responsibility and reported early-detection practices: frequency of breast self-examination and physician breast examinations, frequency of Pap tests, and time lapsed since last Pap test and breast examinations. Health responsibility was a significant independent predictor of breast examination indicators but not of Pap tests. Education level was an important predictor for Pap tests, and age predicted most early-detection practices. The findings lend some support to the role of health responsibility in initiating breast examinations. Better prediction of early-detection practices could be achieved by adding cognitive and emotional components to the existing responsibility scale and by distinguishing between retrospective and prospective responsibility.

  6. Responses to Overdiagnosis in Thyroid Cancer Screening among Korean Women.

    PubMed

    Lee, Sangeun; Lee, Yoon Young; Yoon, Hyo Joong; Choi, Eunji; Suh, Mina; Park, Boyoung; Jun, Jae Kwan; Kim, Yeol; Choi, Kui Son

    2016-07-01

    Communicating the harms and benefits of thyroid screening is necessary to help individuals decide on whether or not to undergo thyroid cancer screening. This study was conducted to assess changes in thyroid cancer screening intention in response to receiving information about overdiagnosis and to determine factors with the greatest influence thereon. Data were acquired from subjects included in the 2013 Korean National Cancer Screening Survey (KNCSS), a nationwide, population-based, cross-sectional survey. Of the 4,100 respondents in the 2013 KNCSS, women were randomly subsampled and an additional face-to-face interview was conducted. Finally, a total of 586 female subjects were included in this study. Intention to undergo thyroid cancer screening was assessed before and after receiving information on overdiagnosis. Prior awareness of overdiagnosis in thyroid cancer screening was 27.8%. The majority of subjects intended to undergo thyroid cancer screening before and after receiving information on overdiagnosis (87% and 74%, respectively). Only a small number of subjects changed their intention to undergo thyroid cancer screening from positive to negative after receiving information on overdiagnosis. Women of higher education level and Medical Aid Program recipients reported being significantly more likely to change their intention to undergo thyroid cancer screening afterreceiving information on overdiagnosis,whilewomen with stronger beliefs on the efficacy of cancer screening were less likely to change their intention. Women in Korea appeared to be less concerned about overdiagnosis when deciding whether or not to undergo thyroid cancer screening.

  7. Current Approaches and Challenges for Monitoring Treatment Response in Colon and Rectal Cancer

    PubMed Central

    McKeown, Elizabeth; Nelson, Daniel W.; Johnson, Eric K.; Maykel, Justin A.; Stojadinovic, Alexander; Nissan, Aviram; Avital, Itzhak; Brücher, Björn LDM; Steele, Scott R.

    2014-01-01

    Introduction: With the advent of multidisciplinary and multimodality approaches to the management of colorectal cancer patients, there is an increasing need to define how we monitor response to novel therapies in these patients. Several factors ranging from the type of therapy used to the intrinsic biology of the tumor play a role in tumor response. All of these can aid in determining the ideal course of treatment, and may fluctuate over time, pending down-staging or progression of disease. Therefore, monitoring how disease responds to therapy requires standardization in order to ultimately optimize patient outcomes. Unfortunately, how best to do this remains a topic of debate among oncologists, pathologists, and colorectal surgeons. There may not be one single best approach. The goal of the present article is to shed some light on current approaches and challenges to monitoring treatment response for colorectal cancer. Methods: A literature search was conducted utilizing PubMed and the OVID library. Key-word combinations included colorectal cancer metastases, neoadjuvant therapy, rectal cancer, imaging modalities, CEA, down-staging, tumor response, and biomarkers. Directed searches of the embedded references from the primary articles were also performed in selected circumstances. Results: Pathologic examination of the post-treatment surgical specimen is the gold standard for monitoring response to therapy. Endoscopy is useful for evaluating local recurrence, but not in assessing tumor response outside of the limited information gained by direct examination of intra-lumenal lesions. Imaging is used to monitor tumors throughout the body for response, with CT, PET, and MRI employed in different circumstances. Overall, each has been validated in the monitoring of patients with colorectal cancer and residual tumors. Conclusion: Although there is no imaging or serum test to precisely correlate with a tumor's response to chemo- or radiation therapy, these modalities

  8. Using response evaluation criteria in solid tumors in real-world evidence cancer research.

    PubMed

    Feinberg, Bruce A; Bharmal, Murtuza; Klink, Andrew J; Nabhan, Chadi; Phatak, Hemant

    2018-05-31

    Real-world evidence of charted treatment responses to cancer drug therapy was compared with medical record derived radiographic measurements of target lesions per Response Evaluation Criteria in Solid Tumors (RECIST). 15 physicians treating 59 metastatic Merkel cell cancer (mMCC) patients contributed patient-level data. A comparison of medical record reported best response with radiographic measurements per RECIST of pre- and post-treatment target lesions. RECIST response rates were significantly lower compared with medical record reported with a concordance of 43.2% (95% CI: 28.0-58.4%). Subjective assessment of tumor response collected via traditional chart abstraction may overestimate benefit and limit the potential role of real-world evidence in value-based care research. The use of target lesion measurements presents an attractive alternative that better aligns with trial results.

  9. Identifying Regulators of the Immune Response to Dying Cells | Center for Cancer Research

    Cancer.gov

    Cytotoxic T cells are responsible for carrying out antigen-mediated immune responses against virally-infected and malignant cells. In both cases, cytotoxic T cells are stimulated by interacting with antigen presenting cells, such as dendritic cells (DCs). Infected cells produce virus-specific antigens and pathogen associated molecular patterns, which are recognized by DCs and lead to robust T cell activation. Dead or dying uninfected cells, on the other hand, release damage associated molecular patterns, but their release does not always appear to be sufficient to induce cytotoxic T cell activity. Tim Greten, M.D., of CCR’s Medical Oncology Branch, and a group of international collaborators set out to understand how immune responses against dying cancer cells are regulated. These processes are likely to be important for improving the efficacy of cancer treatment vaccines, which induce an immune reaction against a patient’s cancer cells.

  10. FAS Death Receptor: A Breast Cancer Subtype-Specific Radiation Response Biomarker and Potential Therapeutic Target

    PubMed Central

    Horton, Janet K.; Siamakpour-Reihani, Sharareh; Lee, Chen-Ting; Zhou, Ying; Chen, Wei; Geradts, Joseph; Fels, Diane R.; Hoang, Peter; Ashcraft, Kathleen A.; Groth, Jeff; Kung, Hsiu-Ni; Dewhirst, Mark W.; Chi, Jen-Tsan A.

    2015-01-01

    Although a standardized approach to radiotherapy has been used to treat breast cancer, regardless of subtype (e.g., luminal, basal), recent clinical data suggest that radiation response may vary significantly among subtypes. We hypothesized that this clinical variability may be due, in part, to differences in cellular radiation response. In this study, we utilized RNA samples for microarray analysis from two sources: 1. Paired pre- and postirradiation breast tumor tissue from 32 early-stage breast cancer patients treated in our unique preoperative radiation Phase I trial; and 2. Sixteen biologically diverse breast tumor cell lines exposed to 0 and 5 Gy irradiation. The transcriptome response to radiation exposure was derived by comparing gene expression in samples before and after irradiation. Genes with the highest coefficient of variation were selected for further evaluation and validated at the RNA and protein level. Gene editing and agonistic antibody treatment were performed to assess the impact of gene modulation on radiation response. Gene expression in our cohort of luminal breast cancer patients was distinctly different before and after irradiation. Further, two distinct patterns of gene expression were observed in our biologically diverse group of breast cancer cell lines pre- versus postirradiation. Cell lines that showed significant change after irradiation were largely luminal subtype, while gene expression in the basal and HER2+ cell lines was minimally impacted. The 100 genes with the most significant response to radiation in patients were identified and analyzed for differential patterns of expression in the radiation-responsive versus nonresponsive cell lines. Fourteen genes were identified as significant, including FAS, a member of the tumor necrosis factor receptor family known to play a critical role in programed cell death. Modulation of FAS in breast cancer cell lines altered radiation response phenotype and enhanced radiation sensitivity in

  11. Bladder Cancer Treatment Response Assessment in CT using Radiomics with Deep-Learning.

    PubMed

    Cha, Kenny H; Hadjiiski, Lubomir; Chan, Heang-Ping; Weizer, Alon Z; Alva, Ajjai; Cohan, Richard H; Caoili, Elaine M; Paramagul, Chintana; Samala, Ravi K

    2017-08-18

    Cross-sectional X-ray imaging has become the standard for staging most solid organ malignancies. However, for some malignancies such as urinary bladder cancer, the ability to accurately assess local extent of the disease and understand response to systemic chemotherapy is limited with current imaging approaches. In this study, we explored the feasibility that radiomics-based predictive models using pre- and post-treatment computed tomography (CT) images might be able to distinguish between bladder cancers with and without complete chemotherapy responses. We assessed three unique radiomics-based predictive models, each of which employed different fundamental design principles ranging from a pattern recognition method via deep-learning convolution neural network (DL-CNN), to a more deterministic radiomics feature-based approach and then a bridging method between the two, utilizing a system which extracts radiomics features from the image patterns. Our study indicates that the computerized assessment using radiomics information from the pre- and post-treatment CT of bladder cancer patients has the potential to assist in assessment of treatment response.

  12. Characterizing Cancer Drug Response and Biological Correlates: A Geometric Network Approach.

    PubMed

    Pouryahya, Maryam; Oh, Jung Hun; Mathews, James C; Deasy, Joseph O; Tannenbaum, Allen R

    2018-04-23

    In the present work, we apply a geometric network approach to study common biological features of anticancer drug response. We use for this purpose the panel of 60 human cell lines (NCI-60) provided by the National Cancer Institute. Our study suggests that mathematical tools for network-based analysis can provide novel insights into drug response and cancer biology. We adopted a discrete notion of Ricci curvature to measure, via a link between Ricci curvature and network robustness established by the theory of optimal mass transport, the robustness of biological networks constructed with a pre-treatment gene expression dataset and coupled the results with the GI50 response of the cell lines to the drugs. Based on the resulting drug response ranking, we assessed the impact of genes that are likely associated with individual drug response. For genes identified as important, we performed a gene ontology enrichment analysis using a curated bioinformatics database which resulted in biological processes associated with drug response across cell lines and tissue types which are plausible from the point of view of the biological literature. These results demonstrate the potential of using the mathematical network analysis in assessing drug response and in identifying relevant genomic biomarkers and biological processes for precision medicine.

  13. Response to luteinizing releasing hormone, thyrotrophic releasing hormone, and human chorionic gonadotropin administration in healthy men at different risks for prostatic cancer and in prostatic cancer patients.

    PubMed

    Hill, P; Wynder, E L; Garbaczewski, L; Garnes, H; Walker, A R

    1982-05-01

    A comparative study of the pituitary and testicular response to luteinizing releasing hormone (LHRH), thyrotrophic releasing hormone (TRH), and human chorionic gonadotrophin (HCG) administration was carried out in (a) low-risk young South African black men and high-risk North American black men for prostatic cancer and (b) healthy elderly South African men and South African black men with prostatic cancer. A comparable HCG response occurred in young South African and North American black men, while a greater release of prolactin, but a lesser release of luteinizing hormone in response to LHRH:TRH occurred in South African black men. The response to HCG was comparable in elderly and young South African black men, although the prolactin release in response to TRH was greater in elderly men. A more prolonged release of luteinizing hormone was evident in men with prostatic cancer. Higher estradiol and estrone but lower androstenedione levels occurred in men with prostatic cancer. Data suggest that, in the elderly South African black men with prostatic cancer, estrogen metabolism is modified and that either the estrogen level or the higher estrogen:androgen levels modify the pituitary response to LHRH:TRH. A Western diet enhanced the changes in hormone profiles evident in black South African men with prostatic cancer.

  14. At the Bench: Helicobacter pylori, dysregulated host responses, DNA damage, and gastric cancer

    PubMed Central

    Hardbower, Dana M.; Peek, Richard M.; Wilson, Keith T.

    2014-01-01

    Helicobacter pylori infection is the strongest known risk factor for the development of gastric cancer. Given that ∼50% of the global population is infected with this pathogen, there is great impetus to elucidate underlying causes that mediate progression from infection to cancer. Recent evidence suggests that H. pylori-induced chronic inflammation and oxidative stress create an environment conducive to DNA damage and tissue injury. DNA damage leads to genetic instability and eventually, neoplastic transformation. Pathogen-encoded virulence factors induce a robust but futile immune response and alter host pathways that lower the threshold for carcinogenesis, including DNA damage repair, polyamine synthesis and catabolism, antioxidant responses, and cytokine production. Collectively, such dysregulation creates a protumorigenic microenvironment within the stomach. This review seeks to address each of these aspects of H. pylori infection and to call attention to areas of particular interest within this field of research. This review also seeks to prioritize areas of translational research related to H. pylori-induced gastric cancer based on insights garnered from basic research in this field. See related review by Dalal and Moss, At the Bedside: H. pylori, dysregulated host responses, DNA damage, and gastric cancer. PMID:24868089

  15. Heterogeneity in cancer cells: variation in drug response in different primary and secondary colorectal cancer cell lines in vitro.

    PubMed

    Arul, Melanie; Roslani, April Camilla; Cheah, Swee Hung

    2017-05-01

    Tumor heterogeneity may give rise to differential responses to chemotherapy drugs. Therefore, unraveling tumor heterogeneity has an implication for biomarker discovery and cancer therapeutics. To test this phenomenon, we investigated the differential responses of three secondary colorectal cancer cell lines of different origins (HCT116, HT29, and SW620 cells) and four novel primary cell lines obtained from different colorectal cancer patients to 5-fluorouracil (5-FU) and oxaliplatin (L-OHP) and explored the differences in gene expression among the primary cell lines in response to exposure to cytotoxic drugs. Cells were exposed to different doses of 5-FU and L-OHP separately or in combinations of equitoxic drug or equimolar drug ratios (median effect of Chou-Talalay principle). Cell viability was assessed using MTT assay and the respective IC 50 values were determined. Changes in gene expression in primary cell lines after exposure to the same drug doses were compared using real-time PCR array. The sensitivities (IC 50 ) of different cell lines, both secondary and primary, to 5-FU and L-OHP were significantly different, whether in monotherapy or combined treatment. Primary cell lines needed higher doses to reach IC 50 . There were variations in gene expression among the primary cell lines of different chemosensitivities to the challenge of the same combined dose of 5-FU and L-OHP. The results confirm the heterogeneous nature of colorectal cancer cells from different patient tumors. Studies using primary cancer cells established from patient's tumors rather than secondary cell lines will more closely reflect the actual character of the disease.

  16. Coffee Consumption and Risk of Biliary Tract Cancers and Liver Cancer: A Dose–Response Meta-Analysis of Prospective Cohort Studies

    PubMed Central

    Micek, Agnieszka; Marranzano, Marina; Ray, Sumantra

    2017-01-01

    Background: A meta-analysis was conducted to summarize the evidence from prospective cohort and case-control studies regarding the association between coffee intake and biliary tract cancer (BTC) and liver cancer risk. Methods: Eligible studies were identified by searches of PubMed and EMBASE databases from the earliest available online indexing year to March 2017. The dose–response relationship was assessed by a restricted cubic spline model and multivariate random-effect meta-regression. A stratified and subgroup analysis by smoking status and hepatitis was performed to identify potential confounding factors. Results: We identified five studies on BTC risk and 13 on liver cancer risk eligible for meta-analysis. A linear dose–response meta-analysis did not show a significant association between coffee consumption and BTC risk. However, there was evidence of inverse correlation between coffee consumption and liver cancer risk. The association was consistent throughout the various potential confounding factors explored including smoking status, hepatitis, etc. Increasing coffee consumption by one cup per day was associated with a 15% reduction in liver cancer risk (RR 0.85; 95% CI 0.82 to 0.88). Conclusions: The findings suggest that increased coffee consumption is associated with decreased risk of liver cancer, but not BTC. PMID:28846640

  17. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers

    PubMed Central

    Bronte, Vincenzo; Kasic, Tihana; Gri, Giorgia; Gallana, Keti; Borsellino, Giovanna; Marigo, Ilaria; Battistini, Luca; Iafrate, Massimo; Prayer-Galetti, Tommaso; Pagano, Francesco; Viola, Antonella

    2005-01-01

    Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix–supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy. PMID:15824085

  18. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers.

    PubMed

    Bronte, Vincenzo; Kasic, Tihana; Gri, Giorgia; Gallana, Keti; Borsellino, Giovanna; Marigo, Ilaria; Battistini, Luca; Iafrate, Massimo; Prayer-Galetti, Tommaso; Pagano, Francesco; Viola, Antonella

    2005-04-18

    Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix-supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy.

  19. pH-Responsive Wormlike Micelles with Sequential Metastasis Targeting Inhibit Lung Metastasis of Breast Cancer.

    PubMed

    He, Xinyu; Yu, Haijun; Bao, Xiaoyue; Cao, Haiqiang; Yin, Qi; Zhang, Zhiwen; Li, Yaping

    2016-02-18

    Cancer metastasis is the main cause for the high mortality in breast cancer patients. Herein, we first report succinobucol-loaded pH-responsive wormlike micelles (PWMs) with sequential targeting capability to inhibit lung metastasis of breast cancer. PWMs can in a first step be delivered specifically to the sites of metastases in the lungs and then enable the intracellular pH-stimulus responsive drug release in cancer cells to improve the anti-metastatic effect. PWMs are identified as nanofibrillar assemblies with a diameter of 19.9 ± 1.9 nm and a length within the 50-200 nm range, and exhibited pH-sensitive drug release behavior in response to acidic intracellular environments. Moreover, PWMs can obviously inhibit the migration and invasion abilities of metastatic 4T1 breast cancer cells, and reduce the expression of the metastasis-associated vascular cell adhesion molecule-1 (VCAM-1) at 400 ng mL(-1) of succinobucol. In particular, PWMs can induce a higher specific accumulation in lung and be specifically delivered to the sites of metastases in lung, thereby leading to an 86.6% inhibition on lung metastasis of breast cancer. Therefore, the use of sequentially targeting PWMs can become an encouraging strategy for specific targeting and effective treatment of cancer metastasis. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Pattern response of dendritic cells in the tumor microenvironment and breast cancer

    PubMed Central

    da Cunha, Alessandra; Michelin, Marcia A; Murta, Eddie FC

    2014-01-01

    Breast cancer (BC) is the most common malignant neoplasm and the cause of death by cancer among women worldwide. Its development, including malignancy grade and patient prognosis, is influenced by various mutations that occur in the tumor cell and by the immune system’s status, which has a direct influence on the tumor microenvironment and, consequently, on interactions with non-tumor cells involved in the immunological response. Among the immune response cells, dendritic cells (DCs) play a key role in the induction and maintenance of anti-tumor responses owing to their unique abilities for antigen cross-presentation and promotion of the activation of specific lymphocytes that target neoplasic cells. However, the tumor microenvironment can polarize DCs, transforming them into immunosuppressive regulatory DCs, a tolerogenic phenotype which limits the activity of effector T cells and supports tumor growth and progression. Various factors and signaling pathways have been implicated in the immunosuppressive functioning of DCs in cancer, and researchers are working on resolving processes that can circumvent tumor escape and developing viable therapeutic interventions to prevent or reverse the expression of immunosuppressive DCs in the tumor microenvironment. A better understanding of the pattern of DC response in patients with BC is fundamental to the development of specific therapeutic approaches to enable DCs to function properly. Various studies examining DCs immunotherapy have demonstrated its great potential for inducing immune responses to specific antigens and thereby reversing immunosuppression and related to clinical response in patients with BC. DC-based immunotherapy research has led to immense scientific advances, both in our understanding of the anti-tumor immune response and for the treatment of these patients. PMID:25114862

  1. Photodynamic therapy for cancer and activation of immune response

    NASA Astrophysics Data System (ADS)

    Mroz, Pawel; Huang, Ying-Ying; Hamblin, Michael R.

    2010-02-01

    Anti-tumor immunity is stimulated after PDT for cancer due to the acute inflammatory response, exposure and presentation of tumor-specific antigens, and induction of heat-shock proteins and other danger signals. Nevertheless effective, powerful tumor-specific immune response in both animal models and also in patients treated with PDT for cancer, is the exception rather than the rule. Research in our laboratory and also in others is geared towards identifying reasons for this sub-optimal immune response and discovering ways of maximizing it. Reasons why the immune response after PDT is less than optimal include the fact that tumor-antigens are considered to be self-like and poorly immunogenic, the tumor-mediated induction of CD4+CD25+foxP3+ regulatory T-cells (T-regs), that are able to inhibit both the priming and the effector phases of the cytotoxic CD8 T-cell anti-tumor response and the defects in dendritic cell maturation, activation and antigen-presentation that may also occur. Alternatively-activated macrophages (M2) have also been implicated. Strategies to overcome these immune escape mechanisms employed by different tumors include combination regimens using PDT and immunostimulating treatments such as products obtained from pathogenic microorganisms against which mammals have evolved recognition systems such as PAMPs and toll-like receptors (TLR). This paper will cover the use of CpG oligonucleotides (a TLR9 agonist found in bacterial DNA) to reverse dendritic cell dysfunction and methods to remove the immune suppressor effects of T-regs that are under active study.

  2. Diet Modulation is an Effective Complementary Agent in Preventing and Treating Breast Cancer Lung Metastasis

    PubMed Central

    Zhao, Xiangmin; Rezonzew, Gabriel; Wang, Dezhi; Siegal, Gene P.; Hardy, Robert W.

    2014-01-01

    A significant percentage of breast cancer victims will suffer from metastases indicating that new approaches to preventing breast cancer metastasis are thus needed. Dietary stearate and chemotherapy have been shown to reduce breast cancer metastasis. We tested the complementary use of dietary stearate with a taxol-based chemotherapy which work through separate mechanisms to reduce breast cancer metastasis. We therefore carried out a prevention study in which diets were initiated prior to human MDA-MB-435 cancer cells being injected into the host and a treatment study in which diets were combined with paclitaxel (PTX). Using an orthotopic athymic nude mouse model and three diets (corn oil control diet/CO, low fat /LF or stearate/ST) the prevention study demonstrated that the ST diet decreased the incidence of lung metastasis by 50% compared to both the LF and CO diets. The ST diet also reduced the number and size of metastatic lung nodules compared to the LF diet. Results of the treatment study indicated that both the CO and ST diets decreased the number of mice with lung metastasis compared to the LF diet. Both CO and ST also decreased the number of lung metastases per mouse compared to the LF diet however only the ST diet cohort was significant. Histomorphometric analysis of the lung tumor tissue indicated that the ST diet plus PTX decreased angiogenesis compared to the LF diet plus PTX. In conclusion these results support combining diet with chemotherapy in both treatment and prevention settings. PMID:24832758

  3. Dual stimuli-responsive smart beads that allow "on-off" manipulation of cancer cells.

    PubMed

    Kim, Young-Jin; Kim, Soo Hyeon; Fujii, Teruo; Matsunaga, Yukiko T

    2016-06-24

    Temperature- and electric field-responsive polymer-conjugated polystyrene beads, termed smart beads, are designed to isolate cancer cells. In smart beads, the reversible "on-off" antigen-antibody reaction and dielectrophoresis force on an electrode are accomplished to realize "on-off" remote manipulation of smart beads and cancer cells. Both the zeta-potential and the hydrodynamic diameter of the smart beads are sensitive to temperature, allowing "on-off" reversible capture and release of cancer cells. Cancer cell-captured smart beads are then localized on electrodes by applying an electrical signal.

  4. Complete radiotherapy response in rectal cancer: A review of the evidence

    PubMed Central

    Couch, Daniel G; Hemingway, David M

    2016-01-01

    Complete response to chemoradiotherapy for rectal cancer is becoming a common clinical entity. Techniques to diagnose complete response and how to survey these patients without operative intervention are still unclear. We review the most recent evidence. Barriers to firm conclusions regarding this are heterogeneity of diagnostic definitions, differing surveillance protocols, and a lack of randomised studies. PMID:26811600

  5. Complete radiotherapy response in rectal cancer: A review of the evidence.

    PubMed

    Couch, Daniel G; Hemingway, David M

    2016-01-14

    Complete response to chemoradiotherapy for rectal cancer is becoming a common clinical entity. Techniques to diagnose complete response and how to survey these patients without operative intervention are still unclear. We review the most recent evidence. Barriers to firm conclusions regarding this are heterogeneity of diagnostic definitions, differing surveillance protocols, and a lack of randomised studies.

  6. [Persistence of chronic inflammatory responses, role in the development of chronic pancreatitis, obesity and pancreatic cancer].

    PubMed

    Khristich, T N

    2014-11-01

    The purpose of the review--to analyze the basic data of the role of chronic low-intensity inflammatory response as general biological process in the development and progression of chronic pancreatitis, obesity, and pancreatic cancer. Highlighted evidence from epidemiological studies showing that chronic pancreatitis and obesity are independent risk factors for pancreatic cancer, regardless of diabetes. Studied role of adipokines as Cytokines regulating of immune inflammatory response. Draws attention to the staging of pancreatic cancer in obesity.

  7. Prognostic value of neoadjuvant treatment response in locally advanced rectal cancer.

    PubMed

    Sada, Yvonne H; Tran Cao, Hop S; Chang, George J; Artinyan, Avo; Musher, Benjamin L; Smaglo, Brandon G; Massarweh, Nader N

    2018-06-01

    For locally advanced rectal cancer, response to neoadjuvant radiation has been associated with improved outcomes but has not been well characterized in general practice. The goals of this study were to describe disease response rates after neoadjuvant treatment and to evaluate the association between disease response and survival. Retrospective cohort study of patients aged 18-80 y with clinical stage II and III rectal adenocarcinoma in the National Cancer Database (2006-2012). All patients underwent radical resection after neoadjuvant treatment. Treatment responses were defined as follows: no tumor response; intermediate-T and/or N downstaging with residual disease; and complete-ypT0N0. Multivariable, multinomial regression was used to evaluate the association between neoadjuvant radiation use and disease response. Multivariable Cox regression was used to evaluate the association between disease response and overall risk of death. Among 12,024 patients, 12% had a complete and 30% an intermediate response. Neoadjuvant chemotherapy alone was less likely to achieve an intermediate (relative risk ratio: 0.70 [0.56-0.88]) or a complete response (relative risk ratio: 0.59 [0.41-0.84]) relative to neoadjuvant radiation. Tumor response was associated with improved 5-y overall survival (complete = 90.2%, intermediate = 82.0%, no response = 70.5%; log-rank, P < 0.001). Complete and intermediate pathologic responses were associated with decreases in risk of death (hazard ratio: 0.40 [0.34-0.48] and 0.63 [0.57-0.69], respectively) compared to no response. Primary tumor and nodal response were independently associated with decreased risk of death. Neoadjuvant radiation is associated with treatment response, and pathologic response is associated with improved survival. Pathologic response may be an early benchmark for the oncologic effectiveness of neoadjuvant treatment. Published by Elsevier Inc.

  8. Systematic review of FDG-PET prediction of complete pathological response and survival in rectal cancer.

    PubMed

    Memon, Sameer; Lynch, A Craig; Akhurst, Timothy; Ngan, Samuel Y; Warrier, Satish K; Michael, Michael; Heriot, Alexander G

    2014-10-01

    Advances in the management of rectal cancer have resulted in an increased application of multimodal therapy with the aim of tailoring therapy to individual patients. Complete pathological response (pCR) is associated with improved survival and may be potentially managed without radical surgical resection. Over the last decade, there has been increasing interest in the ability of functional imaging to predict complete response to treatment. The aim of this review was to assess the role of (18)F-flurordeoxyglucose positron emission tomography (FDG-PET) in prediction of pCR and prognosis in resectable locally advanced rectal cancer. A search of the MEDLINE and Embase databases was conducted, and a systematic review of the literature investigating positron emission tomography (PET) in the prediction of pCR and survival in rectal cancer was performed. Seventeen series assessing PET prediction of pCR were included in the review. Seven series assessed postchemoradiation SUVmax, which was significantly different between response groups in all six studies that assessed this. Nine series assessed the response index (RI) for SUVmax, which was significantly different between response groups in seven series. Thirteen studies investigated PET response for prediction of survival. Metabolic complete response assessed by SUV2max or visual response and RISUVmax showed strong associations with disease-free survival (DFS) and overall survival (OS). SUV2max and RISUVmax appear to be useful FDG-PET markers for prediction of pCR and these parameters also show strong associations with DFS and OS. FDG-PET may have a role in outcome prediction in patients with advanced rectal cancer.

  9. Development of a stress response therapy targeting aggressive prostate cancer.

    PubMed

    Nguyen, Hao G; Conn, Crystal S; Kye, Yae; Xue, Lingru; Forester, Craig M; Cowan, Janet E; Hsieh, Andrew C; Cunningham, John T; Truillet, Charles; Tameire, Feven; Evans, Michael J; Evans, Christopher P; Yang, Joy C; Hann, Byron; Koumenis, Constantinos; Walter, Peter; Carroll, Peter R; Ruggero, Davide

    2018-05-02

    Oncogenic lesions up-regulate bioenergetically demanding cellular processes, such as protein synthesis, to drive cancer cell growth and continued proliferation. However, the hijacking of these key processes by oncogenic pathways imposes onerous cell stress that must be mitigated by adaptive responses for cell survival. The mechanism by which these adaptive responses are established, their functional consequences for tumor development, and their implications for therapeutic interventions remain largely unknown. Using murine and humanized models of prostate cancer (PCa), we show that one of the three branches of the unfolded protein response is selectively activated in advanced PCa. This adaptive response activates the phosphorylation of the eukaryotic initiation factor 2-α (P-eIF2α) to reset global protein synthesis to a level that fosters aggressive tumor development and is a marker of poor patient survival upon the acquisition of multiple oncogenic lesions. Using patient-derived xenograft models and an inhibitor of P-eIF2α activity, ISRIB, our data show that targeting this adaptive brake for protein synthesis selectively triggers cytotoxicity against aggressive metastatic PCa, a disease for which presently there is no cure. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  10. Identification of the Microtubule-Inhibitor Activated Bcl-xL Kinase: A Regulator of Breast Cancer Cell Chemosensitivity to Taxol

    DTIC Science & Technology

    2011-08-01

    not shown). 1 5 Translational research study We continued the clinical protocol entitled “Alterations in the Bcl-2 Family Proteins...Bcl- 2 protein phosphorylation in hematopoietic cells may be more likely to have fever, neutropenia than others, for example. While effective...Alterations in the Bcl-2 Family Proteins in the Peripheral Blood Following Treatment with Taxanes in Patients with Breast Cancer.” Accepted by the UAMS

  11. Young women's responses to smoking and breast cancer risk information

    PubMed Central

    Bottorff, Joan L.; McKeown, Stephanie Barclay; Carey, Joanne; Haines, Rebecca; Okoli, Chizimuzo; Johnson, Kenneth C.; Easley, Julie; Ferrence, Roberta; Baillie, Lynne; Ptolemy, Erin

    2010-01-01

    Current evidence confirms that young women who smoke or who have regular long-term exposure to secondhand smoke (SHS) have an increased risk of developing premenopausal breast cancer. The aim of this research was to examine the responses of young women to health information about the links between active smoking and SHS exposure and breast cancer and obtain their advice about messaging approaches. Data were collected in focus groups with 46 women, divided in three age cohorts: 15–17, 18–19 and 20–24 and organized according to smoking status (smoking, non-smoking and mixed smoking status groups). The discussion questions were preceded by information about passive and active smoking and its associated breast cancer risk. The study findings show young women's interest in this risk factor for breast cancer. Three themes were drawn from the analysis: making sense of the information on smoking and breast cancer, personal susceptibility and tobacco exposure and suggestions for increasing awareness about tobacco exposure and breast cancer. There was general consensus on framing public awareness messages about this risk factor on ‘protecting others’ from breast cancer to catch smokers’ attention, providing young women with the facts and personal stories of breast cancer to help establish a personal connection with this information and overcome desensitization related to tobacco messages, and targeting all smokers who may place young women at risk. Cautions were also raised about the potential for stigmatization. Implications for raising awareness about this modifiable risk factor for breast cancer are discussed. PMID:20080807

  12. State of the Art of Stimuli-Responsive Liposomes for Cancer Therapy

    PubMed Central

    Heidarli, Elmira; Dadashzadeh, Simin; Haeri, Azadeh

    2017-01-01

    Specific delivery of therapeutic agents to solid tumors and their bioavailability at the target site are the most clinically important and challenging goals in cancer therapy. Liposomes are promising nanocarriers and have been well investigated for cancer therapy. In spite of preferred accumulation in tumors via the enhanced permeability and retention (EPR) effect, inefficient drug release at the target site and endosomal entrapment of long circulating liposomes are very important obstacles for achieving maximum anticancer efficacy. Thus, additional strategies such as stimulus-sensitive drug release are necessary to improve efficacy. Stimuli-sensitive liposomes are stable in blood circulation, however, activated by responding to external or internal stimuli and control the cargo release at the target site. This review focuses on state of the art of stimuli-responsive liposomes. Both external stimuli-responsive liposomes, including hyperthermia (HT), magnetic, light, and ultrasound-sensitive liposomes and internal stimuli (pH, reduction, and enzyme) responsive liposomes are covered. PMID:29552041

  13. State of the Art of Stimuli-Responsive Liposomes for Cancer Therapy.

    PubMed

    Heidarli, Elmira; Dadashzadeh, Simin; Haeri, Azadeh

    2017-01-01

    Specific delivery of therapeutic agents to solid tumors and their bioavailability at the target site are the most clinically important and challenging goals in cancer therapy. Liposomes are promising nanocarriers and have been well investigated for cancer therapy. In spite of preferred accumulation in tumors via the enhanced permeability and retention (EPR) effect, inefficient drug release at the target site and endosomal entrapment of long circulating liposomes are very important obstacles for achieving maximum anticancer efficacy. Thus, additional strategies such as stimulus-sensitive drug release are necessary to improve efficacy. Stimuli-sensitive liposomes are stable in blood circulation, however, activated by responding to external or internal stimuli and control the cargo release at the target site. This review focuses on state of the art of stimuli-responsive liposomes. Both external stimuli-responsive liposomes, including hyperthermia (HT), magnetic, light, and ultrasound-sensitive liposomes and internal stimuli (pH, reduction, and enzyme) responsive liposomes are covered.

  14. Pathological response of locally advanced rectal cancer to preoperative chemotherapy without pelvic irradiation.

    PubMed

    Bensignor, T; Brouquet, A; Dariane, C; Thirot-Bidault, A; Lazure, T; Julié, C; Nordlinger, B; Penna, C; Benoist, S

    2015-06-01

    Pathological response to chemotherapy without pelvic irradiation is not well defined in rectal cancer. This study aimed to evaluate the objective pathological response to preoperative chemotherapy without pelvic irradiation in middle or low locally advanced rectal cancer (LARC). Between 2008 and 2013, 22 patients with middle or low LARC (T3/4 and/or N+ and circumferential resection margin < 2 mm) and synchronous metastatic disease or a contraindication to pelvic irradiation underwent rectal resection after preoperative chemotherapy. The pathological response of rectal tumour was analysed according to the Rödel tumour regression grading (TRG) system. Predictive factors of objective pathological response (TRG 2-4) were analysed. All patients underwent rectal surgery after a median of six cycles of preoperative chemotherapy. Of these, 20 (91%) had sphincter saving surgery and an R0 resection. Twelve (55%) patients had an objective pathological response (TRG 2-4), including one complete response. Poor response (TRG 0-1) to chemotherapy was noted in 10 (45%) patients. In univariate analyses, none of the factors examined was found to be predictive of an objective pathological response to chemotherapy. At a median follow-up of 37.2 months, none of the 22 patients experienced local recurrence. Of the 19 patients with Stage IV rectal cancer, 15 (79%) had liver surgery with curative intent. Preoperative chemotherapy without pelvic irradiation is associated with objective pathological response and adequate local control in selected patients with LARC. Further prospective controlled studies will address the question of whether it can be used as a valuable alternative to radiochemotherapy in LARC. Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.

  15. Predictors of Responses to Corticosteroids for Cancer-Related Fatigue in Advanced Cancer Patients: A Multicenter, Prospective, Observational Study.

    PubMed

    Matsuo, Naoki; Morita, Tatsuya; Matsuda, Yoshinobu; Okamoto, Kenichiro; Matsumoto, Yoshihisa; Kaneishi, Keisuke; Odagiri, Takuya; Sakurai, Hiroki; Katayama, Hideki; Mori, Ichiro; Yamada, Hirohide; Watanabe, Hiroaki; Yokoyama, Taro; Yamaguchi, Takashi; Nishi, Tomohiro; Shirado, Akemi; Hiramoto, Shuji; Watanabe, Toshio; Kohara, Hiroyuki; Shimoyama, Satofumi; Aruga, Etsuko; Baba, Mika; Sumita, Koki; Iwase, Satoru

    2016-07-01

    Although corticosteroids are widely used to relieve cancer-related fatigue (CRF), information regarding the factors predicting responses to corticosteroids remains limited. The aim of this study was to identify potential factors predicting responses to corticosteroids for CRF in advanced cancer patients. Inclusion criteria for this multicenter, prospective, observational study were patients who had metastatic or locally advanced cancer and had a fatigue intensity score of 4 or more on a 0-10 Numerical Rating Scale (NRS). Univariate and multivariate analyses were conducted to identify the factors predicting two-point reduction or more in NRS on day 3. Among 179 patients who received corticosteroids, 86 (48%; 95% CI 41%-56%) had a response with two-point reduction or more. Factors that significantly predicted responses were performance status score of 3 or more, Palliative Performance Scale score more than 40, absence of ascites, absence of drowsiness, absence of depression, serum albumin level greater than 3 mg/dL, serum sodium level greater than 135 mEq/L, and baseline NRS score greater than 5. A multivariate analysis showed that the independent factors predicting responses were baseline NRS score greater than 5 (odds ratio [OR] 6.6, 95% CI 2.8-15.4), Palliative Performance Scale score more than 40 (OR 4.4, 95% CI 2.1-9.3), absence of drowsiness (OR 3.4, 95% CI 1.7-6.9), absence of ascites (OR 2.3, 95% CI 1.1-4.7), and absence of pleural effusion (OR 2.2, 95% CI 1.0-5.0). Treatment responses to corticosteroids for CRF may be predicted by baseline symptom intensity, performance status, drowsiness, and severity of fluid retention symptoms. Larger prospective studies are needed to confirm these results. Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

  16. Cellular immune responses against CT7 (MAGE-C1) and humoral responses against other cancer-testis antigens in multiple myeloma patients

    PubMed Central

    Lendvai, Nikoletta; Gnjatic, Sacha; Ritter, Erika; Mangone, Michael; Austin, Wayne; Reyner, Karina; Jayabalan, David; Niesvizky, Ruben; Jagannath, Sundar; Bhardwaj, Nina; Chen-Kiang, Selina; Old, Lloyd J.

    2010-01-01

    The type I melanoma antigen gene (MAGE) proteins CT7 (MAGE-C1) and MAGE-A3 are commonly expressed in multiple myeloma (MM), and their expression correlates with increased plasma cell proliferation and poor clinical outcome. They belong to the cancer-testis antigen (CTAg) group of tumor-associated proteins, some of which elicit spontaneous immune responses in cancer patients. CT7 and MAGE-A3 are promising antigenic targets for therapeutic tumor vaccines in myeloma; therefore, it is critical to determine if they are immunogenic in MM patients. We analyzed cellular and humoral immune responses against CTAgs in patients with plasma cell dyscrasias: MM, monoclonal gammopathy of undetermined significance (MGUS), and Waldenström's macroglobulinemia (WM). Bone marrow lymphocytes from two of four untreated MM patients exhibited CT7-specific cellular immune responses as measured by an autologous cellular immunity assay, the first such immune response to CT7 to be reported in cancer patients. Sera from 24 patients were screened by ELISA for humoral immune responses to CTAgs. Two patients with MM demonstrated positive titers, one for MAGE-A1 and the other for SSX1. These data demonstrate that CTAgs, particularly CT7, are immunogenic in MM patients and merit further exploration as targets of immunological therapy in MM. PMID:20108890

  17. Cellular immune responses against CT7 (MAGE-C1) and humoral responses against other cancer-testis antigens in multiple myeloma patients.

    PubMed

    Lendvai, Nikoletta; Gnjatic, Sacha; Ritter, Erika; Mangone, Michael; Austin, Wayne; Reyner, Karina; Jayabalan, David; Niesvizky, Ruben; Jagannath, Sundar; Bhardwaj, Nina; Chen-Kiang, Selina; Old, Lloyd J; Cho, Hearn Jay

    2010-01-29

    The type I melanoma antigen gene (MAGE) proteins CT7 (MAGE-C1) and MAGE-A3 are commonly expressed in multiple myeloma (MM), and their expression correlates with increased plasma cell proliferation and poor clinical outcome. They belong to the cancer-testis antigen (CTAg) group of tumor-associated proteins, some of which elicit spontaneous immune responses in cancer patients. CT7 and MAGE-A3 are promising antigenic targets for therapeutic tumor vaccines in myeloma; therefore, it is critical to determine if they are immunogenic in MM patients. We analyzed cellular and humoral immune responses against CTAgs in patients with plasma cell dyscrasias: MM, monoclonal gammopathy of undetermined significance (MGUS), and Waldenström's macroglobulinemia (WM). Bone marrow lymphocytes from two of four untreated MM patients exhibited CT7-specific cellular immune responses as measured by an autologous cellular immunity assay, the first such immune response to CT7 to be reported in cancer patients. Sera from 24 patients were screened by ELISA for humoral immune responses to CTAgs. Two patients with MM demonstrated positive titers, one for MAGE-A1 and the other for SSX1. These data demonstrate that CTAgs, particularly CT7, are immunogenic in MM patients and merit further exploration as targets of immunological therapy in MM.

  18. Baseline survey of root-associated microbes of Taxus chinensis (Pilger) Rehd.

    PubMed

    Zhang, Qian; Liu, Hongwei; Sun, Guiling; Wilson, Iain W; Wu, Jianqiang; Hoffman, Angela; Cheng, Junwen; Qiu, Deyou

    2015-01-01

    Taxol (paclitaxel) a diterpenoid is one of the most effective anticancer drugs identified. Biosynthesis of taxol was considered restricted to the Taxus genera until Stierle et al. discovered that an endophytic fungus isolated from Taxus brevifolia could independently synthesize taxol. Little is known about the mechanism of taxol biosynthesis in microbes, but it has been speculated that its biosynthesis may differ from plants. The microbiome from the roots of Taxus chinensis have been extensively investigated with culture-dependent methods to identify taxol synthesizing microbes, but not using culture independent methods.,Using bar-coded high-throughput sequencing in combination with a metagenomics approach, we surveyed the microbial diversity and gene composition of the root-associated microbiomefrom Taxus chinensis (Pilger) Rehd. High-throughput amplicon sequencing revealed 187 fungal OTUs which is higher than any previously reported fungal number identified with the culture-dependent method, suggesting that T. chinensis roots harbor novel and diverse fungi. Some operational taxonomic units (OTU) identified were identical to reported microbe strains possessing the ability to synthesis taxol and several genes previously associated with taxol biosynthesis were identified through metagenomics analysis.

  19. Humoral Immune Response against Neural Antigens and Its Effects on Cognition in Lung Cancer Patients.

    PubMed

    Rybacka-Mossakowska, J; Ramlau, R; Gazdulska, J; Gołda-Gocka, I; Kozubski, W; Michalak, S

    2016-01-01

    Cognitive impairment develops as a clinical manifestation of immune-mediated indirect effects of malignancy in lung cancer patients. This study aimed to evaluate the effects of humoral immune response on cognition in lung cancer patients. Fifty-one lung cancer patients were subjected to neurological examination: Mini Mental State Examination (MMSE), Trail Making Test (TMT), and Hamilton scale. The Psychology Experiment Building Language software was used for the evaluation of digit span, simple reaction time (SRT), and choice reaction time (CRT) tests. Serum samples were tested for the presence of onconeuronal antibodies and antineural antibodies. The results demonstrate that autoantibodies were found in 31 % patients. MMSE scores were lower (26.7 ± 2.7) in seropositive patients than in seronegative subjects (28.7 ± 1.2; p = 0.013). Executive functions were also influenced by the presence of autoantibodies. The humoral immune response in lung cancer patients affected both SRT and CRT. We conclude that the humoral immune response in lung cancer patients is associated with cognitive impairment. Cognitive impairment is associated with both specific reactions against onconeuronal or antineural antigens and non-organ specific reactions against nucleosome antigens.

  20. Does chronomodulated radiotherapy improve pathological response in locally advanced rectal cancer?

    PubMed

    Squire, Tim; Buchanan, Grant; Rangiah, David; Davis, Ian; Yip, Desmond; Chua, Yu Jo; Rich, Tyvin; Elsaleh, Hany

    2017-01-01

    The predominant mode of radiation-induced cell death for solid tumours is mitotic catastrophe, which is in part dependent on sublethal damage repair being complete at around 6 h. Circadian variation appears to play a role in normal cellular division, and this could influence tumour response of radiation treatment depending on the time of treatment delivery. We tested the hypothesis that radiation treatment later in the day may improve tumour response and nodal downstaging in rectal cancer patients treated neoadjuvantly with radiation therapy. Recruitment was by retrospective review of 267 rectal cancer patients treated neoadjuvantly in the Department of Radiation Oncology at the Canberra Hospital between January 2010 and November 2015. One hundred and fifty-five patients met the inclusion criteria for which demographic, pathological and imaging data were collected, as well as the time of day patients received treatment with each fraction of radiotherapy. Data analysis was performed using the Statistical Package R with nonparametric methods of significance for all tests set at p < 0.05. Of the 45 female and 110 male patients, the median age was 64. Seventy-three percent had cT3 disease and there was a mean tumour distance from the anal verge of 7 cm. Time to surgical resection following radiotherapy ranged from 4 to 162 days with a median of 50 days, with a complete pathological response seen in 21% of patients. Patients exhibiting a favourable pathological response had smaller median pre- and postradiotherapy tumour size and had a greater change in tumour size following treatment (p < 0.01). Patients who received the majority of their radiotherapy fractions after 12:00 pm were more likely to show a complete or moderate pathological response (p = 0.035) and improved nodal downstaging. There were also more favourable responses amongst patients with longer time to surgical resection postradiotherapy (p < 0.004), although no relationship was seen between response and

  1. WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response.

    PubMed

    Janczar, Szymon; Nautiyal, Jaya; Xiao, Yi; Curry, Edward; Sun, Mingjun; Zanini, Elisa; Paige, Adam Jw; Gabra, Hani

    2017-07-27

    There are clear gaps in our understanding of genes and pathways through which cancer cells facilitate survival strategies as they become chemoresistant. Paclitaxel is used in the treatment of many cancers, but development of drug resistance is common. Along with being an antimitotic agent paclitaxel also activates endoplasmic reticulum (ER) stress. Here, we examine the role of WWOX (WW domain containing oxidoreductase), a gene frequently lost in several cancers, in mediating paclitaxel response. We examine the ER stress-mediated apoptotic response to paclitaxel in WWOX-transfected epithelial ovarian cancer (EOC) cells and following siRNA knockdown of WWOX. We show that WWOX-induced apoptosis following exposure of EOC cells to paclitaxel is related to ER stress and independent of the antimitotic action of taxanes. The apoptotic response to ER stress induced by WWOX re-expression could be reversed by WWOX siRNA in EOC cells. We report that paclitaxel treatment activates both the IRE-1 and PERK kinases and that the increase in paclitaxel-mediated cell death through WWOX is dependent on active ER stress pathway. Log-rank analysis of overall survival (OS) and progression-free survival (PFS) in two prominent EOC microarray data sets (Tothill and The Cancer Genome Atlas), encompassing ~800 patients in total, confirmed clinical relevance to our findings. High WWOX mRNA expression predicted longer OS and PFS in patients treated with paclitaxel, but not in patients who were treated with only cisplatin. The association of WWOX and survival was dependent on the expression level of glucose-related protein 78 (GRP78), a key ER stress marker in paclitaxel-treated patients. We conclude that WWOX sensitises EOC to paclitaxel via ER stress-induced apoptosis, and predicts clinical outcome in patients. Thus, ER stress response mechanisms could be targeted to overcome chemoresistance in cancer.

  2. Tumor response ratio predicts overall survival in breast cancer patients treated with neoadjuvant chemotherapy.

    PubMed

    Miller, Marian; Ottesen, Rebecca A; Niland, Joyce C; Kruper, Laura; Chen, Steven L; Vito, Courtney

    2014-10-01

    Neoadjuvant chemotherapy (NAC) is commonly used to treat locally advanced breast cancer. Pathologic complete response (pCR) predicts improved overall survival (OS); however, prognosis of patients with partial response remains unclear. We evaluated whether tumor response ratio (TRR) is a better predictor of OS than current staging methods. Using the National Comprehensive Cancer Network Breast Cancer Outcomes Database, we identified patients with stage I-III breast cancer who had NAC and pretreatment imaging at City of Hope (1997-2010). Patient demographics, tumor characteristics, and OS were analyzed. TRR was calculated as residual in-breast disease divided by size on pre-NAC imaging. Four TRR groups were stratified; TRR 0 (pCR), TRR > 0-0.4 (strong partial response, SPR), TRR > 0.4-1.0 (weak partial response, WPR), or TRR > 1.0 (tumor growth, TG). OS was estimated by the Kaplan-Meier method and tested by the log-rank test. Cox regression was performed to evaluate associations between OS and TRR in a multivariable analysis while controlling for potential confounders. There were 218 eligible patients identified; 59 (27 %) had pCR, 61 (28 %) SPR, 72 (33 %) WPR, and 26 (12 %) TG. Five-year OS decreased continuously with increasing TRR:pCR (90 %), SPR (79 %), WPR (66 %), and TG (60 %). TRR was the only measure that significantly predicted OS (p = 0.0035); pathologic stage (p = 0.23) and pre-NAC clinical tumor stage (cT) (p = 0.87) were not significant. TRR continued to be statistically significant by multivariable analysis (p = 0.016). TRR takes into account both pretreatment and residual disease and more accurately predicts OS than pathologic stage and pre-NAC cT. TRR may be useful to more accurately assess prognosis and OS in breast cancer patients undergoing NAC.

  3. Cytotoxic T lymphocyte response to peptide vaccination predicts survival in stage III colorectal cancer.

    PubMed

    Kawamura, Junichiro; Sugiura, Fumiaki; Sukegawa, Yasushi; Yoshioka, Yasumasa; Hida, Jin-Ichi; Hazama, Shoichi; Okuno, Kiyotaka

    2018-02-23

    We previously reported a phase I clinical trial of a peptide vaccine ring finger protein 43 (RNF43) and 34-kDa translocase of the outer mitochondrial membrane (TOMM34) combined with uracil-tegafur (UFT)/LV for patients with metastatic colorectal cancer (CRC), and demonstrated the safety and immunological responsiveness of this combination therapy. In this study, we evaluated vaccination-induced immune responses to clarify the survival benefit of the combination therapy as adjuvant treatment. We enrolled 44 patients initially in an HLA-masked fashion. After the disclosure of HLA, 28 patients were in the HLA-A*2402-matched and 16 were in the unmatched group. In the HLA-matched group, 14 patients had positive CTL responses specific for the RNF43 and/or TOMM34 peptides after 2 cycles of treatment and 9 had negative responses; in the HLA-unmatched group, 10 CTL responses were positive and 2 negative. In the HLA-matched group, 3-year relapse-free survival (RFS) was significantly better in the positive CTL subgroup than in the negative-response subgroup. Patients with negative vaccination-induced CTL responses showed a significant trend towards shorter RFS than those with positive responses. Moreover, in the HLA-unmatched group, the positive CTL response subgroup showed an equally good 3-year RFS as in the HLA-matched group. In conclusion, vaccination-induced CTL response to peptide vaccination could predict survival in the adjuvant setting for stage III CRC. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  4. Assessing the response to opioids in cancer patients: a methodological proposal and the results.

    PubMed

    Corli, O; Roberto, A; Greco, M T; Montanari, M

    2015-07-01

    The efficacy of treatment with opioids in cancer pain is variable. To evaluate this variability, we (1) applied two parameters, changes in pain intensity (PI) and opioid daily doses (DDs), to distinguish different responses to opioids. The need to switch to another opioid was recorded. We then (2) evaluated the distribution of the responses depending on these parameters, alone and taken together, in cancer patients with pain. The cutoffs between positive and negative responses related to PI and DD were defined on the basis of the literature. For PI, responders were patients who obtained simultaneously a decrease of 30% or more and a final score ≤4 points (numerical rating scale 0 to 10). For DD changes, we applied the opioid escalation index percentage, a positive response corresponding to a dose increase ≤5%. These criteria were applied to 201 cancer patients treated with WHO step III "strong" opioids for 21 days. The results were mainly analyzed case by case. Of the patients, 63.7% obtained a positive analgesic response and 80.1% a dose-related positive response. Combining the parameters, the response was double positive in 55.2% of cases, double negative in 11.4%, a good analgesic response with a large dose escalation in 8.5%, and no pain relief with a stable dose in 24.9%. Switches were made 21 times, 15 because of the lack of analgesia. Different degrees of response to opioids were observed, PI and DD changes both contributing. Only over half the patients had a full positive response.

  5. Subtype-Specific Radiation Response and Therapeutic Effect of FAS Death Receptor Modulation in Human Breast Cancer.

    PubMed

    Lee, Chen-Ting; Zhou, Yingchun; Roy-Choudhury, Kingshuk; Siamakpour-Reihani, Sharareh; Young, Kenneth; Hoang, Peter; Kirkpatrick, John P; Chi, Jen-Tsan A; Dewhirst, Mark W; Horton, Janet K

    2017-08-01

    Breast cancer is the most common malignancy diagnosed among women and represents a heterogeneous group of subtypes. Radiation therapy is a critical component of treatment for breast cancer patients. However, little is known about radiation response among these intrinsic subtypes. In previous studies, we identified a significant induction of FAS after irradiation in biologically favorable breast cancer patients and breast cancer cell lines. Here, we expanded our study and investigated radiation response in a mouse model of breast cancer. MCF7 (luminal), HCC1954 (HER2 + ) or SUM159 (basal) cells were implanted orthotopically into the dorsal mammary fat pad of nude mice. These mice were then treated with different doses of radiation to assess tumor growth control. We further investigated the therapeutic effect of FAS modulation by silencing FAS in radiation-responsive tumors and injecting FAS agonist antibody into radiation-resistant tumors. Exposure to radiation inhibited MCF7, and to a lesser extent HCC1954 tumor growth in a dose-dependent manner. In contrast, SUM159 tumors were resistant to radiation. The estimated TCD 50 values were 19.3 Gy for MCF7 and 44.9 Gy for SUM159. Radiation induced FAS expression in MCF7 tumors, but not SUM159 tumors. We found that silencing of FAS did not negatively impact radiation response in MCF7 tumors, possibly due to compensation by other apoptotic pathways. On the other hand, FAS activating antibody in combination with radiation treatment delayed SUM159 and HCC1954 tumor growth. However, it did not reach statistical significance compared to radiation treatment alone. Our results suggest that there is intrinsic variation in radiation response among breast cancer subtypes. FAS activation concurrent with radiation slows tumor growth in the radiation-resistant subtypes, but the effect was not significant. Alternative subtype-specific modulators of radiation response are under investigation.

  6. Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy

    PubMed Central

    Martínez, C; García-Martín, E; Pizarro, R M; García-Gamito, F J; Agúndez, J A G

    2002-01-01

    Cytochrome P450 3A is a drug-metabolising enzyme activity due to CYP3A4 and CYP3A5 gene products, that is involved in the inactivation of anticancer drugs. This study analyses the potential of cytochrome P450 3A enzyme in human colorectal cancer to impact anticancer therapy with drugs that are cytochrome P450 3A substrates. Enzyme activity, variability and properties, and the ability to inactivate paclitaxel (taxol) were analysed in human colorectal cancer and healthy colorectal epithelium. Cytochrome P450 3A enzyme activity is present in healthy and tumoral samples, with a nearly 10-fold interindividual variability. Nifedipine oxidation activity±s.d. for colorectal cancer microsomes was 67.8±36.6 pmol min−1 mg−1. The Km of the tumoral enzyme (42±8 μM) is similar to that in healthy colorectal epithelium (36±8 μM) and the human liver enzyme. Colorectal cancer microsomes metabolised the anticancer drug paclitaxel with a mean activity was 3.1±1.2 pmol min−1 mg−1. The main metabolic pathway is carried out by cytochrome P450 3A, and it is inhibited by the cytochrome P450 3A-specific inhibitor ketoconazole with a KI value of 31 nM. This study demonstrates the occurrence of cytochrome P450 3A-dependent metabolism in colorectal cancer tissue. The metabolic activity confers to cancer cells the ability to inactivate cytochrome P450 3A substrates and may modulate tumour sensitivity to anticancer drugs. British Journal of Cancer (2002) 87, 681–686. doi:10.1038/sj.bjc.6600494 www.bjcancer.com © 2002 Cancer Research UK PMID:12237780

  7. Lynn Sorbara, PhD | Division of Cancer Prevention

    Cancer.gov

    Dr. Lynn Sorbara earned her PhD from Albert Einstein College of Medicine in 1986. Her thesis research was in the areas of the mechanism of action of the drug, Taxol, and of multidrug resistance. After postdoctoral fellowships at the Rockefeller University and the Mount Sinai College of Medicine in Manhattan, she came to the NIH as a Senior Staff Fellow in the Diabetes Branch

  8. microRNA-451a regulates colorectal cancer proliferation in response to radiation.

    PubMed

    Ruhl, Rebecca; Rana, Shushan; Kelley, Katherine; Espinosa-Diez, Cristina; Hudson, Clayton; Lanciault, Christian; Thomas, Charles R; Liana Tsikitis, V; Anand, Sudarshan

    2018-05-03

    Colorectal cancer (CRC) is a leading cause of cancer-related death. The biologic response of CRC to standard of care adjuvant therapies such as chemotherapy and radiation are poorly understood. MicroRNAs (miRs) have been shown to affect CRC progression and metastasis. Therefore, we hypothesized that specific miRs modulate CRC response to chemoradiation. In this study, we used miR expression profiling and discovered a set of microRNAs upregulated rapidly in response to either a single 2 Gy dose fraction or a 10 Gy dose of γ-radiation in mouse colorectal carcinoma models. We used gain and loss-of-function studies in 2D and 3Dcell proliferation assays and colony formation assays to understand the role of the top miR candidate from our profiling. We used Student's T-tests for simple comparisons and two-factor ANOVA for evaluating significance. The most upregulated candidate at early time points in our signature, miR-451a inhibited tumor cell proliferation and attenuated surviving fraction in longer-term cultures. Conversely, inhibition of miR-451a increased proliferation, tumorsphere formation, and surviving fraction of tumor cells. Using a bioinformatics approach, we identified four genes, CAB39, EMSY, MEX3C, and EREG, as targets of miR-451a. Transfection of miR-451a decreased both mRNA and protein levels of these targets. Importantly, we found miR-451a expression was high and CAB39, EMSY levels were low in a small subset of rectal cancer patients who had a partial response to chemoradiation when compared to patients that had no response. Finally, analysis of a TCGA colorectal cancer dataset revealed that CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients. Higher levels of CAB39 and EMSY correlated with poorer overall survival. Taken together, our data indicates miR-451a is induced by radiation and may influence colorectal carcinoma proliferation via CAB39 and EMSY pathways.

  9. BIM expression in treatment naïve cancers predicts responsiveness to kinase inhibitors

    PubMed Central

    Faber, Anthony; Corcoran, Ryan B.; Ebi, Hiromichi; Sequist, Lecia V.; Waltman, Belinda A.; Chung, Euiheon; Incio, Joao; Digumarthy, Subba R.; Pollack, Sarah F.; Song, Youngchul; Muzikansky, Alona; Lifshits, Eugene; Roberge, Sylvie; Coffman, Erik J.; Benes, Cyril; Gómez, Henry; Baselga, Jose; Arteaga, Carlos L.; Rivera, Miguel N.; Dias-Santagata, Dora; Jain, Rakesh K.; Engelman, Jeffrey A.

    2011-01-01

    Cancers with specific genetic mutations are susceptible to selective kinase inhibitors. However, there is wide spectrum of benefit among cancers harboring the same sensitizing genetic mutations. Herein, we measured apoptotic rates among cell lines sharing the same driver oncogene following treatment with the corresponding kinase inhibitor. There was a wide range of kinase inhibitor-induced apoptosis despite comparable inhibition of the target and associated downstream signaling pathways. Surprisingly, pre-treatment RNA levels of the BH3-only pro-apoptotic BIM strongly predicted the capacity of EGFR, HER2, and PI3K inhibitors to induce apoptosis in EGFR mutant, HER2 amplified, and PIK3CA mutant cancers, respectively, but BIM levels did not predict responsiveness to standard chemotherapies. Furthermore, BIM RNA levels in EGFR mutant lung cancer specimens predicted response and duration of clinical benefit from EGFR inhibitors. These findings suggest assessment of BIM levels in treatment naïve tumor biopsies may indicate the degree of benefit from single-agent kinase inhibitors in multiple oncogene-addiction paradigms. PMID:22145099

  10. Bio-production of Baccatin III, an Important Precursor of Paclitaxel by a Cost-Effective Approach.

    PubMed

    Lin, Shu-Ling; Wei, Tao; Lin, Jun-Fang; Guo, Li-Qiong; Wu, Guang-Pei; Wei, Jun-Bin; Huang, Jia-Jun; Ouyang, Ping-Lan

    2018-07-01

    Natural production of anti-cancer drug taxol from Taxus has proved to be environmentally unsustainable and economically unfeasible. Currently, bioengineering the biosynthetic pathway of taxol is an attractive alternative production approach. 10-deacetylbaccatin III-10-O-acetyl transferase (DBAT) was previously characterized as an acyltransferase, using 10-deacetylbaccatin III (10-DAB) and acetyl CoA as natural substrates, to form baccatin III in the taxol biosynthesis. Here, we report that other than the natural acetyl CoA (Ac-CoA) substrate, DBAT can also utilize vinyl acetate (VA), which is commercially available at very low cost, acylate quickly and irreversibly, as acetyl donor in the acyl transfer reaction to produce baccatin III. Furthermore, mutants were prepared via a semi-rational design in this work. A double mutant, I43S/D390R was constructed to combine the positive effects of the different single mutations on catalytic activity, and its catalytic efficiency towards 10-DAB and VA was successfully improved by 3.30-fold, compared to that of wild-type DBAT, while 2.99-fold higher than the catalytic efficiency of WT DBAT towards 10-DAB and Ac-CoA. These findings can provide a promising economically and environmentally friendly method for exploring novel acyl donors to engineer natural product pathways.

  11. Tumor responsive targeted multifunctional nanosystems for cancer imaging, chemo- and siRNA therapy

    NASA Astrophysics Data System (ADS)

    Savla, Ronak

    Cancer is one of the most insidious diseases. Compromising of over 100 different types and sharing the unifying factors of uncontrolled growth and metastasis, unmet clinical needs in terms of cancer diagnosis and treatment continue to exist. It is widely accepted that most forms of cancer are treatable or even curable if detected before widespread metastasis occurs. Nearly a quarter of deaths in the United States is the result of cancer and it only trails heart disease in terms of annual mortality. Surgery, chemotherapy, and radiation therapy are the primary treatment modalities for cancer. Research in these procedures has resulted in substantial benefits for cancer patients, but there is still room for an improvement. However, a time has been reached at which it appears that the benefits from these modalities have been reached the maximum. Therefore, it is vital to develop new strategies for the diagnosis and treatment of cancer. The field of nanotechnology is concerned with structures in the nanometer size range and holds the potential to drastically impact and improve the lives of patients suffering from cancer. Not only can nanotechnology improve current methods of diagnosis and treatment, it has a possibility of introducing newer and better modalities. The overall purpose of this work is to develop novel nanotechnology-based methodologies for the diagnosis and treatment of various forms of cancers. The first aim of the project is the development of a multifunctional targeted nanosystem for the delivery of siRNA to overcome drug resistance. The second aspect is the synthesis of a quantum dot-based delivery system that releases drug in response to pH changes. The third aim is the development of a targeted, tumor environment responsive magnetic resonance nanoparticle contrast agent coupled with a nanoparticle-based treatment.

  12. Diversity of endophytic fungi and screening of fungal paclitaxel producer from Anglojap yew, Taxus x media

    PubMed Central

    2013-01-01

    Background Endophytic fungi represent underexplored resource of novel lead compounds and have a capacity to produce diverse class of plant secondary metabolites. Here we investigated endophytic fungi diversity and screening of paclitaxel-producing fungi from Taxus x media. Results Eighty-one endophytic fungi isolated from T. media were grouped into 8 genera based on the morphological and molecular identification. Guignardia and Colletotrichum were the dominant genera, whereas the remaining genera were infrequent groups. The genera Glomerella and Gibberella were first reported in Taxus. Three representative species of the distinct genera gave positive hits by molecular marker screening and were capable of producing taxol which were validated by HPLC-MS. Among these 3 taxol-producing fungi, the highest yield of taxol was 720 ng/l by Guignardia mangiferae HAA11 compared with those of Fusarium proliferatum HBA29 (240 ng/l) and Colletotrichum gloeosporioides TA67 (120 ng/l). This is the first report of taxol producer from Guignardia. Moreover, the lower similarities of ts and bapt between microbial and plant origin suggested that fungal taxol biosynthetic cluster might be repeatedly invented during evolution, nor horizontal gene transfer from Taxus species. Conclusions Taxol-producing endophytic fungi could be a fascinating reservoir to generate taxol-related drug lead and to elucidate the remained 5 unknown genes or the potential regulation mechanism in the taxol biosynthesis pathway. PMID:23537181

  13. Preparing patients with cancer who work and treatment responsiveness.

    PubMed

    Kamau, Caroline

    2017-03-01

    Many patients with life-limiting illnesses continue to work because of financial reasons and because work provides good psychosocial support. A lack of appropriate advice/support through patient education could, however, make having a job detrimental to well-being (eg, symptom worsening). This study investigated the frequency with which patients received information that empowers their understanding of their condition, treatment, side effects of treatment and the likely impact on occupational functioning. A cross-sectional study. An analysis of survey data from 3457 patients with cancer in employment. Logistic regression showed that patients who received information about the impact of cancer on work life or education are 1.72 times more likely to have a positive treatment outcome. Patients who receive written information about the type of cancer are 1.99 times more likely to have a positive treatment outcome. Also, patients who receive written information before a cancer-related operation are 1.90 times more likely to have a positive treatment outcome. Information about the side effects of cancer treatment produces worse odds of a positive treatment outcome (0.65-1). A stepwise logistic regression analysing the effects irrespective of current employment status in 6710 patients showed that preparing them produces nearly twice better odds of cancer treatment responsiveness. Palliative care teams should consider ways of actively advising patients who work. Whereas the results showed evidence of good practice in cancer care, there is a need to ensure that all working patients with potentially life-limiting illnesses receive similar support. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  14. The role of the polyamine catabolic enzymes SSAT and SMO in the synergistic effects of standard chemotherapeutic agents with a polyamine analogue in human breast cancer cell lines

    PubMed Central

    Pledgie-Tracy, Allison; Billam, Madhavi; Hacker, Amy; Sobolewski, Michele D; Woster, Patrick M.; Zhang, Zhe; Casero, Robert A.; Davidson, Nancy E

    2009-01-01

    with paclitaxel on tumor regression was evaluated in xenograft mice models generated with MDA-MB-231 cells. Intraperitoneal exposure to BENSpm or taxol singly and in combination for 4 weeks resulted in significant inhibition in tumor growth These findings help elucidate the mechanisms involved in synergistic drug response and support combinations of polyamine analogues with chemotherapeutic agents which could potentially be used in the treatment of breast cancer. PMID:19727732

  15. TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor-Positive Breast Cancer.

    PubMed

    Jeselsohn, Rinath; Barry, William T; Migliaccio, Ilenia; Biagioni, Chiara; Zhao, Jin; De Tribolet-Hardy, Jonas; Guarducci, Cristina; Bonechi, Martina; Laing, Naomi; Winer, Eric P; Brown, Myles; Leo, Angelo Di; Malorni, Luca

    2016-12-01

    Fulvestrant is an estrogen receptor (ER) antagonist and an approved treatment for metastatic estrogen receptor-positive (ER + ) breast cancer. With the exception of ER levels, there are no established predictive biomarkers of response to single-agent fulvestrant. We attempted to identify a gene signature of response to fulvestrant in advanced breast cancer. Primary tumor samples from 134 patients enrolled in the phase III CONFIRM study of patients with metastatic ER + breast cancer comparing treatment with either 250 mg or 500 mg fulvestrant were collected for genome-wide transcriptomic analysis. Gene expression profiling was performed using Affymetrix microarrays. An exploratory analysis was performed to identify biologic pathways and new signatures associated with response to fulvestrant. Pathway analysis demonstrated that increased EGF pathway and FOXA1 transcriptional signaling is associated with decreased response to fulvestrant. Using a multivariate Cox model, we identified a novel set of 37 genes with an expression that is independently associated with progression-free survival (PFS). TFAP2C, a known regulator of ER activity, was ranked second in this gene set, and high expression was associated with a decreased response to fulvestrant. The negative predictive value of TFAP2C expression at the protein level was confirmed by IHC. We identified biologic pathways and a novel gene signature in primary ER + breast cancers that predicts for response to treatment in the CONFIRM study. These results suggest potential new therapeutic targets and warrant further validation as predictive biomarkers of fulvestrant treatment in metastatic breast cancer. Clin Cancer Res; 22(23); 5755-64. ©2016 AACR. ©2016 American Association for Cancer Research.

  16. Digitoxin medication and cancer; case control and internal dose-response studies

    PubMed Central

    Haux, Johan; Klepp, Olbjørn; Spigset, Olav; Tretli, Steinar

    2001-01-01

    Background Digitoxin induces apoptosis in different human malignant cell lines in vitro. In this paper we investigated if patients taking digitoxin for cardiac disease have a different cancer incidence compared to the general population. Methods Computer stored data on digitoxin concentrations in plasma from 9271 patients with cardiac disease were used to define a user population. Age and sex matched controls from the Norwegian Cancer Registry were used to calculate the number of expected cancer cases. Results The population on digitoxin showed a higher incidence of cancer compared to the control population. However, an additional analysis showed that the population on digitoxin had a general increased risk of cancer already, before the start on digitoxin. Leukemia/lymphoma were the cancer types which stood out with the highest risk in the digitoxin population before starting on digitoxin. This indicates that yet unknown risk factors exist for cardiovascular disease and lymphoproliferative cancer. An internal dose-response analysis revealed a relationship between high plasma concentration of digitoxin and a lower risk for leukemia/lymphoma and for cancer of the kidney/urinary tract. Conclusion Morbidity and mortality are high in the population on digitoxin, due to high age and cardiac disease.These factors disturb efforts to isolate an eventual anticancer effect of digitoxin in this setting. Still, the results may indicate an anticancer effect of digitoxin for leukemia/lymphoma and kidney/urinary tract cancers. Prospective clinical cancer trials have to be done to find out if digitoxin and other cardiac glycosides are useful as anticancer agents. PMID:11532201

  17. Baseline Survey of Root-Associated Microbes of Taxus chinensis (Pilger) Rehd

    PubMed Central

    Sun, Guiling; Wilson, Iain W.; Wu, Jianqiang; Hoffman, Angela; Cheng, Junwen; Qiu, Deyou

    2015-01-01

    Taxol (paclitaxel) a diterpenoid is one of the most effective anticancer drugs identified. Biosynthesis of taxol was considered restricted to the Taxus genera until Stierle et al. discovered that an endophytic fungus isolated from Taxus brevifolia could independently synthesize taxol. Little is known about the mechanism of taxol biosynthesis in microbes, but it has been speculated that its biosynthesis may differ from plants. The microbiome from the roots of Taxus chinensis have been extensively investigated with culture-dependent methods to identify taxol synthesizing microbes, but not using culture independent methods.,Using bar-coded high-throughput sequencing in combination with a metagenomics approach, we surveyed the microbial diversity and gene composition of the root-associated microbiomefrom Taxus chinensis (Pilger) Rehd. High-throughput amplicon sequencing revealed 187 fungal OTUs which is higher than any previously reported fungal number identified with the culture-dependent method, suggesting that T. chinensis roots harbor novel and diverse fungi. Some operational taxonomic units (OTU) identified were identical to reported microbe strains possessing the ability to synthesis taxol and several genes previously associated with taxol biosynthesis were identified through metagenomics analysis. PMID:25821956

  18. Malignant mixed Mullerian tumour of uterus secondary to tamoxifen therapy for hormone responsive breast cancer.

    PubMed

    Gupta, Mayank; Kiruthiga, Kala Gnanasekaran

    2015-06-29

    Tamoxifen is used in the treatment of hormone responsive breast cancer because of its antiestrogenic effect. However, it also has an estrogenic effect on the uterus, thereby increasing the risk of endometrial hyperplasia, endometrial polyp and endometrial neoplasms such as endometrial adenocarcinoma and malignant mixed Mullerian tumour (MMMT). This case describes the possible pathogenesis and risk of developing MMMT due to long-term tamoxifen intake in hormone responsive breast cancer. 2015 BMJ Publishing Group Ltd.

  19. Immunotherapy for Prostate Cancer: Lessons from Responses to Tumor-Associated Antigens

    PubMed Central

    Westdorp, Harm; Sköld, Annette E.; Snijer, Berit A.; Franik, Sebastian; Mulder, Sasja F.; Major, Pierre P.; Foley, Ronan; Gerritsen, Winald R.; de Vries, I. Jolanda M.

    2014-01-01

    Prostate cancer (PCa) is the most common cancer in men and the second most common cause of cancer-related death in men. In recent years, novel therapeutic options for PCa have been developed and studied extensively in clinical trials. Sipuleucel-T is the first cell-based immunotherapeutic vaccine for treatment of cancer. This vaccine consists of autologous mononuclear cells stimulated and loaded with an immunostimulatory fusion protein containing the prostate tumor antigen prostate acid posphatase. The choice of antigen might be key for the efficiency of cell-based immunotherapy. Depending on the treatment strategy, target antigens should be immunogenic, abundantly expressed by tumor cells, and preferably functionally important for the tumor to prevent loss of antigen expression. Autoimmune responses have been reported against several antigens expressed in the prostate, indicating that PCa is a suitable target for immunotherapy. In this review, we will discuss PCa antigens that exhibit immunogenic features and/or have been targeted in immunotherapeutic settings with promising results, and we highlight the hurdles and opportunities for cancer immunotherapy. PMID:24834066

  20. A confidence building exercise in data and identifiability: Modeling cancer chemotherapy as a case study.

    PubMed

    Eisenberg, Marisa C; Jain, Harsh V

    2017-10-27

    Mathematical modeling has a long history in the field of cancer therapeutics, and there is increasing recognition that it can help uncover the mechanisms that underlie tumor response to treatment. However, making quantitative predictions with such models often requires parameter estimation from data, raising questions of parameter identifiability and estimability. Even in the case of structural (theoretical) identifiability, imperfect data and the resulting practical unidentifiability of model parameters can make it difficult to infer the desired information, and in some cases, to yield biologically correct inferences and predictions. Here, we examine parameter identifiability and estimability using a case study of two compartmental, ordinary differential equation models of cancer treatment with drugs that are cell cycle-specific (taxol) as well as non-specific (oxaliplatin). We proceed through model building, structural identifiability analysis, parameter estimation, practical identifiability analysis and its biological implications, as well as alternative data collection protocols and experimental designs that render the model identifiable. We use the differential algebra/input-output relationship approach for structural identifiability, and primarily the profile likelihood approach for practical identifiability. Despite the models being structurally identifiable, we show that without consideration of practical identifiability, incorrect cell cycle distributions can be inferred, that would result in suboptimal therapeutic choices. We illustrate the usefulness of estimating practically identifiable combinations (in addition to the more typically considered structurally identifiable combinations) in generating biologically meaningful insights. We also use simulated data to evaluate how the practical identifiability of the model would change under alternative experimental designs. These results highlight the importance of understanding the underlying mechanisms

  1. Overexpression of CYP3A4 in a COLO 205 Colon Cancer Stem Cell Model in vitro

    PubMed Central

    Olszewski, Ulrike; Liedauer, Richard; Ausch, Christoph; Thalhammer, Theresia; Hamilton, Gerhard

    2011-01-01

    Cancer stem cells (CSCs) seem to constitute a subpopulation of tumor cells that escape from chemotherapy and cause recurrent disease. Low proliferation rates, protection in a stem cell niche and overexpression of drug resistance proteins are considered to confer chemoresistance. We established an in vitro colon CSC-like model using the COLO 205 cell line, which revealed transiently increased expression of CD133 when transferred to serum-free stem cell culture medium. Assessment of global gene expression of COLO 205 cells under these conditions identified a set of upregulated genes including cytochrome P450 3A4 (CYP3A4) and aldehyde dehydrogenase 1A1 (ALDH1A1), as confirmed by real-time qPCR. ALDH1A1 is a CSC marker for certain tumor entities and confers resistance to cyclophosphamide. CYP3A4 is expressed in liver and colon and its overexpression seems particularly relevant in colon cancer, since it inactivates irinotecan and other xenobiotics, such as taxols and vinca alkaloids. In conclusion, this COLO 205 model provides evidence for CD133 induction concomitant with overexpression of CYP3A4, which, together with ATP-binding cassette, subfamily G, member 2 (ABCG2) and others, may have a role in chemoresistant colon CSCs and a negative impact on disease-free survival in colon cancer patients. PMID:24212669

  2. Household physical activity and cancer risk: a systematic review and dose-response meta-analysis of epidemiological studies

    PubMed Central

    Shi, Yun; Li, Tingting; Wang, Ying; Zhou, Lingling; Qin, Qin; Yin, Jieyun; Wei, Sheng; Liu, Li; Nie, Shaofa

    2015-01-01

    Controversial results of the association between household physical activity and cancer risk were reported among previous epidemiological studies. We conducted a meta-analysis to investigate the relationship of household physical activity and cancer risk quantitatively, especially in dose-response manner. PubMed, Embase, Web of science and the Cochrane Library were searched for cohort or case-control studies that examined the association between household physical activity and cancer risks. Random–effect models were conducted to estimate the summary relative risks (RRs), nonlinear or linear dose–response meta-analyses were performed to estimate the trend from the correlated log RR estimates across levels of household physical activity quantitatively. Totally, 30 studies including 41 comparisons met the inclusion criteria. Total cancer risks were reduced 16% among the people with highest household physical activity compared to those with lowest household physical activity (RR = 0.84, 95% CI = 0.76–0.93). The dose-response analyses indicated an inverse linear association between household physical activity and cancer risk. The relative risk was 0.98 (95% CI = 0.97–1.00) for per additional 10 MET-hours/week and it was 0.99 (95% CI = 0.98–0.99) for per 1 hour/week increase. These findings provide quantitative data supporting household physical activity is associated with decreased cancer risk in dose-response effect. PMID:26443426

  3. Long non-coding RNA MIAT regulates apoptosis and the apoptotic response to chemotherapeutic agents in breast cancer cell lines.

    PubMed

    Almnaseer, Z A; Mourtada-Maarabouni, M

    2018-06-18

    The lncRNA Myocardial Infarction Associated Transcript (MIAT) is involved in a number of diseases, including myocardial infarction and diabetic retinopathy. Emerging evidence suggests that MIAT expression levels are increased in different type of cancers, including breast cancer. In this study we further evaluated the role of MIAT in breast cancer and investigated the consequences of its silencing on breast cancer response to chemotherapeutic agents. Expression levels of MIAT mRNA in breast cancer were determined using TissueScan™ Breast Cancer cDNA Arrays. Breast cancer cell lines were transfected with MIAT specific siRNAs, with silencing confirmed using RT-qPCR and the effects on breast cancer cell survival and response to different apoptotic stimuli determined. MIAT transcript levels were significantly elevated in breast cancer samples. Such increase was specific to the early stages of the disease, ER, PR +ve, HER -ve and TNBC samples. Silencing of MIAT induced growth arrest and increased basal apoptosis. Reduced levels of MIAT augmented the apoptotic response of breast cancer cells to a wide range of apoptotic stimuli. Our results also showed that MIAT down-regulation was associated with a decrease in OCT4 mRNA, suggesting the existence of a MIAT/OCT4 regulatory loop, similar to that observed in malignant mature B cells. Taken together with the recent demonstration of oncogene characteristics, our observations suggest that MIAT plays an important role in breast tumorigenesis. St rategies to decrease MIAT expression levels may improve sensitivity to therapy in breast cancer by enhancing the apoptotic responses to conventional chemotherapies. ©2018 The Author(s).

  4. Pathway-Enriched Gene Signature Associated with 53BP1 Response to PARP Inhibition in Triple-Negative Breast Cancer.

    PubMed

    Hassan, Saima; Esch, Amanda; Liby, Tiera; Gray, Joe W; Heiser, Laura M

    2017-12-01

    Effective treatment of patients with triple-negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients who will most benefit from anti-PARP therapy. We determined the responses of three PARP inhibitors (veliparib, olaparib, and talazoparib) in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved PARP). We determined the pharmacodynamic changes as percentage of cells positive for 53BP1, mean number of 53BP1 foci per cell, and percentage of cells positive for cleaved PARP. Inspired by traditional dose-response measures of cell viability, an EC 50 value was calculated for each cellular phenotype and each PARP inhibitor. The EC 50 values for both 53BP1 metrics strongly correlated with IC 50 values for each PARP inhibitor. Pathway enrichment analysis identified a set of DNA repair and cell cycle-associated genes that were associated with 53BP1 response following PARP inhibition. The overall accuracy of our 63 gene set in predicting response to olaparib in seven breast cancer patient-derived xenograft tumors was 86%. In triple-negative breast cancer patients who had not received anti-PARP therapy, the predicted response rate of our gene signature was 45%. These results indicate that 53BP1 is a biomarker of response to anti-PARP therapy in the laboratory, and our DNA damage response gene signature may be used to identify patients who are most likely to respond to PARP inhibition. Mol Cancer Ther; 16(12); 2892-901. ©2017 AACR . ©2017 American Association for Cancer Research.

  5. PCBs: Cancer Dose-Response Assessment and Application to Environmental Mixtures (1996)

    EPA Science Inventory

    This report updates the cancer dose-response assessment for polychlorinated biphenyls (PCBs) and shows how information on toxicity, disposition, and environmental processes can be considered together to evaluate health risks from PCB mixtures in the environment. Processes that ch...

  6. Clinical impact of circulating tumor cells and therapy response in pancreatic cancer.

    PubMed

    Okubo, K; Uenosono, Y; Arigami, T; Mataki, Y; Matsushita, D; Yanagita, S; Kurahara, H; Sakoda, M; Kijima, Y; Maemura, K; Natsugoe, S

    2017-06-01

    Among gastrointestinal cancers, the prognosis of pancreatic cancer is one of the poorest, with a large number of patients being diagnosed with unresectable tumors at the first visit to a doctor. The aims of the present study were to investigate the circulating tumor cells (CTC) in peripheral blood in order to assess their clinical significance in patients with pancreatic cancer. Sixty-five patients with advanced pancreatic cancer were enrolled. Borderline resectable pancreatic tumor patients were 9, and Unresectable patients were 56. The CellSearch system was used to isolate and enumerate CTCs. CTCs were identified in 21 out of 65 patients (32.3%) with only unresectable tumors. The overall survival rate was significantly lower in unresectable patients with than in those without CTCs (P = 0.0051). CTC positivity was significantly higher in patients with than in those without liver metastasis. A multivariate analysis identified the presence or absence of CTCs as an independent prognostic factor. Follow-up blood specimens were obtained from 40 patients treated with chemotherapy or chemoradiotherapy. The incidences of CTC positivity at three months after beginning of treatments in patients with progressive disease and stable disease or a partial response were 45.4% and 24.1%, respectively. The overall survival rate was significantly lower in patients with than in those without CTCs even after treatments (P = 0.045). CTC numbers represents a useful tool for predicting prognoses and therapeutic responses to chemotherapy among patients with advanced pancreatic cancer. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

  7. Folate intake, serum folate levels and esophageal cancer risk: an overall and dose-response meta-analysis.

    PubMed

    Zhao, Yan; Guo, Chenyang; Hu, Hongtao; Zheng, Lin; Ma, Junli; Jiang, Li; Zhao, Erjiang; Li, Hailiang

    2017-02-07

    Previously reported findings on the association between folate intake or serum folate levels and esophageal cancer risk have been inconsistent. This study aims to summarize the evidence regarding these relationships using a dose-response meta-analysis approach. We performed electronic searches of the Pubmed, Medline and Cochrane Library electronic databases to identify studies examining the effect of folate on the risk of esophageal cancer. Ultimately, 19 studies were included in the meta-analysis. Summary odds ratios (ORs) were estimated using a random effects model. A linear regression analysis of the natural logarithm of the OR was carried out to assess the possible dose-response relationship between folate intake and esophageal cancer risk. The pooled ORs for esophageal cancer in the highest vs. lowest levels of dietary folate intake and serum folate were 0.63 (95% CI: 0.56-0.71) and 0.71 (95% CI: 0.55-0.92), respectively. The dose-response meta-analysis indicated that a 100 μg/day increment in dietary folate intake reduced the estimate risk of esophageal cancer by 12%. These findings suggest that dietary and serum folate exert a protective effect against esophageal carcinogenesis.

  8. Time and dose-response effects of honokiol on UVB-induced skin cancer development.

    PubMed

    Guillermo, Ruth F; Chilampalli, Chandeshwari; Zhang, Xiaoying; Zeman, David; Fahmy, Hesham; Dwivedi, Chandradhar

    2012-06-01

    Honokiol has shown chemopreventive effects in chemically-induced and UVB-induced skin cancer in mice. In this investigation, we assessed the time-effects of a topical low dose of honokiol (30 μg), and then the effects of different honokiol doses (30, 45, and 60 μg) on a UVB-induced skin cancer model to find an optimal dose and time for desirable chemopreventive effects. UVB radiation (30 mJ/cm(2), 5 days/week for 25 or 27 weeks) was used to induce skin carcinogenesis in SKH-1 mice. For the time-response experiment 30 μg honokiol in acetone was applied topically to the animals before the UVB exposure (30 min, 1 h, and 2 h) and after the UVB exposure (immediately, 30 min, and 1 h). Control groups were treated with acetone. For the dose-response study, animals were treated topically with acetone or honokiol (30, 45, and 60 μg) one hour before the UVB exposure. In the time-response experiment, honokiol inhibited skin tumor multiplicity by 49-58% while reducing tumor volumes by 70-89%. In the dose-response study, honokiol (30, 45, and 60 μg) significantly decreased skin tumor multiplicity by 36-78% in a dose-dependent manner, while tumor area was reduced by 76-94%. Honokiol (60 μg) significantly reduced tumor incidence by 40% as compared to control group. Honokiol applied in very low doses (30 μg) either before or after UVB radiation shows chemopreventive effects. Honokiol (30, 45, and 60 μg) prevents UVB-induced skin cancer in a dose-dependent manner. Honokiol can be an effective chemopreventive agent against skin cancer.

  9. Integrative Analysis of Response to Tamoxifen Treatment in ER-Positive Breast Cancer Using GWAS Information and Transcription Profiling.

    PubMed

    Hicks, Chindo; Kumar, Ranjit; Pannuti, Antonio; Miele, Lucio

    2012-01-01

    Variable response and resistance to tamoxifen treatment in breast cancer patients remains a major clinical problem. To determine whether genes and biological pathways containing SNPs associated with risk for breast cancer are dysregulated in response to tamoxifen treatment, we performed analysis combining information from 43 genome-wide association studies with gene expression data from 298 ER(+) breast cancer patients treated with tamoxifen and 125 ER(+) controls. We identified 95 genes which distinguished tamoxifen treated patients from controls. Additionally, we identified 54 genes which stratified tamoxifen treated patients into two distinct groups. We identified biological pathways containing SNPs associated with risk for breast cancer, which were dysregulated in response to tamoxifen treatment. Key pathways identified included the apoptosis, P53, NFkB, DNA repair and cell cycle pathways. Combining GWAS with transcription profiling provides a unified approach for associating GWAS findings with response to drug treatment and identification of potential drug targets.

  10. GENOMIC PREDICTOR OF RESPONSE AND SURVIVAL FOLLOWING TAXANE-ANTHRACYCLINE CHEMOTHERAPY FOR INVASIVE BREAST CANCER

    PubMed Central

    Hatzis, Christos; Pusztai, Lajos; Valero, Vicente; Booser, Daniel J.; Esserman, Laura; Lluch, Ana; Vidaurre, Tatiana; Holmes, Frankie; Souchon, Eduardo; Martin, Miguel; Cotrina, José; Gomez, Henry; Hubbard, Rebekah; Chacón, J. Ignacio; Ferrer-Lozano, Jaime; Dyer, Richard; Buxton, Meredith; Gong, Yun; Wu, Yun; Ibrahim, Nuhad; Andreopoulou, Eleni; Ueno, Naoto T.; Hunt, Kelly; Yang, Wei; Nazario, Arlene; DeMichele, Angela; O’Shaughnessy, Joyce; Hortobagyi, Gabriel N.; Symmans, W. Fraser

    2017-01-01

    CONTEXT Accurate prediction of who will (or won’t) have high probability of survival benefit from standard treatments is fundamental for individualized cancer treatment strategies. OBJECTIVE To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer. DESIGN Development of different predictive signatures for resistance and response to neoadjuvant chemotherapy (stratified according to estrogen receptor (ER) status) from gene expression microarrays of newly diagnosed breast cancer (310 patients). Then prediction of breast cancer treatment-sensitivity using the combination of signatures for: 1) sensitivity to endocrine therapy, 2) chemo-resistance, and 3) chemo-sensitivity. Independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response. SETTING Prospective multicenter study to develop and test genomic predictors for neoadjuvant chemotherapy. PATIENTS Newly diagnosed HER2-negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline-based regimens then endocrine therapy (if hormone receptor-positive). MAIN OUTCOME MEASURES Distant relapse-free survival (DRFS) if predicted treatment-sensitive and absolute risk reduction (ARR, difference in DRFS of the two predicted groups) at median follow-up (3 years), and their 95% confidence intervals (CI). RESULTS Patients in the independent validation cohort (99% clinical Stage II–III) who were predicted to be treatment-sensitive (28% of total) had DRFS of 92% (CI 85–100) and survival benefit compared to others (absolute risk reduction (ARR) 18%; CI 6–28). Predictions were accurate if breast cancer was ER-positive (30% predicted sensitive, DRFS 97%, CI 91–100; ARR 11%, CI 0.1–21) or ER-negative (26% predicted sensitive, DRFS 83%, CI 68–100; ARR 26%, CI 4–28), and were significant in multivariate analysis after adjusting for relevant clinical-pathologic characteristics. Other

  11. Tumor Radiation Therapy Creates Therapeutic Vaccine Responses to the Colorectal Cancer Antigen GUCY2C

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Witek, Matthew; Blomain, Erik S.; Magee, Michael S.

    Purpose: Radiation therapy (RT) is thought to produce clinical responses in cancer patients, not only through direct toxicity to cancer cells and supporting tumor stroma cells, but also through activation of immunologic effectors. More recently, RT has potentiated the local and systemic effects of cancer immunotherapy (IT). However, combination regimens that maximize immunologic and clinical efficacy remain undefined. Methods and Materials: We evaluated the impact of local RT on adenoviral-mediated vaccination against the colorectal cancer antigen GUCY2C (Ad5-GUCY2C) in a murine subcutaneous tumor model using mouse CT26 colon cancer cells (CT26-GUCY2C). Immune responses were assessed by ELISpot, and clinical responsesmore » were assessed by tumor size and incidence. Results: The specific sequence of tumor-directed RT preceding Ad5-GUCY2C IT transformed inactive therapeutic Ad5-GUCY2C vaccination into a curative vaccine. GUCY2C-specific T cell responses were amplified (P<.05), tumor eradication was maximized (P<.01), and tumor volumes were minimized (P<.001) in mice whose tumors were irradiated before, compared with after, Ad5-GUCY2C vaccination. The immunologic and antitumor efficacy of Ad5-GUCY2C was amplified comparably by unfractionated (8 Gy × 1), or biologically equivalent doses of fractionated (3.5 Gy × 3), RT. The antitumor effects of sequential RT and IT (RT-IT) depended on expression of GUCY2C by tumor cells and the adenoviral vaccine vector, and tumor volumes were inversely related to the magnitude of GUCY2C-specific T cell responses. Moreover, mice cured of CT26-GUCY2C tumors by RT-IT showed long-lasting antigen-dependent protection, resisting tumors formed by GUCY2C-expressing 4T1 breast cancer cells inoculated 50 days after CT26 cells. Conclusions: Optimal sequencing of RT and IT amplifies antigen-specific local and systemic immune responses, revealing novel acute and long-term therapeutic antitumor protection. These observations underscore the

  12. Multispectral and phase-contrast diffuse optical tomography of breast cancer during neoadjuvant chemotherapy: a case study

    NASA Astrophysics Data System (ADS)

    Liang, Xiaoping; Zhang, Qizhi; Staal, Stephen; Grobmyer, Stephen; Jiang, Huabei

    2009-02-01

    Multispectral and phase-contrast diffuse optical tomography are used to track treatment progress in a patient with locally advanced invasive carcinoma of the breast cancer during neoadjuvant chemotherapy. Two types of chemotherapy treatment including four cycles of Adriamycin/Cytoxin (AC cycles) and twelve cycles of Taxol/Herceptin (TH cycles) were applied to patient. A total of eight optical exams were performed before and within the chemotherapy. Images of tissue refractive index, and absorption and scattering coefficients, as well as oxy-hemoglobin and deoxy-hemoglobin concentrations along with scattering particle volume fraction and mean diameter of cellular components were all obtained. The tumor was identified through absorption and scattering images. Tumor shrinkage was observed during the course of chemotherapy from all the optical images. Our results show that oxy-hemoglobin, deoxy-hemoglobin and total hemoglobin in tumor decreased after chemotherapy compared to that of before chemotherapy. Significant changes in tumor refractive index along with tumor cellular morphology during the entire chemotherapy are also observed.

  13. Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine

    PubMed Central

    Nagarajah, James; Le, Mina; Montero-Conde, Cristina; Pillarsetty, Nagavarakishore; Bolaender, Alexander; Irwin, Christopher; Krishnamoorthy, Gnana Prakasam; Larson, Steven M.; Ho, Alan L.; Seshan, Venkatraman; Ishii, Nobuya; Carrasco, Nancy; Rosen, Neal; Weber, Wolfgang A.; Fagin, James A.

    2016-01-01

    Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer. Although the MEK inhibitor selumetinib transiently inhibited ERK signaling, which subsequently rebounded, the MEK inhibitor CKI suppressed ERK signaling in a sustained manner by preventing RAF reactivation. A small increase in ERK inhibition markedly increased the expression of thyroid differentiation genes, increased iodide accumulation in cancer cells, and thereby improved responses to RAI therapy. Only a short exposure to the drug was necessary to obtain a maximal response to RAI. These data suggest that potent inhibition of ERK signaling is required to adequately induce iodide uptake and indicate that this is a promising strategy for the treatment of BRAF-mutant thyroid cancer. PMID:27669459

  14. Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine.

    PubMed

    Nagarajah, James; Le, Mina; Knauf, Jeffrey A; Ferrandino, Giuseppe; Montero-Conde, Cristina; Pillarsetty, Nagavarakishore; Bolaender, Alexander; Irwin, Christopher; Krishnamoorthy, Gnana Prakasam; Saqcena, Mahesh; Larson, Steven M; Ho, Alan L; Seshan, Venkatraman; Ishii, Nobuya; Carrasco, Nancy; Rosen, Neal; Weber, Wolfgang A; Fagin, James A

    2016-11-01

    Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer. Although the MEK inhibitor selumetinib transiently inhibited ERK signaling, which subsequently rebounded, the MEK inhibitor CKI suppressed ERK signaling in a sustained manner by preventing RAF reactivation. A small increase in ERK inhibition markedly increased the expression of thyroid differentiation genes, increased iodide accumulation in cancer cells, and thereby improved responses to RAI therapy. Only a short exposure to the drug was necessary to obtain a maximal response to RAI. These data suggest that potent inhibition of ERK signaling is required to adequately induce iodide uptake and indicate that this is a promising strategy for the treatment of BRAF-mutant thyroid cancer.

  15. Rapid evolutionary response to a transmissible cancer in Tasmanian devils

    PubMed Central

    Epstein, Brendan; Jones, Menna; Hamede, Rodrigo; Hendricks, Sarah; McCallum, Hamish; Murchison, Elizabeth P.; Schönfeld, Barbara; Wiench, Cody; Hohenlohe, Paul; Storfer, Andrew

    2016-01-01

    Although cancer rarely acts as an infectious disease, a recently emerged transmissible cancer in Tasmanian devils (Sarcophilus harrisii) is virtually 100% fatal. Devil facial tumour disease (DFTD) has swept across nearly the entire species' range, resulting in localized declines exceeding 90% and an overall species decline of more than 80% in less than 20 years. Despite epidemiological models that predict extinction, populations in long-diseased sites persist. Here we report rare genomic evidence of a rapid, parallel evolutionary response to strong selection imposed by a wildlife disease. We identify two genomic regions that contain genes related to immune function or cancer risk in humans that exhibit concordant signatures of selection across three populations. DFTD spreads between hosts by suppressing and evading the immune system, and our results suggest that hosts are evolving immune-modulated resistance that could aid in species persistence in the face of this devastating disease. PMID:27575253

  16. RNA Disruption and Drug Response in Breast Cancer Primary Systemic Therapy.

    PubMed

    Pritzker, Kenneth; Pritzker, Laura; Generali, Daniele; Bottini, Alberto; Cappelletti, Maria Rosa; Guo, Baoqing; Parissenti, Amadeo; Trudeau, Maureen

    2015-05-01

    As there is now evidence that switching clinical nonresponders early in primary systemic therapy to alternate treatment regimens can enhance survival in some breast cancer patients, the need for a robust intermediate endpoint that can guide treatment response across all tumor subtypes is urgent. Recently, chemotherapy drugs have been shown to induce a decrease in RNA quality in tumor cells from breast cancer biopsies in some patients at midtherapy, and that this has been associated with subsequent achievement of pathological complete response (pCR). The decrease in RNA quality has been shown to be associated with RNA disruption; aberrant RNA bands visualized by RNA electrophoresis have been associated with subsequent tumor cell death. The objectives of these studies are to show that a new assay based on induction of RNA disruption in tumor cells by chemotherapy can stratify at midtherapy, pCR responders from non-pCR responders irrespective of clinical response and to present early evidence that clinically useful RNA disruption can be detected as early as 14 days after initiation of treatment. RNA disruption in tumor cells was quantified by analysis of the RNA electrophoresis banding pattern and expressed as an RNA disruption index (RDI). To develop the RNA disruption assay (RDA), RDI was correlated with clinical outcome (pCR) from the NCIC-CTG MA.22 breast cancer clinical trial (ClinicalTrials.gov NCT00066443). RDA Zones were established by stratifying patients using RDI values into Zone 1, Zone 2, and Zone 3. Zone 3 included seven out of eight pCR responders, whereas Zone 1 contained no pCR responders. An intermediate zone (Zone 2) was established which contained one pCR. Subsequently, to determine early drug response, RNA disruption was examined by RDI after 14 days exposure to trastuzumab, zoledronic acid, or letrozole + cyclophosphamide ± sorafenib therapy. In MA.22, RDA stratified 23 of 85 patients in Zone 1 as pCR nonresponders, 24 patients in Zone 2, an

  17. Glutathione- and pH-responsive nonporous silica prodrug nanoparticles for controlled release and cancer therapy

    NASA Astrophysics Data System (ADS)

    Xu, Zhigang; Liu, Shiying; Kang, Yuejun; Wang, Mingfeng

    2015-03-01

    A myriad of drug delivery systems such as liposomes, micelles, polymers and inorganic nanoparticles (NPs) have been developed for cancer therapy. Very few of them, however, have the ability to integrate multiple functionalities such as specific delivery, high circulation stability, controllable release and good biocompatibility and biodegradability in a single system to improve the therapeutic efficacy. Herein, we report two types of stimuli-responsive nonporous silica prodrug NPs towards this goal for controlled release of anticancer drugs and efficient combinatorial cancer therapy. As a proof of concept, anticancer drugs camptothecin (CPT) and doxorubicin (DOX) were covalently encapsulated into silica matrices through glutathione (GSH)-responsive disulfide and pH-responsive hydrazone bonds, respectively, resulting in NPs with sizes tunable in the range of 50-200 nm. Both silica prodrug NPs showed stimuli-responsive controlled release upon exposure to a GSH-rich or acidic environment, resulting in improved anticancer efficacy. Notably, two prodrug NPs simultaneously taken up by HeLa cells showed a remarkable combinatorial efficacy compared to free drug pairs. These results suggest that the stimuli-responsive silica prodrug NPs are promising anticancer drug carriers for efficient cancer therapy.A myriad of drug delivery systems such as liposomes, micelles, polymers and inorganic nanoparticles (NPs) have been developed for cancer therapy. Very few of them, however, have the ability to integrate multiple functionalities such as specific delivery, high circulation stability, controllable release and good biocompatibility and biodegradability in a single system to improve the therapeutic efficacy. Herein, we report two types of stimuli-responsive nonporous silica prodrug NPs towards this goal for controlled release of anticancer drugs and efficient combinatorial cancer therapy. As a proof of concept, anticancer drugs camptothecin (CPT) and doxorubicin (DOX) were

  18. Metabolic autofluorescence imaging of head and neck cancer organoids quantifies cellular heterogeneity and treatment response (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Shah, Amy T.; Heaster, Tiffany M.; Skala, Melissa C.

    2017-02-01

    Treatment options for head and neck cancer are limited, and can cause an impaired ability to eat, talk, and breathe. Therefore, optimized and personalized therapies could reduce unnecessary toxicities from ineffective treatments. Organoids are generated from primary tumor tissue and provide a physiologically-relevant in vitro model to measure drug response. Additionally, multiphoton fluorescence lifetime imaging (FLIM) of the metabolic cofactors NAD(P)H and FAD can resolve dynamic cellular response to anti-cancer treatment. This study applies FLIM of NAD(P)H and FAD to head and neck cancer organoids. Head and neck cancer tissue was digested and grown in culture as three-dimensional organoids. Gold standard measures of therapeutic response in vivo indicate stable disease after treatment with cetuximab (antibody therapy) or cisplatin (chemotherapy), and treatment response after combination treatment. In parallel, organoids were treated with cetuximab, cisplatin, or combination therapy for 24 hours. Treated organoids exhibit decreased NAD(P)H lifetime (p<0.05) and increased FAD lifetime (p<0.05) compared with control organoids. Additionally, analysis of cellular heterogeneity identifies distinct subpopulations of cells in response to treatment. A quantitative heterogeneity index predicts in vivo treatment response and demonstrates increased cellular heterogeneity in organoids treated with cetuximab or cisplatin compared with combination treatment. Mapping of cell subpopulations enables characterization of spatial relationships between cell subpopulations. Ultimately, an organoid model combined with metabolic fluorescence imaging could provide a high-throughput platform for drug discovery. Organoids grown from patient tissue could enable individualized treatment planning. These achievements could optimize quality of life and treatment outcomes for head and neck cancer patients.

  19. POLE proofreading mutations elicit an anti-tumor immune response in endometrial cancer

    PubMed Central

    van Gool, Inge C; Eggink, Florine A; Freeman-Mills, Luke; Stelloo, Ellen; Marchi, Emanuele; de Bruyn, Marco; Palles, Claire; Nout, Remi A; de Kroon, Cor D; Osse, Elisabeth M; Klenerman, Paul; Creutzberg, Carien L; Tomlinson, Ian PM; Smit, Vincent THBM; Nijman, Hans W

    2015-01-01

    Purpose Recent studies have shown that 7-12% of endometrial cancers (ECs) are ultramutated due to somatic mutation in the proofreading exonuclease domain of the DNA replicase POLE. Interestingly, these tumors have an excellent prognosis. In view of the emerging data linking mutation burden, immune response and clinical outcome in cancer, we investigated whether POLE-mutant ECs showed evidence of increased immunogenicity. Experimental design We examined immune infiltration and activation according to tumor POLE proofreading mutation in a molecularly defined EC cohort including 47 POLE-mutant tumors. We sought to confirm our results by analysis of RNAseq data from the TCGA EC series and used the same series to examine whether differences in immune infiltration could be explained by an enrichment of immunogenic neoepitopes in POLE-mutant ECs. Results Compared to other ECs, POLE-mutants displayed an enhanced cytotoxic T cell response, evidenced by increased numbers of CD8+ tumor infiltrating lymphocytes and CD8A expression, enrichment for a tumor-infiltrating T cell gene signature, and strong upregulation of the T cell cytotoxic differentiation and effector markers T-bet, Eomes, IFNG, PRF and granzyme B. This was accompanied by upregulation of T cell exhaustion markers, consistent with chronic antigen exposure. In-silico analysis confirmed that POLE-mutant cancers are predicted to display more antigenic neo-epitopes than other ECs, providing a potential explanation for our findings. Conclusions Ultramutated POLE proofreading-mutant ECs are characterized by a robust intratumoral T cell response, which correlates with, and may be caused by an enrichment of antigenic neo-peptides. Our study provides a plausible mechanism for the excellent prognosis of these cancers. PMID:25878334

  20. DNA Repair Biomarkers Predict Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Alexander, Brian M., E-mail: bmalexander@lroc.harvard.edu; Wang Xiaozhe; Niemierko, Andrzej

    2012-05-01

    Purpose: The addition of neoadjuvant chemoradiotherapy prior to surgical resection for esophageal cancer has improved clinical outcomes in some trials. Pathologic complete response (pCR) following neoadjuvant therapy is associated with better clinical outcome in these patients, but only 22% to 40% of patients achieve pCR. Because both chemotherapy and radiotherapy act by inducing DNA damage, we analyzed proteins selected from multiple DNA repair pathways, using quantitative immunohistochemistry coupled with a digital pathology platform, as possible biomarkers of treatment response and clinical outcome. Methods and Materials: We identified 79 patients diagnosed with esophageal cancer between October 1994 and September 2002, withmore » biopsy tissue available, who underwent neoadjuvant chemoradiotherapy prior to surgery at the Massachusetts General Hospital and used their archived, formalin-fixed, paraffin-embedded biopsy samples to create tissue microarrays (TMA). TMA sections were stained using antibodies against proteins in various DNA repair pathways including XPF, FANCD2, PAR, MLH1, PARP1, and phosphorylated MAPKAP kinase 2 (pMK2). Stained TMA slides were evaluated using machine-based image analysis, and scoring incorporated both the intensity and the quantity of positive tumor nuclei. Biomarker scores and clinical data were assessed for correlations with clinical outcome. Results: Higher scores for MLH1 (p = 0.018) and lower scores for FANCD2 (p = 0.037) were associated with pathologic response to neoadjuvant chemoradiation on multivariable analysis. Staining of MLH1, PARP1, XPF, and PAR was associated with recurrence-free survival, and staining of PARP1 and FANCD2 was associated with overall survival on multivariable analysis. Conclusions: DNA repair proteins analyzed by immunohistochemistry may be useful as predictive markers for response to neoadjuvant chemoradiotherapy in patients with esophageal cancer. These results are hypothesis generating and need

  1. Stimuli-responsive chitosan-based nanocarriers for cancer therapy

    PubMed Central

    Fathi, Marziyeh; Sahandi Zangabad, Parham; Majidi, Sima; Barar, Jaleh; Erfan-Niya, Hamid

    2017-01-01

    Introduction: Stimuli-responsive nanocarriers offer unique advantages over the traditional drug delivery systems (DDSs) in terms of targeted drug delivery and on-demand release of cargo drug molecules. Of these, chitosan (CS)-based DDSs offer several advantages such as high compatibility with biological settings. Methods: In this study, we surveyed the literature in terms of the stimuli-responsive nanocarriers and discussed the most recent advancements in terms of CS-based nanosystems and their applications in cancer therapy and diagnosis. Results: These advanced DDSs are able to release the entrapped drugs in response to a specific endogenous stimulus (e.g., pH, glutathione concentration or certain enzymes) or exogenous stimulus (e.g., temperature, light, ultrasound, and magnetic field) at the desired time and target site. Dual-responsive nanocarriers by the combination of different stimuli have also been developed as efficient and improved DDSs. Among the stimuli-responsive nanocarriers, CS-based DDSs offer several advantages, including biocompatibility and biodegradability, antibacterial activity, ease of modification and functionalization, and non-immunogenicity. They are as one of the most ideal smart multifunction DDSs. Conclusion: The CS-based stimuli-responsive multifunctional nanosystems (NSs) offer unique potential for the targeted delivery of anticancer agents and provide great potential for on-demand and controlled-release of anticancer agents in response to diverse external/internal stimuli. PMID:29435435

  2. Stimuli-responsive chitosan-based nanocarriers for cancer therapy.

    PubMed

    Fathi, Marziyeh; Sahandi Zangabad, Parham; Majidi, Sima; Barar, Jaleh; Erfan-Niya, Hamid; Omidi, Yadollah

    2017-01-01

    Introduction: Stimuli-responsive nanocarriers offer unique advantages over the traditional drug delivery systems (DDSs) in terms of targeted drug delivery and on-demand release of cargo drug molecules. Of these, chitosan (CS)-based DDSs offer several advantages such as high compatibility with biological settings. Methods: In this study, we surveyed the literature in terms of the stimuli-responsive nanocarriers and discussed the most recent advancements in terms of CS-based nanosystems and their applications in cancer therapy and diagnosis. Results: These advanced DDSs are able to release the entrapped drugs in response to a specific endogenous stimulus (e.g., pH, glutathione concentration or certain enzymes) or exogenous stimulus (e.g., temperature, light, ultrasound, and magnetic field) at the desired time and target site. Dual-responsive nanocarriers by the combination of different stimuli have also been developed as efficient and improved DDSs. Among the stimuli-responsive nanocarriers, CS-based DDSs offer several advantages, including biocompatibility and biodegradability, antibacterial activity, ease of modification and functionalization, and non-immunogenicity. They are as one of the most ideal smart multifunction DDSs. Conclusion: The CS-based stimuli-responsive multifunctional nanosystems (NSs) offer unique potential for the targeted delivery of anticancer agents and provide great potential for on-demand and controlled-release of anticancer agents in response to diverse external/internal stimuli.

  3. Cancer Education Program Evaluation: A Responsive Approach to Planning an Evaluation and Initial Results.

    ERIC Educational Resources Information Center

    Pearsol, James A.

    This paper describes evaluation planning for the Cancer Education Program (CEP) at Ohio State University (OSU). The three-year OSU CEP project was designed as a multidisciplinary cancer education program. A responsive method, which trades off some measurement precision in order to increase the usefulness of the findings, was employed in the…

  4. Induction therapy with carboplatin/paclitaxel followed by concurrent carboplatin/paclitaxel and dose-escalating conformal radiotherapy in the treatment of locally advanced, unresectable non-small cell lung cancer: preliminary report of a phase I trial.

    PubMed

    Socinski, M A; Clark, J A; Halle, J; Steagall, A; Kaluzny, B; Rosenman, J G

    1997-08-01

    Locally advanced non-small cell lung cancer is optimally managed with chemotherapy and thoracic irradiation, although the most appropriate strategy is not yet defined. In this phase I trial, we use two 21-day cycles of induction chemotherapy with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (225 mg/m2 over 3 hours) and carboplatin (area under the concentration-time curve = 6) followed by concurrent weekly paclitaxel (45 mg/m2/wk x 6) and carboplatin (area under the concentration-time curve = 2/wk x 6) and thoracic irradiation. Patients undergo three-dimensional treatment planning (conformal radiotherapy) to define the cancer target volume precisely. The phase I question being addressed in this study is the maximum tolerated radiation dose given concurrently with low-dose paclitaxel and carboplatin. The initial radiation dose is 60 Gy, with dose escalations to 66 Gy, 70 Gy, and 74 Gy being planned. Ten patients have been entered thus far (eight men and two women). Their median age is 67 years (range, 59 to 78 years), and none of the patients has had greater than 5% pretreatment weight loss. Seven of 10 are evaluable for response to induction carboplatin and paclitaxel, with a response rate of 57% (three partial responses and one minor response). Three patients had stable disease and none of the patients had evidence of progressive disease during induction chemotherapy. Three patients have completed all treatment at 60 Gy and one has completed all treatment at 66 Gy. Three of the four patients have had partial responses (75%), with the remaining patient having stable disease. Toxicity in the concurrent chemoradiotherapy portion of the trial thus far has consisted of grade 3 neutropenia in one patient and grade 4 lymphocytopenia in all four patients. No grade 3 or 4 nonhematologic toxicity has been seen. The trial data are not yet mature enough to report on survival. Accrual and treatment is continuing at the 66 Gy radiation dose level.

  5. Genomancy: predicting tumour response to cancer therapy based on the oracle of genetics.

    PubMed

    Williams, P D; Lee, J K; Theodorescu, D

    2009-01-01

    Cells are complex systems that regulate a multitude of biologic pathways involving a diverse array of molecules. Cancer can develop when these pathways become deregulated as a result of mutations in the genes coding for these proteins or of epigenetic changes that affect gene expression, or both1,2. The diversity and interconnectedness of these pathways and their molecular components implies that a variety of mutations may lead to tumorigenic cellular deregulation3-6. This variety, combined with the requirement to overcome multiple anticancer defence mechanisms7, contributes to the heterogeneous nature of cancer. Consequently, tumours with similar histology may vary in their underlying molecular circuitry8-10, with resultant differences in biologic behaviour, manifested in proliferation rate, invasiveness, metastatic potential, and unfortunately, response to cytotoxic therapy. Thus, cancer can be thought of as a family of related tumour subtypes, highlighting the need for individualized prediction both of disease progression and of treatment response, based on the molecular characteristics of the tumour.

  6. Evaluation of Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy

    DTIC Science & Technology

    2015-09-01

    Award Number: W81XWH-11-1-0384 TITLE: Evaluation of Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells : Implications for...Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells : Implications for Cancer Vaccine Therapy 5b. GRANT NUMBER CA100463 5c...Listeria monocytogenes (Lm) on human dendritic cells (DCs) to optimize Lm-based DC cancer vaccines. The project aims are: 1) Compare the activation and

  7. Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility.

    PubMed

    Snijders, Antoine M; Marchetti, Francesco; Bhatnagar, Sandhya; Duru, Nadire; Han, Ju; Hu, Zhi; Mao, Jian-Hua; Gray, Joe W; Wyrobek, Andrew J

    2012-01-01

    High dose ionizing radiation (IR) is a well-known risk factor for breast cancer but the health effects after low-dose (LD, <10 cGy) exposures remain highly uncertain. We explored a systems approach that compared LD-induced chromosome damage and transcriptional responses in strains of mice with genetic differences in their sensitivity to radiation-induced mammary cancer (BALB/c and C57BL/6) for the purpose of identifying mechanisms of mammary cancer susceptibility. Unirradiated mammary and blood tissues of these strains differed significantly in baseline expressions of DNA repair, tumor suppressor, and stress response genes. LD exposures of 7.5 cGy (weekly for 4 weeks) did not induce detectable genomic instability in either strain. However, the mammary glands of the sensitive strain but not the resistant strain showed early transcriptional responses involving: (a) diminished immune response, (b) increased cellular stress, (c) altered TGFβ-signaling, and (d) inappropriate expression of developmental genes. One month after LD exposure, the two strains showed opposing responses in transcriptional signatures linked to proliferation, senescence, and microenvironment functions. We also discovered a pre-exposure expression signature in both blood and mammary tissues that is predictive for poor survival among human cancer patients (p = 0.0001), and a post-LD-exposure signature also predictive for poor patient survival (p<0.0001). There is concordant direction of expression in the LD-exposed sensitive mouse strain, in biomarkers of human DCIS and in biomarkers of human breast tumors. Our findings support the hypothesis that genetic mechanisms that determine susceptibility to LD radiation induced mammary cancer in mice are similar to the tissue mechanisms that determine poor-survival in breast cancer patients. We observed non-linearity of the LD responses providing molecular evidence against the LNT risk model and obtained new evidence that LD responses are strongly

  8. Clinical utility of pretreatment prediction of chemoradiotherapy response in rectal cancer: a review.

    PubMed

    Yoo, Byong Chul; Yeo, Seung-Gu

    2017-03-01

    Approximately 20% of all patients with locally advanced rectal cancer experience pathologically complete responses following neoadjuvant chemoradiotherapy (CRT) and standard surgery. The utility of radical surgery for patients exhibiting good CRT responses has been challenged. Organ-sparing strategies for selected patients exhibiting complete clinical responses include local excision or no immediate surgery. The subjects of this tailored management are patients whose presenting disease corresponds to current indications of neoadjuvant CRT, and their post-CRT tumor response is assessed by clinical and radiological examinations. However, a model predictive of the CRT response, applied before any treatment commenced, would be valuable to facilitate such a personalized approach. This would increase organ preservation, particularly in patients for whom upfront CRT is not generally prescribed. Molecular biomarkers hold the greatest promise for development of a pretreatment predictive model of CRT response. A combination of clinicopathological, radiological, and molecular markers will be necessary to render the model robust. Molecular research will also contribute to the development of drugs that can overcome the radioresistance of rectal tumors. Current treatments for rectal cancer are based on the expected prognosis given the presenting disease extent. In the future, treatment schemes may be modified by including the predicted CRT response evaluated at presentation.

  9. Epigenetic Mechanisms Regulating Adaptive Responses to Targeted Kinase Inhibitors in Cancer.

    PubMed

    Angus, Steven P; Zawistowski, Jon S; Johnson, Gary L

    2018-01-06

    Although targeted inhibition of oncogenic kinase drivers has achieved remarkable patient responses in many cancers, the development of resistance has remained a significant challenge. Numerous mechanisms have been identified, including the acquisition of gatekeeper mutations, activating pathway mutations, and copy number loss or gain of the driver or alternate nodes. These changes have prompted the development of kinase inhibitors with increased selectivity, use of second-line therapeutics to overcome primary resistance, and combination treatment to forestall resistance. In addition to genomic resistance mechanisms, adaptive transcriptional and signaling responses seen in tumors are gaining appreciation as alterations that lead to a phenotypic state change-often observed as an epithelial-to-mesenchymal shift or reversion to a cancer stem cell-like phenotype underpinned by remodeling of the epigenetic landscape. This epigenomic modulation driving cell state change is multifaceted and includes modulation of repressive and activating histone modifications, DNA methylation, enhancer remodeling, and noncoding RNA species. Consequently, the combination of kinase inhibitors with drugs targeting components of the transcriptional machinery and histone-modifying enzymes has shown promise in preclinical and clinical studies. Here, we review mechanisms of resistance to kinase inhibition in cancer, with special emphasis on the rewired kinome and transcriptional signaling networks and the potential vulnerabilities that may be exploited to overcome these adaptive signaling changes.

  10. Molecular subtypes of metastatic colorectal cancer are associated with patient response to irinotecan-based therapies.

    PubMed

    Del Rio, M; Mollevi, C; Bibeau, F; Vie, N; Selves, J; Emile, J-F; Roger, P; Gongora, C; Robert, J; Tubiana-Mathieu, N; Ychou, M; Martineau, P

    2017-05-01

    Currently, metastatic colorectal cancer is treated as a homogeneous disease and only RAS mutational status has been approved as a negative predictive factor in patients treated with cetuximab. The aim of this study was to evaluate if recently identified molecular subtypes of colon cancer are associated with response of metastatic patients to first-line therapy. We collected and analysed 143 samples of human colorectal tumours with complete clinical annotations, including the response to treatment. Gene expression profiling was used to classify patients in three to six classes using four different molecular classifications. Correlations between molecular subtypes, response to treatment, progression-free and overall survival were analysed. We first demonstrated that the four previously described molecular classifications of colorectal cancer defined in non-metastatic patients also correctly classify stage IV patients. One of the classifications is strongly associated with response to FOLFIRI (P=0.003), but not to FOLFOX (P=0.911) and FOLFIRI + Bevacizumab (P=0.190). In particular, we identify a molecular subtype representing 28% of the patients that shows an exceptionally high response rate to FOLFIRI (87.5%). These patients have a two-fold longer overall survival (40.1 months) when treated with FOLFIRI, as first-line regimen, instead of FOLFOX (18.6 months). Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer and a strong impact of the first-line regimen on the overall survival of some patients. This however remains to be confirmed in a large prospective clinical trial. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Real-Time Moment-to-Moment Emotional Responses to Narrative and Informational Breast Cancer Videos in African American Women

    ERIC Educational Resources Information Center

    Bollinger, Sarah; Kreuter, Matthew W.

    2012-01-01

    In a randomized experiment using moment-to-moment audience analysis methods, we compared women's emotional responses with a narrative versus informational breast cancer video. Both videos communicated three key messages about breast cancer: (i) understand your breast cancer risk, (ii) talk openly about breast cancer and (iii) get regular…

  12. Microarray profile of the humoral immune response to influenza vaccination in breast cancer patients treated with chemotherapy.

    PubMed

    Wumkes, M L; van der Velden, A M T; de Bruin, E; Meerveld-Eggink, A; Koopmans, M P G; Rimmelzwaan, G F; Rijkers, G T; Biesma, D H

    2017-03-01

    Patients treated with chemotherapy have an impaired response to influenza virus vaccination compared to healthy controls. Little is known about the broadness of the antibody response in these patients. Breast cancer patients on FEC (5-fluorouracil, epirubicin and cyclophosphamide) chemotherapy regimens were vaccinated with influenza virus vaccine. Sera were obtained before and three weeks after vaccination. In addition to the determination of virus-specific antibody titres by hemagglutination inhibition assay, the broadness of the response was assessed by the use of a protein microarray and baseline titres were compared with an age-matched reference group. We included 38 breast cancer patients and found a wide variety in serum antibody response after vaccination. Patients with a history of influenza vaccination had higher pre-vaccination titres, which were comparable to the reference group. Increasing number of cycles of chemotherapy did not have a negative effect on influenza array antibody levels, nor on the HI antibody response. Overall there was a broad serum antibody response to the influenza virus vaccine in patients treated with chemotherapy for breast cancer. Copyright © 2017. Published by Elsevier Ltd.

  13. The Gα1-cAMP signaling pathway controls conidiation, development and secondary metabolism in the taxol-producing fungus Pestalotiopsis microspora.

    PubMed

    Yu, Xi; Liu, Heng; Niu, Xueliang; Akhberdi, Oren; Wei, Dongsheng; Wang, Dan; Zhu, Xudong

    2017-10-01

    G-protein-mediated signaling pathways regulate fungal morphogenesis, development and secondary metabolism. In this study, we report a gene, pgα1, that putatively encodes the α-subunit of a group I G protein in Pestalotiopsis microspora NK17, which is known to produce various secondary metabolites, including the antitumor drug taxol and pestalotiollide B (PB). Mutants of pgα1 showed retarded vegetative growth, aging of the mycelium, premature conidiation, deformed conidia, significantly increased melanin production, and a sharp decrease in PB production. The introduction of extra copies of pgα1 led to a different phenotype that was characterized by enhanced production of PB. qRT-PCR revealed that the expression of pks1, which encodes melanin polyketide synthase, an enzyme that is involved in 1, 8-dihydroxynaphthalene (DHN) melanin biosynthesis, was up regulated by 55-fold in the absence of pgα1. Changes in conidiation and PB production in pgα1 mutants were able to be restored by the addition of exogenous cAMP. The deficiencies of PB production and conidiation in Δpgα1 were not able to be rescued by deletion or overexpression of a previously reported histone deacetylase gene (hid1), suggesting that pgα1 is able to override the effect of hid1 on PB production and conidiation. Our results suggested that the G protein-cAMP pathway plays a critical role in vegetative growth as well as in asexual development of P. microspora. Copyright © 2017 Elsevier GmbH. All rights reserved.

  14. IAP Antagonists Enhance Apoptotic Response to Enzalutamide in Castration-Resistant Prostate Cancer Cells via Autocrine TNF-α Signaling.

    PubMed

    Pilling, Amanda B; Hwang, Ok; Boudreault, Alain; Laurent, Alain; Hwang, Clara

    2017-06-01

    Castration-resistant prostate cancer (CRPC) remains incurable and identifying effective treatments continues to present a clinical challenge. Although treatment with enzalutamide, a second generation androgen receptor (AR) antagonist, prolongs survival in prostate cancer patients, responses can be limited by intrinsic resistance or acquired resistance. A potential mechanism of resistance to androgen axis inhibition is evasion of apoptosis. Inhibitor of apoptosis proteins (IAPs) are found to be overexpressed in prostate cancer and function to block apoptosis and promote survival signaling. Novel, small-molecule IAP antagonists, such as AEG40995, are emerging as a strategy to induce apoptosis and increase therapeutic response in cancer. Human prostate cancer cell lines LNCaP and C4-2 were treated with enzalutamide with or without addition of IAP antagonist AEG40995 and proliferation and survival were determined by MTS and clonogenic assay. Western blot was used to evaluate IAP protein expression changes and PARP-1 cleavage was assessed as indication of apoptosis. Flow cytometry was performed to analyze apoptosis in treated cells. Caspase activity was determined by luminescence assay. Quantitative real-time PCR and immunometric ELISA was used to assess TNF-α (transcript and protein levels, respectively) in response to treatment. In this study, we demonstrate that IAP antagonist AEG40995 exhibits minimal effects on prostate cancer cell proliferation or survival, but rapidly degrades cIAP1 protein. Combination treatment with enzalutamide demonstrates that AEG40995 increases apoptosis and reduces proliferation and clonogenic survival in cell line models of prostate cancer. Mechanistically, we demonstrate that apoptosis in response to enzalutamide and IAP antagonist requires activation of caspase-8, suggesting extrinsic/death receptor apoptosis signaling. Assessment of TNF-α in response to combination treatment with enzalutamide and AEG40995 reveals increased m

  15. Flavonoid silybin improves the response to radiotherapy in invasive bladder cancer.

    PubMed

    Prack Mc Cormick, Barbara; Langle, Yanina; Belgorosky, Denise; Vanzulli, Silvia; Balarino, Natalia; Sandes, Eduardo; Eiján, Ana M

    2018-01-24

    Conservative treatment for invasive bladder cancer (BC) involves a complete transurethral tumor resection combined with chemotherapy (CT) and radiotherapy (RT). The major obstacles of chemo-radiotherapy are the addition of the toxicities of RT and CT, and the recurrence due to RT and CT resistances. The flavonoid Silybin (Sb) inhibits pathways involved in cell survival and resistance mechanisms, therefore the purpose of this paper was to study in vitro and in vivo, the ability of Sb to improve the response to RT, in two murine BC cell lines, with different levels of invasiveness, placing emphasis on radio-sensitivity, and pathways involved in radio-resistance and survival. In vitro, Sb radio-sensitized murine invasive cells through the inhibition of RT-induced NF-κB and PI3K pathways, and the increase of oxidative stress, while non-invasive cells did not show to be sensitized. In vivo, Sb improved RT-response and overall survival in invasive murine tumors. As Sb is already being tested in clinical trials for other urological cancers and it improves RT-response in invasive BC, these results could have translational relevance, supporting further research. © 2018 Wiley Periodicals, Inc.

  16. Young Women's Responses to Smoking and Breast Cancer Risk Information

    ERIC Educational Resources Information Center

    Bottorff, Joan L.; McKeown, Stephanie Barclay; Carey, Joanne; Haines, Rebecca; Okoli, Chizimuzo; Johnson, Kenneth C.; Easley, Julie; Ferrence, Roberta; Baillie, Lynne; Ptolemy, Erin

    2010-01-01

    Current evidence confirms that young women who smoke or who have regular long-term exposure to secondhand smoke (SHS) have an increased risk of developing premenopausal breast cancer. The aim of this research was to examine the responses of young women to health information about the links between active smoking and SHS exposure and breast cancer…

  17. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans.

    PubMed

    Abegglen, Lisa M; Caulin, Aleah F; Chan, Ashley; Lee, Kristy; Robinson, Rosann; Campbell, Michael S; Kiso, Wendy K; Schmitt, Dennis L; Waddell, Peter J; Bhaskara, Srividya; Jensen, Shane T; Maley, Carlo C; Schiffman, Joshua D

    2015-11-03

    Evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology. To identify mechanisms for cancer resistance in elephants and compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS). A comprehensive survey of necropsy data was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11). Human samples were collected at the University of Utah between June 2014 and July 2015. Ionizing radiation and doxorubicin. Cancer mortality across species was calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes. Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% [95% CI, 0%-5%]; African wild dog, 8% [95% CI, 0%-16%]; lion, 2% [95% CI, 0%-7%]). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95% CI, 3.14%-6.49%), compared with humans, who have 11% to 25% cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain reaction. In response to DNA damage, elephant lymphocytes underwent p53-mediated apoptosis

  18. Biological oscillations: Fluorescence monitoring by confocal microscopy

    NASA Astrophysics Data System (ADS)

    Chattoraj, Shyamtanu; Bhattacharyya, Kankan

    2016-09-01

    Fluctuations play a vital role in biological systems. Single molecule spectroscopy has recently revealed many new kinds of fluctuations in biological molecules. In this account, we focus on structural fluctuations of an antigen-antibody complex, conformational dynamics of a DNA quadruplex, effects of taxol on dynamics of microtubules, intermittent red-ox oscillations at different organelles in a live cell (mitochondria, lipid droplets, endoplasmic reticulum and cell membrane) and stochastic resonance in gene silencing. We show that there are major differences in these dynamics between a cancer cell and the corresponding non-cancer cell.

  19. Taste intensity and hedonic responses to simple beverages in gastrointestinal cancer patients.

    PubMed

    Bossola, Maurizio; Cadoni, Gabriella; Bellantone, Rocco; Carriero, Concetta; Carriero, Elena; Ottaviani, Fabrizio; Borzomati, Domenico; Tortorelli, Antonio; Doglietto, Giovan Battista

    2007-11-01

    Changes in the taste of food have been implicated as a potential cause of reduced dietary intake among cancer patients. However, data on intensity and hedonic responses to the four basic tastes in cancer are scanty and contradictory. The present study aimed at evaluating taste intensity and hedonic responses to simple beverages in 47 anorectic patients affected by gastrointestinal cancer and in 55 healthy subjects. Five suprathreshold concentrations of each of the four test substances (sucrose in black current drinks, citric acid in lemonade, NaCl in unsalted tomato juice, and urea in tonic water) were used. Patients were invited to express a judgment of intensity and pleasantness ranging from 0 to 10. Mean intensity scores directly correlated with concentrations of sour, salty, bitter, and sweet stimuli, in both normals and those with cancer. Intensity judgments were higher in cancer patients with respect to sweet (for median and high concentrations, P<0.05), salty (for all concentrations, P<0.05), and bitter tastes (for median concentration, P<0.01). Hedonic function increased with the increase of the stimuli only for the sweet taste. A negative linear correlation was found between sour, bitter, and salty concentrations and hedonic score. Both in cancer patients and in healthy subjects, hedonic judgments increased with the increase of the stimulus for the sweet taste (r=0.978 and r=0.985, P=0.004 and P=0.002, respectively), and decreased for the salty (r=-0.827 and r=-0.884, P=0.084 and P=0.047, respectively) and bitter tastes (r=-0.990 and r=-0.962, P=0.009 and P=0.001, respectively). For the sour taste, the hedonic scores remained stable with the increase of the stimulus in noncancer controls (r=-0.785, P=0.115) and decreased in cancer patients (r=-0.996, P=0.0001). The hedonic scores for the sweet taste and the bitter taste were similar in cancer patients and healthy subjects, and these scores were significantly higher in cancer patients than in healthy

  20. Sexual Dimorphism of Immune Responses: A New Perspective in Cancer Immunotherapy

    PubMed Central

    Capone, Imerio; Marchetti, Paolo; Ascierto, Paolo Antonio; Malorni, Walter; Gabriele, Lucia

    2018-01-01

    Nowadays, several types of tumors can benefit from the new frontier of immunotherapy, due to the recent increasing knowledge of the role of the immune system in cancer control. Among the new therapeutic strategies, there is the immune checkpoint blockade (ICB), able to restore an efficacious antitumor immunity and significantly prolong the overall survival (OS) of patients with advanced tumors such as melanoma and non-small cell lung cancer (NSCLC). Despite the impressive efficacy of these agents in some patients, treatment failure and resistance are frequently observed. In this regard, the signaling governed by IFN type I (IFN-I) has emerged as pivotal in orchestrating host defense. This pathway displays different activation between sexes, thus potentially contributing to sexual dimorphic differences in the immune responses to immunotherapy. This perspective article aims to critically consider the immune signals, with particular attention to IFN-I, that may differently affect female and male antitumor responses upon immunotherapy. PMID:29619026

  1. Sexual Dimorphism of Immune Responses: A New Perspective in Cancer Immunotherapy.

    PubMed

    Capone, Imerio; Marchetti, Paolo; Ascierto, Paolo Antonio; Malorni, Walter; Gabriele, Lucia

    2018-01-01

    Nowadays, several types of tumors can benefit from the new frontier of immunotherapy, due to the recent increasing knowledge of the role of the immune system in cancer control. Among the new therapeutic strategies, there is the immune checkpoint blockade (ICB), able to restore an efficacious antitumor immunity and significantly prolong the overall survival (OS) of patients with advanced tumors such as melanoma and non-small cell lung cancer (NSCLC). Despite the impressive efficacy of these agents in some patients, treatment failure and resistance are frequently observed. In this regard, the signaling governed by IFN type I (IFN-I) has emerged as pivotal in orchestrating host defense. This pathway displays different activation between sexes, thus potentially contributing to sexual dimorphic differences in the immune responses to immunotherapy. This perspective article aims to critically consider the immune signals, with particular attention to IFN-I, that may differently affect female and male antitumor responses upon immunotherapy.

  2. Major Histocompatibilty Complex-Restricted Adaptive Immune Responses to CT26 Colon Cancer Cell Line in Mixed Allogeneic Chimera.

    PubMed

    Lee, K W; Choi, B; Kim, Y M; Cho, C W; Park, H; Moon, J I; Choi, G-S; Park, J B; Kim, S J

    2017-06-01

    Although the induction of mixed allogeneic chimera shows promising clinical tolerance results in organ transplantation, its clinical relevance as an anti-cancer therapy is yet unknown. We introduced a mixed allogenic chimera setting with the use of a murine colon cancer cell line, CT26, by performing double bone marrow transplantation. We analyzed donor- and recipient-restricted anti-cancer T-cell responses, and phenotypes of subpopulations of T cells. The protocol involves challenging 1 × 10 5 cells of CT26 cells intra-hepatically on day 50 after bone marrow transplantation, and, by use of CT26 lysates and an H-2L d -restricted AH1 pentamer, flow cytometric analysis was performed to detect the generation of cancer-specific CD4 + and CD8 + T cells at various time points. We found that immunocompetence against tumors depends heavily on cancer-specific CD8 + T-cell responses in a major histocompatibility complex-restricted manner; the evidence was further supported by the increase of interferon-γ-secreting CD4 + T cells. Moreover, we demonstrated that during the effector immune response to CT26 cancer challenge, there was a presence of central memory cells (CD62L hi CCR7 + ) as well as effector memory cells (CD62L lo CCR7 - ). Moreover, mixed allogeneic chimeras (BALB/c to C56BL/6 or vice versa) showed similar or heightened immune responses to CT26 cells compared with that of wild-type mice. Our results suggest that the responses of primary immunocompetency and of pre-existing memory T cells against allogeneic cancer are sustained and preserved long-term in a mixed allogeneic chimeric environment. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. The anticancer immune response of anti-PD-1/PD-L1 and the genetic determinants of response to anti-PD-1/PD-L1 antibodies in cancer patients

    PubMed Central

    Han, Weidong; Wang, Xian; Fang, Yong; Li, Da; Pan, Hongming; Zhang, Li

    2015-01-01

    The programmed death-1 (PD-1), a coinhibitory receptor expressed on activated T cells and B cells, is demonstrated to induce an immune-mediated response and play a critical role in tumor initiation and development. The cancer patients harboring PD-1 or PD ligand 1 (PD-L1) protein expression have often a poor prognosis and clinical outcome. Currently, targeting PD-1 pathway as a potential new anticancer strategy is attracting more and more attention in cancer treatment. Several monoclonal antibodies against PD-1 or PD-L1 have been reported to enhance anticancer immune responses and induce tumor cell death. Nonetheless, the precise molecular mechanisms by which PD-1 affects various cancers remain elusive. Moreover, this therapy is not effective for all the cancer patients and only a fraction of patients respond to the antibodies targeting PD-1 or PD-L1, indicating these antibodies may only works in a subset of certain cancers. Thus, understanding the novel function of PD-1 and genetic determinants of response to anti-PD-1 therapy will allow us to develop a more effective and individualized immunotherapeutic strategy for cancer. PMID:26305724

  4. Holding back sharing concerns, dispositional emotional expressivity, perceived unsupportive responses and distress among women newly diagnosed with gynecological cancers.

    PubMed

    Manne, Sharon; Myers, Shannon; Ozga, Melissa; Kissane, David; Kashy, Debby; Rubin, Stephen; Heckman, Carolyn; Rosenblum, Norm

    2014-01-01

    Little attention has been paid to the role of holding back sharing concerns in the psychological adaptation of women newly diagnosed with gynecological cancers. The goal of the present study was to evaluate the role of holding back concerns in psychosocial adjustment and quality of life, as well as a possible moderating role for emotional expressivity and perceived unsupportive responses from family and friends. Two hundred forty-four women diagnosed with gynecological cancer in the past 8 months completed measures of holding back, dispositional emotional expressivity, perceived unsupportive responses from family and friends, cancer-specific distress, depressive symptoms and quality of life. Emotional expressivity moderated the association between holding back and cancer-specific distress and quality of life, but not depressive symptoms. Greater holding back was more strongly associated with higher levels of cancer-related distress among women who were more emotionally expressive than among women who were less expressive. Perceived unsupportive responses did not moderate the associations between holding back and psychosocial outcomes. Holding back sharing concerns was more common in this patient population than other cancer populations. Dispositional expressivity played a role in how harmful holding back concerns was for women, while unsupportive responses from family and friends did not. © 2014.

  5. Self-Control, Self-Efficacy, Role Overload, and Stress Responses among Siblings of Children with Cancer

    ERIC Educational Resources Information Center

    Hamama, Liat; Ronen, Tammie; Rahav, Giora

    2008-01-01

    The study focuses on healthy children's responses to a sibling's cancer and its aftermath, with particular scrutiny directed toward these healthy siblings' stress factors, duress responses, and coping resources. The authors investigated role overload as these siblings' stress factor, anxiety and psychosomatic symptoms as their duress responses,…

  6. Metabolic response of rectal cancer assessed by 18-FDG PET following chemoradiotherapy is prognostic for patient outcome.

    PubMed

    Yeung, J M C; Kalff, V; Hicks, R J; Drummond, E; Link, E; Taouk, Y; Michael, M; Ngan, S; Lynch, A C; Heriot, A G

    2011-05-01

    Complete pathological response has proven prognostic benefits in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Sequential 18-FDG PET may be an early surrogate for pathological response to chemoradiotherapy. The aim of this study was to identify whether metabolic response measured by FDG PET following chemoradiotherapy is prognostic for tumor recurrence and survival following neoadjuvant therapy and surgical treatment for primary rectal cancer. Patients with primary rectal cancer treated by long-course neoadjuvant chemoradiotherapy followed by surgery had FDG PET performed before and 4 weeks after treatment, before surgical resection was performed. Retrospective chart review was undertaken for patient demographics, tumor staging, recurrence rates, and survival. : Between 2000 and 2007, 78 patients were identified (53 male, 25 female; median age, 64 y). After chemoradiotherapy, 37 patients (47%) had a complete metabolic response, 26 (33%) had a partial metabolic response, and 14 (18%) had no metabolic response as assessed by FDG PET (1 patient had missing data). However, only 4 patients (5%) had a complete pathological response. The median postoperative follow-up period was 3.1 years during which 14 patients (19%) had a recurrence: 2 local, 9 distant, and 3 with both local and distant. The estimated percentage without recurrence was 77% at 5 years (95% CI 66%-89%). There was an inverse relationship between FDG PET metabolic response and the incidence of recurrence within 3 years (P = .04). Kaplan-Meier analysis of FDG PET metabolic response and overall survival demonstrated a significant difference in survival among patients in the 3 arms: complete, partial, and no metabolic response (P = .04); the patients with complete metabolic response had the best prognosis. Complete or partial metabolic response on PET following neoadjuvant chemoradiotherapy and surgery predicts a lower local recurrence rate and improved survival

  7. Targeting Tumor Metabolism to Enhance the Effectiveness of Antitumor Immune Response in the Treatment of Breast Cancer

    DTIC Science & Technology

    2013-11-01

    glycolytic inhibitor, 3 - bromopyruvate ( 3 -BrPA) show a better response to antitumor immunotherapy. One of the major implications of the current finding is...effectiveness of immunotherapeutics in the treatment of human breast cancer15. SUBJECT TERMS Breast cancer, Energy metabolism, 3 - bromopyruvate , immune... bromopyruvate ( 3 -BrPA) show an improved-response to antitumor immunotherapy. The outcome of our study suggests that antiglycolytic pre-treatment sensitizes

  8. Overexpression of early growth response-1 as a metastasis-regulatory factor in gastric cancer.

    PubMed

    Kobayashi, Daisuke; Yamada, Mikako; Kamagata, Chinatsu; Kaneko, Reiko; Tsuji, Naoki; Nakamura, Masashi; Yagihashi, Atsuhito; Watanabe, Naoki

    2002-01-01

    To investigate the potential role of a nuclear transcription factor, early growth response-1 (Egr-1), in formation and progression of gastric cancer, we compared its expression in gastric cancers with that in non-cancerous tissues. Egr-1 mRNA expression was measured using TaqMan RT-PCR. The corresponding protein expression was examined immunohistochemically. Egr-1 mRNA expression was significantly higher in gastric cancer tissues than in normal mucosa (p < 0.0005). These differences were also reflected by protein product expression. Moreover, Egr-1 mRNA expression was higher in cases with metastasis to lymph nodes or remote organs. In cultured gastric cancer cells known to have a high metastatic potential, expression of this mRNA was higher than that of parental cells. It was suggested that Egr-1 has a significant role in carcinogenesis and in cancer progression, especially metastasis. Measurement of this mRNA should be useful for evaluation of the metastatic potential of gastric cancer.

  9. Expression of MUC17 Is Regulated by HIF1α-Mediated Hypoxic Responses and Requires a Methylation-Free Hypoxia Responsible Element in Pancreatic Cancer

    PubMed Central

    Kitamoto, Sho; Yokoyama, Seiya; Higashi, Michiyo; Yamada, Norishige; Matsubara, Shyuichiro; Takao, Sonshin; Batra, Surinder K.; Yonezawa, Suguru

    2012-01-01

    MUC17 is a type 1 membrane-bound glycoprotein that is mainly expressed in the digestive tract. Recent studies have demonstrated that the aberrant overexpression of MUC17 is correlated with the malignant potential of pancreatic ductal adenocarcinomas (PDACs); however, the exact regulatory mechanism of MUC17 expression has yet to be identified. Here, we provide the first report of the MUC17 regulatory mechanism under hypoxia, an essential feature of the tumor microenvironment and a driving force of cancer progression. Our data revealed that MUC17 was significantly induced by hypoxic stimulation through a hypoxia-inducible factor 1α (HIF1α)-dependent pathway in some pancreatic cancer cells (e.g., AsPC1), whereas other pancreatic cancer cells (e.g., BxPC3) exhibited little response to hypoxia. Interestingly, these low-responsive cells have highly methylated CpG motifs within the hypoxia responsive element (HRE, 5′-RCGTG-3′), a binding site for HIF1α. Thus, we investigated the demethylation effects of CpG at HRE on the hypoxic induction of MUC17. Treatment of low-responsive cells with 5-aza-2′-deoxycytidine followed by additional hypoxic incubation resulted in the restoration of hypoxic MUC17 induction. Furthermore, DNA methylation of HRE in pancreatic tissues from patients with PDACs showed higher hypomethylation status as compared to those from non-cancerous tissues, and hypomethylation was also correlated with MUC17 mRNA expression. Taken together, these findings suggested that the HIF1α-mediated hypoxic signal pathway contributes to MUC17 expression, and DNA methylation of HRE could be a determinant of the hypoxic inducibility of MUC17 in pancreatic cancer cells. PMID:22970168

  10. Bypassing multidrug resistant ovarian cancer using ultrasound responsive doxorubicin/curcumin co-deliver alginate nanodroplets.

    PubMed

    Baghbani, Fatemeh; Moztarzadeh, Fathollah

    2017-05-01

    Ultrasound-responsive perfluorocarbon nanoemulsions are a class of new multifunctional smart nanocarriers which combine diagnostic properties with therapeutic properties and release their drug payload in a controlled manner in response to ultrasound. Therefore, combination therapy using chemotherapeutic and chemosensitizing agents co-entrapped in these nanocarriers seems beneficial for cancer treatment. In the present study, multifunctional smart alginate/perfluorohexane nanodroplets were developed for co-delivery of doxorubicin and curcumin (a strong chemosensitizer). The nanodroplets with the average particle size of 55.1nm were synthesized via nanoemulsion process. The entrapment efficiency of doxorubicin was 92.3%. To improve curcumin entrapment into the alginate shell, Span 60 was added to the formulation as a co-surfactant and finally curcumin entrapment of about 40% was achieved. Ultrasound-mediated drug release kinetic was evaluated at two different frequencies of 28kHz (low frequency) and 1MHz (high frequency). Low frequency ultrasound resulted in higher triggered drug release from nanodroplets. The nanodroplets showed strong ultrasound contrast via droplet to bubble transition as confirmed via B-mode ultrasound imaging. Enhanced cytotoxicity in adriamycin-resistant A2780 ovarian cancer cells was observed for Dox-Cur-NDs compared to Dox-NDs because of the synergistic effects of doxorubicin and curcumin. However, ultrasound irradiation significantly increased the cytotoxicity of Dox-Cur-NDs. Finally, in vivo ovarian cancer treatment using Dox/Cur-NDs combined with ultrasound irradiation resulted in efficient tumor regression. According to the present study, nanotherapy of multidrug resistant human ovarian cancer using ultrasound responsive doxorubicin/curcumin co-loaded alginate-shelled nanodroplets combined with ultrasound irradiation could be a promising modality for the future of cancer treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Audience responses to a research-based drama about life after breast cancer.

    PubMed

    Sinding, Christina; Gray, Ross; Grassau, Pamela; Damianakis, Falia; Hampson, Ann

    2006-08-01

    This article explores audience reactions to the research-based drama Ladies in Waiting? Life After Breast Cancer. Quantitative findings indicate an overwhelmingly positive response, with approximately 90% of those who saw the production agreeing that they benefited from seeing it and indicating that they would recommend it to others. Qualitative data reveal a more complex picture of the range of reactions, allowing us to describe the most valued aspects of the production (mainly how it eased isolation and normalized the difficult aspects of survivorship) and to better understand the few reports of distress. Audience responses to Ladies in Waiting? suggest that chronic aspects of breast cancer are rarely acknowledged. Viewing the production as one that reveals difficult and hidden realities allows for a fuller understanding both of its supportive and unsettling effects. Copyright 2005 John Wiley & Sons, Ltd.

  12. Cyclin D1-AR Crosstalk: Potential Implications for Therapeutic Response in Prostate Cancer

    DTIC Science & Technology

    2013-06-01

    expression of degradation- resistant and –proficient alleles of cyclin D1 in xenograft model (months 18 -21) B. Randomize mice in 6 groups: intact...inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts . Cancer Res 2010; 70: 3228–3238. 33...cancer, cyclin D1 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18 . NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a

  13. Dietary phenethyl isothiocyanate inhibition of androgen-responsive LNCaP prostate cancer cell tumor growth correlates with decreased angiogenesis

    USDA-ARS?s Scientific Manuscript database

    Phenethyl isothiocyanate (PEITC), found in certain cruciferous vegetables, has antitumor activity in several cancer models, including prostate cancer. In our xenograft model, dietary administration of PEITC (100-150 mg/kg/d) inhibited androgen-responsive LNCaP human prostate cancer cell tumor growth...

  14. Tumor-targeting peptide conjugated pH-responsive micelles as a potential drug carrier for cancer therapy.

    PubMed

    Wu, Xiang Lan; Kim, Jong Ho; Koo, Heebeom; Bae, Sang Mun; Shin, Hyeri; Kim, Min Sang; Lee, Byung-Heon; Park, Rang-Woon; Kim, In-San; Choi, Kuiwon; Kwon, Ick Chan; Kim, Kwangmeyung; Lee, Doo Sung

    2010-02-17

    Herein, we prepared tumor-targeting peptide (AP peptide; CRKRLDRN) conjugated pH-responsive polymeric micelles (pH-PMs) in cancer therapy by active and pH-responsive tumor targeting delivery systems, simultaneously. The active tumor targeting and tumoral pH-responsive polymeric micelles were prepared by mixing AP peptide conjugated PEG-poly(d,l-lactic acid) block copolymer (AP-PEG-PLA) into the pH-responsive micelles of methyl ether poly(ethylene glycol) (MPEG)-poly(beta-amino ester) (PAE) block copolymer (MPEG-PAE). These mixed amphiphilic block copolymers were self-assembled to form stable AP peptide-conjugated and pH-responsive AP-PEG-PLA/MPEG-PAE micelles (AP-pH-PMs) with an average size of 150 nm. The AP-pH-PMs containing 10 wt % of AP-PEG-PLA showed a sharp pH-dependent micellization/demicellization transition at the tumoral acid pH. Also, they presented the pH-dependent drug release profile at the acidic pH of 6.4. The fluorescence dye, TRITC, encapsulated AP-pH-PMs (TRITC-AP-pH-PMs) presented the higher tumor-specific targeting ability in vitro cancer cell culture system and in vivo tumor-bearing mice, compared to control pH-responsive micelles of MPEG-PAE. For the cancer therapy, the anticancer drug, doxorubicin (DOX), was efficiently encapsulated into the AP-pH-PMs (DOX-AP-pH-PMs) with a higher loading efficiency. DOX-AP-pH-PMs efficiently deliver anticancer drugs in MDA-MB231 human breast tumor-bearing mice, resulted in excellent anticancer therapeutic efficacy, compared to free DOX and DOX encapsulated MEG-PAE micelles, indicating the excellent tumor targeting ability of AP-pH-PMs. Therefore, these tumor-targeting peptide-conjugated and pH-responsive polymeric micelles have great potential application in cancer therapy.

  15. A Spiritually-based approach to breast cancer awareness: Cognitive response analysis of communication effectiveness

    PubMed Central

    Holt, Cheryl L.; Lee, Crystal; Wright, Katrina

    2017-01-01

    The purpose of this study was to compare the communication effectiveness of a spiritually-based approach to breast cancer early detection education with a secular approach, among African American women, by conducting a cognitive response analysis. A total of 108 women from six Alabama churches were randomly assigned by church to receive a spiritually-based or secular educational booklet discussing breast cancer early detection. Based on the Elaboration Likelihood Model (Petty & Cacioppo, 1981), after reading the booklets participants were asked to complete a thought-listing task writing down any thoughts they experienced and rating them as positive, negative, or neutral. Two independent coders then used five dimensions to code participants thoughts. Compared with the secular booklet, the spiritually-based booklet resulted in significantly more thoughts involving personal connection, self-assessment, and spiritually-based responses. These results suggest that a spiritually-based approach to breast cancer awareness may be more effective than the secular because it caused women to more actively process the message, stimulating central route processing. The incorporation of spiritually-based content into church-based breast cancer education could be a promising health communication approach for African American women. PMID:18443989

  16. Identifying anti-cancer drug response related genes using an integrative analysis of transcriptomic and genomic variations with cell line-based drug perturbations.

    PubMed

    Sun, Yi; Zhang, Wei; Chen, Yunqin; Ma, Qin; Wei, Jia; Liu, Qi

    2016-02-23

    Clinical responses to anti-cancer therapies often only benefit a defined subset of patients. Predicting the best treatment strategy hinges on our ability to effectively translate genomic data into actionable information on drug responses. To achieve this goal, we compiled a comprehensive collection of baseline cancer genome data and drug response information derived from a large panel of cancer cell lines. This data set was applied to identify the signature genes relevant to drug sensitivity and their resistance by integrating CNVs and the gene expression of cell lines with in vitro drug responses. We presented an efficient in-silico pipeline for integrating heterogeneous cell line data sources with the simultaneous modeling of drug response values across all the drugs and cell lines. Potential signature genes correlated with drug response (sensitive or resistant) in different cancer types were identified. Using signature genes, our collaborative filtering-based drug response prediction model outperformed the 44 algorithms submitted to the DREAM competition on breast cancer cells. The functions of the identified drug response related signature genes were carefully analyzed at the pathway level and the synthetic lethality level. Furthermore, we validated these signature genes by applying them to the classification of the different subtypes of the TCGA tumor samples, and further uncovered their in vivo implications using clinical patient data. Our work may have promise in translating genomic data into customized marker genes relevant to the response of specific drugs for a specific cancer type of individual patients.

  17. Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients.

    PubMed

    Tan, Tuan Zea; Miow, Qing Hao; Miki, Yoshio; Noda, Tetsuo; Mori, Seiichi; Huang, Ruby Yun-Ju; Thiery, Jean Paul

    2014-10-01

    Epithelial-mesenchymal transition (EMT) is a reversible and dynamic process hypothesized to be co-opted by carcinoma during invasion and metastasis. Yet, there is still no quantitative measure to assess the interplay between EMT and cancer progression. Here, we derived a method for universal EMT scoring from cancer-specific transcriptomic EMT signatures of ovarian, breast, bladder, lung, colorectal and gastric cancers. We show that EMT scoring exhibits good correlation with previously published, cancer-specific EMT signatures. This universal and quantitative EMT scoring was used to establish an EMT spectrum across various cancers, with good correlation noted between cell lines and tumours. We show correlations between EMT and poorer disease-free survival in ovarian and colorectal, but not breast, carcinomas, despite previous notions. Importantly, we found distinct responses between epithelial- and mesenchymal-like ovarian cancers to therapeutic regimes administered with or without paclitaxel in vivo and demonstrated that mesenchymal-like tumours do not always show resistance to chemotherapy. EMT scoring is thus a promising, versatile tool for the objective and systematic investigation of EMT roles and dynamics in cancer progression, treatment response and survival. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

  18. Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Abegglen, Lisa M.; Caulin, Aleah F.; Chan, Ashley

    Here, evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology. To identify mechanisms for cancer resistance in elephants and compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS). Design, Setting, and Participants A comprehensive survey of necropsy data was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n=644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro inmore » the laboratory for DNA damage response. The study included African and Asian elephants (n=8), patients with LFS (n=10), and age-matched human controls (n=11). Human samples were collected at the University of Utah between June 2014 and July 2015. Exposures Ionizing radiation and doxorubicin. Cancer mortality across species was calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes. Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% [95% CI, 0%-5%]; African wild dog, 8% [95% CI, 0%-16%]; lion, 2% [95% CI, 0%-7%]). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95% CI, 3.14%-6.49%), compared with humans, who have 11% to 25% cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain reaction. In response to DNA damage, elephant lymphocytes

  19. Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans

    DOE PAGES

    Abegglen, Lisa M.; Caulin, Aleah F.; Chan, Ashley; ...

    2015-10-08

    Here, evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology. To identify mechanisms for cancer resistance in elephants and compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS). Design, Setting, and Participants A comprehensive survey of necropsy data was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n=644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro inmore » the laboratory for DNA damage response. The study included African and Asian elephants (n=8), patients with LFS (n=10), and age-matched human controls (n=11). Human samples were collected at the University of Utah between June 2014 and July 2015. Exposures Ionizing radiation and doxorubicin. Cancer mortality across species was calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes. Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% [95% CI, 0%-5%]; African wild dog, 8% [95% CI, 0%-16%]; lion, 2% [95% CI, 0%-7%]). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95% CI, 3.14%-6.49%), compared with humans, who have 11% to 25% cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain reaction. In response to DNA damage, elephant lymphocytes

  20. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans

    PubMed Central

    Abegglen, Lisa M.; Caulin, Aleah F.; Chan, Ashley; Lee, Kristy; Robinson, Rosann; Campbell, Michael S.; Kiso, Wendy K.; Schmitt, Dennis L.; Waddell, Peter J; Bhaskara, Srividya; Jensen, Shane T.; Maley, Carlo C.; Schiffman, Joshua D.

    2016-01-01

    IMPORTANCE Evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology. OBJECTIVE To identify mechanisms for cancer resistance in elephants and compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS). DESIGN, SETTING, AND PARTICIPANTS A comprehensive survey of necropsy data was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11). Human samples were collected at the University of Utah between June 2014 and July 2015. EXPOSURES Ionizing radiation and doxorubicin. MAIN OUTCOMES AND MEASURES Cancer mortality across species was calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes. RESULTS Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% [95%CI, 0%–5%]; African wild dog, 8%[95%CI, 0%–16%]; lion, 2%[95%CI, 0% –7%]). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95%CI, 3.14%–6.49%), compared with humans, who have 11% to 25%cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain

  1. Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers.

    PubMed

    Pearce, Oliver M T; Delaine-Smith, Robin M; Maniati, Eleni; Nichols, Sam; Wang, Jun; Böhm, Steffen; Rajeeve, Vinothini; Ullah, Dayem; Chakravarty, Probir; Jones, Roanne R; Montfort, Anne; Dowe, Tom; Gribben, John; Jones, J Louise; Kocher, Hemant M; Serody, Jonathan S; Vincent, Benjamin G; Connelly, John; Brenton, James D; Chelala, Claude; Cutillas, Pedro R; Lockley, Michelle; Bessant, Conrad; Knight, Martin M; Balkwill, Frances R

    2018-03-01

    We have profiled, for the first time, an evolving human metastatic microenvironment by measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, extracellular matrix organization, and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer metastases that ranged from minimal to extensive disease, we show how nonmalignant cell densities and cytokine networks evolve with disease progression. Multivariate integration of the different components allowed us to define, for the first time, gene and protein profiles that predict extent of disease and tissue stiffness, while also revealing the complexity and dynamic nature of matrisome remodeling during development of metastases. Although we studied a single metastatic site from one human malignancy, a pattern of expression of 22 matrisome genes distinguished patients with a shorter overall survival in ovarian and 12 other primary solid cancers, suggesting that there may be a common matrix response to human cancer. Significance: Conducting multilevel analysis with data integration on biopsies with a range of disease involvement identifies important features of the evolving tumor microenvironment. The data suggest that despite the large spectrum of genomic alterations, some human malignancies may have a common and potentially targetable matrix response that influences the course of disease. Cancer Discov; 8(3); 304-19. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 253 . ©2017 American Association for Cancer Research.

  2. A meta-analysis on dose-response relationship between night shift work and the risk of breast cancer.

    PubMed

    Wang, F; Yeung, K L; Chan, W C; Kwok, C C H; Leung, S L; Wu, C; Chan, E Y Y; Yu, I T S; Yang, X R; Tse, L A

    2013-11-01

    This study aimed to conduct a systematic review to sum up evidence of the associations between different aspects of night shift work and female breast cancer using a dose-response meta-analysis approach. We systematicly searched all cohort and case-control studies published in English on MEDLINE, Embase, PSYCInfo, APC Journal Club and Global Health, from January 1971 to May 2013. We extracted effect measures (relative risk, RR; odd ratio, OR; or hazard ratio, HR) from individual studies to generate pooled results using meta-analysis approaches. A log-linear dose-response regression model was used to evaluate the relationship between various indicators of exposure to night shift work and breast cancer risk. Downs and Black scale was applied to assess the methodological quality of included studies. Ten studies were included in the meta-analysis. A pooled adjusted relative risk for the association between 'ever exposed to night shift work' and breast cancer was 1.19 [95% confidence interval (CI) 1.05-1.35]. Further meta-analyses on dose-response relationship showed that every 5-year increase of exposure to night shift work would correspondingly enhance the risk of breast cancer of the female by 3% (pooled RR = 1.03, 95% CI 1.01-1.05; Pheterogeneity < 0.001). Our meta-analysis also suggested that an increase in 500-night shifts would result in a 13% (RR = 1.13, 95% CI 1.07-1.21; Pheterogeneity = 0.06) increase in breast cancer risk. This systematic review updated the evidence that a positive dose-response relationship is likely to present for breast cancer with increasing years of employment and cumulative shifts involved in the work.

  3. Hypoxia Responsive, Tumor Penetrating Lipid Nanoparticles for Delivery of Chemotherapeutics to Pancreatic Cancer Cell Spheroids.

    PubMed

    Kulkarni, Prajakta; Haldar, Manas K; Katti, Preeya; Dawes, Courtney; You, Seungyong; Choi, Yongki; Mallik, Sanku

    2016-08-17

    Solid tumors are often poorly irrigated due to structurally compromised microcirculation. Uncontrolled multiplication of cancer cells, insufficient blood flow, and the lack of enough oxygen and nutrients lead to the development of hypoxic regions in the tumor tissues. As the partial pressure of oxygen drops below the necessary level (10 psi), the cancer cells modulate their genetic makeup to survive. Hypoxia triggers tumor progression by enhancing angiogenesis, cancer stem cell production, remodeling of the extracellular matrix, and epigenetic changes in the cancer cells. However, the hypoxic regions are usually located deep in the tumors and are usually inaccessible to the intravenously injected drug carrier or the drug. Considering the designs of the reported nanoparticles, it is likely that the drug is delivered to the peripheral tumor tissues, close to the blood vessels. In this study, we prepared lipid nanoparticles (LNs) comprising the synthesized hypoxia-responsive lipid and a peptide-lipid conjugate. We observed that the resultant LNs penetrated to the hypoxic regions of the tumors. Under low oxygen partial pressure, the hypoxia-responsive lipid undergoes reduction, destabilizing the lipid membrane, and releasing encapsulated drugs from the nanoparticles. We demonstrated the results employing spheroidal cultures of the pancreatic cancer cells BxPC-3. We observed that the peptide-decorated, drug encapsulated LNs reduced the viability of pancreatic cancer cells of the spheroids to 35% under hypoxic conditions.

  4. COX-2 verexpression in pretreatment biopsies predicts response of rectal cancers to neoadjuvant radiochemotherapy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Smith, Fraser M.; Reynolds, John V.; Kay, Elaine W.

    2006-02-01

    Purpose: To determine the utility of COX-2 expression as a response predictor for patients with rectal cancer who are undergoing neoadjuvant radiochemotherapy (RCT). Methods and Materials: Pretreatment biopsies (PTB) from 49 patients who underwent RCT were included. COX-2 and proliferation in PTB were assessed by immunohistochemistry (IHC) and apoptosis was detected by TUNEL stain. Response to treatment was assessed by a 5-point tumor-regression grade (TRG) based on the ratio of residual tumor to fibrosis. Results: Good response (TRG 1 + 2), moderate response (TRG 3), and poor response (TRG 4 + 5) were seen in 21 patients (42%), 11 patientsmore » (22%), and 17 patients (34%), respectively. Patients with COX-2 overexpression in PTB were more likely to demonstrate moderate or poor response (TRG 3 + 4) to treatment than were those with normal COX-2 expression (p = 0.026, chi-square test). Similarly, poor response was more likely if patients had low levels of spontaneous apoptosis in PTBs (p = 0.0007, chi-square test). Conclusions: COX-2 overexpression and reduced apoptosis in PTB can predict poor response of rectal cancer to RCT. As COX-2 inhibitors are commercially available, their administration to patients who overexpress COX-2 warrants assessment in clinical trials in an attempt to increase overall response rates.« less

  5. EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer.

    PubMed

    Khan, Sajid A; Zeng, Zhaoshi; Shia, Jinru; Paty, Philip B

    2017-07-01

    Genetic variability in KRAS and EGFR predicts response to cetuximab in irinotecan refractory colorectal cancer. Whether these markers or others remain predictive in combination biologic therapies including bevacizumab is unknown. We identified predictive biomarkers from patients with irinotecan refractory metastatic colorectal cancer treated with cetuximab plus bevacizumab. Patients who received cetuximab plus bevacizumab for irinotecan refractory colorectal cancer in either of two Phase II trials conducted were identified. Tumor tissue was available for 33 patients. Genomic DNA was extracted and used for mutational analysis of KRAS, BRAF, and p53 genes. Fluorescence in situ hybridization was performed to assess EGFR copy number. The status of single genes and various combinations were tested for association with response. Seven of 33 patients responded to treatment. KRAS mutations were found in 14/33 cases, and 0 responded to treatment (p = 0.01). EGFR gene amplification was seen in 3/33 of tumors and in every case was associated with response to treatment (p < 0.001). TP53 and BRAF mutations were found in 18/33 and 0/33 tumors, respectively, and there were no associations with response to either gene. EGFR gene amplification and KRAS mutations are predictive markers for patients receiving combination biologic therapy of cetuximab plus bevacizumab for metastatic colorectal cancer. One marker or the other is present in the tumor of half of all patients allowing treatment response to be predicted with a high degree of certainty. The role for molecular markers in combination biologic therapy seems promising.

  6. Egg intake and cancers of the breast, ovary and prostate: a dose-response meta-analysis of prospective observational studies.

    PubMed

    Keum, N; Lee, D H; Marchand, N; Oh, H; Liu, H; Aune, D; Greenwood, D C; Giovannucci, E L

    2015-10-14

    Evidence suggests that egg intake may be implicated in the aetiology of sex hormone-related cancers. However, dose-response relationships between egg intake and such cancers are unclear. Thus, we conducted a dose-response meta-analysis to summarise the dose-response relationships between egg consumption and the risk of breast, prostate and gynaecological cancers. A literature search was performed using PubMed and Embase up to April 2015 to identify relevant prospective observational studies. Summary relative risk (RR) and 95% CI were estimated using a random-effects model. For breast cancer, the linear dose-response meta-analysis found a non-significantly increased risk (RR for an increase of 5 eggs consumed/week: 1·05, 95% CI 0·99, 1·11, n 16,023 cases). Evidence for non-linearity was not statistically significant (P non-linearity= 0·50, n 15,415 cases) but consuming ≥ 5 eggs/week was significantly associated with an increased risk of breast cancer compared with no egg consumption, with the summary RR being 1·04 (95% CI 1·01, 1·07) for consuming 5 eggs/week and 1·09 (95% CI 1·03, 1·15) for consuming about 9 eggs/week. For other cancers investigated, the summary RR for an increase of 5 eggs consumed/week was 1·09 (95% CI 0·96, 1·24, n 2636 cases) for ovarian cancer; 1·47 (95% CI 1·01, 2·14, n 609 cases) for fatal prostate cancer, with evidence of small-study effects (P Egger= 0·04). No evidence was found for an association with the risk of total prostate cancer. While our conclusion was tempered by the potential for publication bias and confounding, high egg intake may be associated with a modestly elevated risk of breast cancer, and a positive association between egg intake and ovarian and fatal prostate cancers cannot be ruled out.

  7. Coffee consumption is not associated with ovarian cancer risk: a dose-response meta-analysis of prospective cohort studies.

    PubMed

    Berretta, Massimiliano; Micek, Agnieszka; Lafranconi, Alessandra; Rossetti, Sabrina; Di Francia, Raffaele; De Paoli, Paolo; Rossi, Paola; Facchini, Gaetano

    2018-04-17

    Coffee consumption has been associated with numerous cancers, but evidence on ovarian cancer risk is controversial. Therefore, we performed a meta-analysis on prospective cohort studies in order to review the evidence on coffee consumption and risk of ovarian cancer. Studies were identified through searching the PubMed and MEDLINE databases up to March 2017. Risk estimates were retrieved from the studies, and dose-response analysis was modelled by using restricted cubic splines. Additionally, a stratified analysis by menopausal status was performed. A total of 8 studies were eligible for the dose-response meta-analysis. Studies included in the analysis comprised 787,076 participants and 3,541 ovarian cancer cases. The results showed that coffee intake was not associated with ovarian cancer risk (RR = 1.06, 95% CI: 0.89, 1.26). Stratified and subgroup analysis showed consisted results. This comprehensive meta-analysis did not find evidence of an association between the consumption of coffee and risk of ovarian cancer.

  8. Predictive biomarkers for response of esophageal cancer to chemo(radio)therapy: A systematic review and meta-analysis.

    PubMed

    Li, Yang; Huang, He-Cheng; Chen, Long-Qi; Xu, Li-Yan; Li, En-Min; Zhang, Jian-Jun

    2017-12-01

    Esophageal cancer remains a major public health issue worldwide. In clinical practice, chemo(radio)therapy is an important approach to patients with esophageal cancer. Only the part of patients who respond to chemo(radio)therapy achieve better long-term outcome. In this case, predictive biomarkers for response of esophageal cancer patients treated with chemo(radio)therapy are of importance. Meta-analysis of P53 for predicting esophageal cancer response has been reported before and is not included in our study. We performed a systematic review and meta-analysis to summarize and evaluate the biomarkers for predicting response to chemo(radio)therapy. PubMed, Web of Science and the Ovid databases were searched to identify eligible studies published in English before March 2017. The risk ratio (or relative risk, RR) was retrieved in articles regarding biomarkers for predicting response of esophageal cancer patients treated with neoadjuvant therapy or chemo(radio)therapy. Fixed and random effects models were used to undertake the meta-analysis as appropriate. Forty-six articles reporting 56 biomarkers correlated with the response were finally included. Meta-analyses were carried out when there was more than one study related to the reported biomarker. Results indicated that low expression of (or IHC-negative) COX2, miR-200c, ERCC1 and TS was individually associated with prediction of response. The RR was 1.64 (n = 202, 95% CI 1.22-2.19, P < 0.001), 1.96 (n = 162, 95% CI 1.36-2.83, P < 0.001), 2.55 (n = 206, 95% CI 1.80-3.62, P < 0.001) and 1.69 (n = 144, 95% CI 1.10-2.61, P = 0.02), respectively. High expression of (or IHC-positive) CDC25B and p16 was individually related to prediction of response. The RR was 0.62 (n = 159, 95% CI 0.43-0.89, P = 0.01) and 0.62 (n = 142, 95% CI 0.43-0.91, P = 0.01), respectively. Low expression of (or IHC-negative) COX2, miR-200c, ERCC1 and TS, or high expression of (or IHC-positive) CDC25B and p16 are potential

  9. Immune Response Augmentation in Metastasized Breast Cancer by Localized Therapy Utilizing Biocompatible Magnetic Fluids. Addendum

    DTIC Science & Technology

    2009-08-01

    Metastasized Breast Cancer by Localized Therapy Utilizing Biocompatible Magnetic Fluids PRINCIPAL INVESTIGATOR: Cahit A. Evrensel...AND SUBTITLE 5a. CONTRACT NUMBER Immune Response Augmentation in Metastasized Breast Cancer by Localized Therapy Utilizing Biocompatible... Magneto -rheological Fluid (MRF) iron nano-particles were synthesized using the reverse micelle technique and coated with poly(NIPAAm). The size

  10. Modulation of the Immune Response to Androgen Deprivation and Radiation Therapy for the Treatment of Prostate Cancer

    DTIC Science & Technology

    2014-04-01

    skin cancer model and the other in an implantable breast tumor model, depletion of CD20+ cells removed regulatory B cells, which could be...immunosuppressive (13, 14). Interestingly, a group recently studied the effect of B cell depletion using the same αCD20 antibody in a breast cancer model, a... breast cancer-specific immune responses and their correlation to prognosis. Cancer research 69, 8420-8428 (2009); published online EpubNov 1

  11. Response rates in case-control studies of cancer by era of fieldwork and by characteristics of study design.

    PubMed

    Xu, Mengting; Richardson, Lesley; Campbell, Sally; Pintos, Javier; Siemiatycki, Jack

    2018-04-09

    The purpose of this study was to describe time trends in response rates in case-control studies of cancer and identify study design factors that influence response rate. We reviewed 370 case-control studies of cancer published in 12 journals during indicator years in each of the last four decades. We estimated time trends of response rates and reasons for nonresponse in each of the following types of study subjects: cases, medical source controls, and population controls. We also estimated response rates according to characteristics of study context. Median response rates among cases and population controls were between 75% and 80% in the 1970s. Between 1971 and 2010, study response rates declined by 0.31% per year for cases and 0.78% for population controls. Only a minority of studies reported reasons for nonparticipation; subject refusal was the most common reported reason. Studies conducted in North America had lower median response rates than studies conducted in Europe. In-person and telephone interviews elicited higher response rates than mail questionnaires. Response rates from case-control studies of cancer have declined, and this could threaten the validity of results derived from these studies. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Cellular Levels of Oxidative Stress Affect the Response of Cervical Cancer Cells to Chemotherapeutic Agents

    PubMed Central

    Williams, Vonetta M.; Kokoza, Anatolii; Bashkirova, Svetlana; Duerksen-Hughes, Penelope

    2014-01-01

    Treatment of advanced and relapsed cervical cancer is frequently ineffective, due in large part to chemoresistance. To examine the pathways responsible, we employed the cervical carcinoma-derived SiHa and CaSki cells as cellular models of resistance and sensitivity, respectively, to treatment with chemotherapeutic agents, doxorubicin, and cisplatin. We compared the proteomic profiles of SiHa and CaSki cells and identified pathways with the potential to contribute to the differential response. We then extended these findings by comparing the expression level of genes involved in reactive oxygen species (ROS) metabolism through the use of a RT-PCR array. The analyses demonstrated that the resistant SiHa cells expressed higher levels of antioxidant enzymes. Decreasing or increasing oxidative stress led to protection or sensitization, respectively, in both cell lines, supporting the idea that cellular levels of oxidative stress affect responsiveness to treatment. Interestingly, doxorubicin and cisplatin induced different profiles of ROS, and these differences appear to contribute to the sensitivity to treatment displayed by cervical cancer cells. Overall, our findings demonstrate that cervical cancer cells display variable profiles with respect to their redox-generating and -adaptive systems, and that these different profiles have the potential to contribute to their responses to treatments with chemotherapy. PMID:25478571

  13. TP53 status and response to chemotherapy in breast cancer.

    PubMed

    Bertheau, Philippe; Espié, Marc; Turpin, Elisabeth; Lehmann, Jacqueline; Plassa, Louis-François; Varna, Mariana; Janin, Anne; de Thé, Hugues

    2008-01-01

    Despite its central role in the control of apoptosis, senescence and cell cycle arrest, the tumor suppressor protein p53 remains an enigma for its possible role in predicting response to chemotherapy in cancer patients. Many studies remained inconclusive, others showed a better response for tumors with normal p53, and some recent studies showed adverse effects of normal p53 for response to treatment. p53 is not only a powerful pro-apoptotic factor in response to drug-induced DNA damages but also a potential inducer of cell cycle arrest, protecting tumor cells from further cytotoxic damages. Our review describes the classical as well as the more recent concepts. In order to draw definite conclusions, future works should use more reliable methods to assess the TP53 status and should address more homogeneous tumor subpopulations treated with homogeneous chemotherapy regimens. Copyright 2008 S. Karger AG, Basel.

  14. A randomized dose-response trial of aerobic exercise and health-related quality of life in colon cancer survivors.

    PubMed

    Brown, Justin C; Damjanov, Nevena; Courneya, Kerry S; Troxel, Andrea B; Zemel, Babette S; Rickels, Michael R; Ky, Bonnie; Rhim, Andrew D; Rustgi, Anil K; Schmitz, Kathryn H

    2018-04-01

    To examine the dose-response effects of aerobic exercise on health-related quality of life (HRQoL) among colon cancer survivors. Thirty-nine stage I to III colon cancer survivors were randomized to 1 of 3 groups: usual-care control, 150 min·wk -1 of aerobic exercise (low-dose) and 300 min·wk -1 of aerobic exercise (high-dose) for 6 months. HRQoL outcomes included the Short Form (SF)-36 physical and mental component summary, Functional Assessment of Cancer Therapy-Colorectal, Pittsburgh Sleep Quality Index, Fear of Cancer Recurrence Inventory, Fatigue Symptom Inventory, and North Central Cancer Treatment Group bowel function questionnaire, assessed at baseline and post intervention. The primary hypothesis was that exercise would improve HRQoL outcomes in a dose-response fashion, such that high-dose aerobic exercise would yield the largest improvements in HRQoL outcomes. Over 6 months, the low-dose group completed 141 ± 10 min·wk -1 of aerobic exercise, and the high-dose group completed 247 ± 11 min·wk -1 of aerobic exercise. Over 6 months, exercise improved the physical component summary score of the SF-36 (P trend  = 0.002), the Functional Assessment of Cancer Therapy-Colorectal (P trend  = 0.025), the Pittsburgh Sleep Quality Index (P trend  = 0.049), and the Fatigue Symptom Inventory (P trend  = 0.045) in a dose-response fashion. Between-group standardized mean difference effects sizes for the above-described findings were small to moderate in magnitude (0.35-0.75). No dose-response effects were observed for the mental component summary score of the SF-36, the Fear of Cancer Recurrence Inventory, or bowel function. Higher doses of aerobic exercise, up to 300 min·wk -1 , improve multiple HRQoL outcomes among stage I to III colon cancer survivors. These findings provide evidence that aerobic exercise may provide multiple health benefits for colon cancer survivors. Copyright © 2018 John Wiley & Sons, Ltd.

  15. Role of Activin A in Immune Response to Breast Cancer

    DTIC Science & Technology

    2016-12-01

    the response to radiotherapy (RT). 2 KEYWORDS Breast cancer, metastasis, transforming growth factor-beta (TGFβ) superfamily, activin- A, radiotherapy... Transforming Growth Factor-beta (TGFβ) and activin A (actA) are members of the TGFβ superfamily with overlapping as well as distinct functions in many...Vaccination C. Vanpouille-Box, S. Formenti, and S. Demaria; Weill Cornell Medical College, New York, NY Purpose/Objective(s): Transforming Growth

  16. Mindfulness and its efficacy for psychological and biological responses in women with breast cancer.

    PubMed

    Kenne Sarenmalm, Elisabeth; Mårtensson, Lena B; Andersson, Bengt A; Karlsson, Per; Bergh, Ingrid

    2017-05-01

    Many breast cancer survivors have to deal with a variety of psychological and physiological sequelae including impaired immune responses. The primary purpose of this randomized controlled trial was to determine the efficacy of a mindfulness-based stress reduction (MBSR) intervention for mood disorders in women with breast cancer. Secondary outcomes were symptom experience, health status, coping capacity, mindfulness, posttraumatic growth, and immune status. This RTC assigned 166 women with breast cancer to one of three groups: MBSR (8 weekly group sessions of MBSR), active controls (self-instructing MBSR) and non-MBSR. The primary outcome measure was the Hospital Anxiety and Depression Scale. Secondary outcome measures were: Memorial Symptom Assessment Scale, SF-36, Sense of Coherence, Five Facets of Mindfulness Questionnaire, and Posttraumatic Growth Index. Blood samples were analyzed using flow cytometry for NK-cell activity (FANKIA) and lymphocyte phenotyping; concentrations of cytokines were determined in sera using commercial high sensitivity IL-6 and IL-8 ELISA (enzyme-linked immunosorbent assay) kits. Results provide evidence for beneficial effects of MBSR on psychological and biological responses. Women in the MBSR group experienced significant improvements in depression scores, with a mean pre-MBSR HAD-score of 4.3 and post-MBSR score of 3.3 (P = 0.001), and compared to non-MBSR (P = 0.015). Significant improvements on scores for distress, symptom burden, and mental health were also observed. Furthermore, MBSR facilitated coping capacity as well as mindfulness and posttraumatic growth. Significant benefits in immune response within the MBSR group and between groups were observed. MBSR have potential for alleviating depression, symptom experience, and for enhancing coping capacity, mindfulness and posttraumatic growth, which may improve breast cancer survivorship. MBSR also led to beneficial effect on immune function; the clinical implications of this

  17. Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers.

    PubMed

    Drilon, Alexander; Somwar, Romel; Mangatt, Biju P; Edgren, Henrik; Desmeules, Patrice; Ruusulehto, Anja; Smith, Roger S; Delasos, Lukas; Vojnic, Morana; Plodkowski, Andrew J; Sabari, Joshua; Ng, Kenneth; Montecalvo, Joseph; Chang, Jason; Tai, Huichun; Lockwood, William W; Martinez, Victor; Riely, Gregory J; Rudin, Charles M; Kris, Mark G; Arcila, Maria E; Matheny, Christopher; Benayed, Ryma; Rekhtman, Natasha; Ladanyi, Marc; Ganji, Gopinath

    2018-06-01

    NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3-ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1 -rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1 -rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1 -rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers. Significance: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1 -rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identification of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 686-95. ©2018 AACR. See related commentary by Wilson and Politi, p. 676 This article is highlighted in the In This Issue feature, p. 663 . ©2018 American Association for Cancer Research.

  18. Cancer patients treated with sunitinib or sorafenib have sufficient antibody and cellular immune responses to warrant influenza vaccination.

    PubMed

    Mulder, Sasja F; Jacobs, Joannes F M; Olde Nordkamp, Michel A M; Galama, Joep M D; Desar, Ingrid M E; Torensma, Ruurd; Teerenstra, Steven; Mulders, Peter F A; Vissers, Kris C P; Punt, Cornelis J A; de Vries, I Jolanda M; van Herpen, Carla M L

    2011-07-01

    The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib. Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines. Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-γ/IL-2 production and increased IL-10 compared with healthy controls. We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib.

  19. The host immunological response to cancer therapy: An emerging concept in tumor biology

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Voloshin, Tali; Voest, Emile E.; Shaked, Yuval, E-mail: yshaked@tx.technion.ac.il

    Almost any type of anti-cancer treatment including chemotherapy, radiation, surgery and targeted drugs can induce host molecular and cellular immunological effects which, in turn, can lead to tumor outgrowth and relapse despite an initial successful therapy outcome. Tumor relapse due to host immunological effects is attributed to angiogenesis, tumor cell dissemination from the primary tumors and seeding at metastatic sites. This short review will describe the types of host cells that participate in this process, the types of factors secreted from the host following therapy that can promote tumor re-growth, and the possible implications of this unique and yet onlymore » partially-known process. It is postulated that blocking these specific immunological effects in the reactive host in response to cancer therapy may aid in identifying new host-dependent targets for cancer, which in combination with conventional treatments can prolong therapy efficacy and extend survival. Additional studies investigating this specific research direction—both in preclinical models and in the clinical setting are essential in order to advance our understanding of how tumors relapse and evade therapy. -- Highlights: • Cancer therapy induces host molecular and cellular pro-tumorigenic effects. • Host effects in response to therapy may promote tumor relapse and metastasis. • The reactive host consists of immunological mediators promoting tumor re-growth. • Blocking therapy-induced host mediators may improve outcome.« less

  20. Cancer Dose-Response Assessment for Polychlorinated Biphenyls (PCBs) and Application to Environmental Mixtures

    EPA Pesticide Factsheets

    This report updates the cancer dose-response assessment for PCBs and shows how information on toxicity, disposition, and environmental processes can be considered together to evaluate health risks from PCB mixtures in the environment.

  1. Baseline clinical predictors of antitumor response to the PARP inhibitor olaparib in germline BRCA1/2 mutated patients with advanced ovarian cancer.

    PubMed

    Rafii, Saeed; Gourley, Charlie; Kumar, Rajiv; Geuna, Elena; Ern Ang, Joo; Rye, Tzyvia; Chen, Lee-May; Shapira-Frommer, Ronnie; Friedlander, Michael; Matulonis, Ursula; De Greve, Jacques; Oza, Amit M; Banerjee, Susana; Molife, L Rhoda; Gore, Martin E; Kaye, Stan B; Yap, Timothy A

    2017-07-18

    The PARP inhibitor olaparib was recently granted Food and Drug Administration (FDA) accelerated approval in patients with advanced BRCA1/2 mutation ovarian cancer. However, antitumor responses are observed in only approximately 40% of patients and the impact of baseline clinical factors on response to treatment remains unclear. Although platinum sensitivity has been suggested as a marker of response to PARP inhibitors, patients with platinum-resistant disease still respond to olaparib. 108 patients with advanced BRCA1/2 mutation ovarian cancers were included. The interval between the end of the most recent platinum chemotherapy and PARPi (PTPI) was used to predict response to olaparib independent of conventional definition of platinum sensitivity. RECIST complete response (CR) and partial response (PR) rates were 35% in patients with platinum-sensitive versus 13% in platinum-resistant (p<0.005). Independent of platinum sensitivity status, the RECIST CR/PR rates were 42% in patients with PTPI greater than 52 weeks and 18% in patients with PTPI less than 52 weeks (p=0.016). No association was found between baseline clinical factors such as FIGO staging, debulking surgery, BRCA1 versus BRCA2 mutations, prior history of breast cancer and prior chemotherapy for breast cancer, and the response to olaparib. We conducted an international multicenter retrospective study to investigate the association between baseline clinical characteristics of patients with advanced BRCA1/2 mutation ovarian cancers from eight different cancer centers and their antitumor response to olaparib. PTPI may be used to refine the prediction of response to PARP inhibition based on the conventional categorization of platinum sensitivity.

  2. Enzyme and Thermal Dual Responsive Amphiphilic Polymer Core-Shell Nanoparticle for Doxorubicin Delivery to Cancer Cells.

    PubMed

    Kashyap, Smita; Singh, Nitesh; Surnar, Bapurao; Jayakannan, Manickam

    2016-01-11

    Dual responsive polymer nanoscaffolds for administering anticancer drugs both at the tumor site and intracellular compartments are made for improving treatment in cancers. The present work reports the design and development of new thermo- and enzyme-responsive amphiphilic copolymer core-shell nanoparticles for doxorubicin delivery at extracellular and intracellular compartments, respectively. A hydrophobic acrylate monomer was tailor-made from 3-pentadecylphenol (PDP, a natural resource) and copolymerized with oligoethylene glycol acrylate (as a hydrophilic monomer) to make new classes of thermo and enzyme dual responsive polymeric amphiphiles. Both radical and reversible addition-fragmentation chain transfer (RAFT) methodologies were adapted for making the amphiphilic copolymers. These amphiphilic copolymers were self-assembled to produce spherical core-shell nanoparticles in water. Upon heating, the core-shell nanoparticles underwent segregation to produce larger sized aggregates above the lower critical solution temperature (LCST). The dual responsive polymer scaffold was found to be capable of loading water insoluble drug, such as doxorubicin (DOX), and fluorescent probe-like Nile Red. The drug release kinetics revealed that DOX was preserved in the core-shell assemblies at normal body temperature (below LCST, ≤ 37 °C). At closer to cancer tissue temperature (above LCST, ∼43 °C), the polymeric scaffold underwent burst release to deliver 90% of loaded drugs within 2 h. At the intracellular environment (pH 7.4, 37 °C) in the presence of esterase enzyme, the amphiphilic copolymer ruptured in a slow and controlled manner to release >95% of the drugs in 12 h. Thus, both burst release of cargo at the tumor microenvironment and control delivery at intracellular compartments were accomplished in a single polymer scaffold. Cytotoxicity assays of the nascent and DOX-loaded polymer were carried out in breast cancer (MCF-7) and cervical cancer (HeLa) cells. Among

  3. Antigen specific T-cell responses against tumor antigens are controlled by regulatory T cells in patients with prostate cancer.

    PubMed

    Hadaschik, Boris; Su, Yun; Huter, Eva; Ge, Yingzi; Hohenfellner, Markus; Beckhove, Philipp

    2012-04-01

    Immunotherapy is a promising approach in an effort to control castration resistant prostate cancer. We characterized tumor antigen reactive T cells in patients with prostate cancer and analyzed the suppression of antitumor responses by regulatory T cells. Peripheral blood samples were collected from 57 patients with histologically confirmed prostate cancer, 8 patients with benign prostatic hyperplasia and 16 healthy donors. Peripheral blood mononuclear cells were isolated and antigen specific interferon-γ secretion of isolated T cells was analyzed by enzyme-linked immunospot assay. T cells were functionally characterized and T-cell responses before and after regulatory T-cell depletion were compared. As test tumor antigens, a panel of 11 long synthetic peptides derived from a total of 8 tumor antigens was used, including prostate specific antigen and prostatic acid phosphatase. In patients with prostate cancer we noted a 74.5% effector T-cell response rate compared with only 25% in patients with benign prostatic hyperplasia and 31% in healthy donors. In most patients 2 or 3 tumor antigens were recognized. Comparing various disease stages there was a clear increase in the immune response against prostate specific antigens from intermediate to high risk tumors and castration resistant disease. Regulatory T-cell depletion led to a significant boost in effector T-cell responses against prostate specific antigen and prostatic acid phosphatase. Tumor specific effector T cells were detected in most patients with prostate cancer, especially those with castration resistant prostate cancer. Since effector T-cell responses against prostate specific antigens strongly increased after regulatory T-cell depletion, our results indicate that immunotherapy efficacy could be enhanced by decreasing regulatory T cells. Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  4. A Reanalysis of Curvature in the Dose Response for Cancer and Modifications by Age at Exposure Following Radiation Therapy for Benign Disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Little, Mark P., E-mail: mark.little@nih.gov; Stovall, Marilyn; Smith, Susan A.

    Purpose: To assess the shape of the dose response for various cancer endpoints and modifiers by age and time. Methods and Materials: Reanalysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by cancer endpoint (stomach, pancreas, lung, leukemia, all other). Results: There are statistically significant (P<.05) excess risks for all cancer and for lung cancer and borderline statistically significant risks for stomach cancer (P=.07), and leukemia (P=.06), with excess relative risks Gy{sup -1} of 0.024 (95% confidence interval [CI] 0.011, 0.039), 0.559 (95% CI 0.221, 1.021), 0.042 (95% CI -0.002, 0.119), and 1.087 (95% CI -0.018,more » 4.925), respectively. There is statistically significant (P=.007) excess risk of pancreatic cancer when adjusted for dose-response curvature. General downward curvature is apparent in the dose response, statistically significant (P<.05) for all cancers, pancreatic cancer, and all other cancers (ie, other than stomach, pancreas, lung, leukemia). There are indications of reduction in relative risk with increasing age at exposure (for all cancers, pancreatic cancer), but no evidence for quadratic variations in relative risk with age at exposure. If a linear-exponential dose response is used, there is no significant heterogeneity in the dose response among the 5 endpoints considered or in the speed of variation of relative risk with age at exposure. The risks are generally consistent with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers. Conclusions: There are excess risks for various malignancies in this data set. Generally there is a marked downward curvature in the dose response and significant reduction in relative risk with increasing age at exposure. The consistency of risks with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.« less

  5. Psychological responses to terminal illness and eventual death in Koreans with cancer.

    PubMed

    Kang, Kyung-Ah; Miller, Jean R; Lee, Won-Hee

    2006-01-01

    This qualitative study describes the psychological responses of Korean participants with terminal cancer (stages III-IV) from time of diagnosis to death. Eighteen participants, ages 48 to 73, were interviewed at various phases of dying. Using analytic induction, three categories (nonacceptance, resignation, submission), characteristic patterns of responses over the course of illness and typical responses within categories were generated. Nonaccepters denied the possibility of death while struggling to live; their typical response was resistance. Resigners displayed sorrow, thoughts about their destiny, and growing acceptance of their fate. Their typical response was nonresistance. Submitters were shocked initially, searched for God's will, and prepared for death with hope. Their typical response was hopeful that God would care for them and their families. Participants' ages, physical pain, burden to family, and beliefs played important roles in the patterns of responses.

  6. Response of Human Prostate Cancer Cells to Mitoxantrone Treatment in Simulated Microgravity Environment

    NASA Astrophysics Data System (ADS)

    Zhang, Ye; Wu, Honglu

    2012-07-01

    RESPONSE OF HUMAN PROSTATE CANCER CELLS TO MITOXANTRONE TREATMENT IN SIMULATED MICROGRAVITY ENVIRONMENT Ye Zhang1,2, Christopher Edwards3, and Honglu Wu1 1 NASA-Johnson Space Center, Houston, TX 2 Wyle Integrated Science and Engineering Group, Houston, TX 3 Oregon State University, Corvallis, OR This study explores the changes in growth of human prostate cancer cells (LNCaP) and their response to the treatment of an antineoplastic agent, mitoxantrone, under the simulated microgravity condition. In comparison to static 1g, microgravity and simulated microgravity have been shown to alter global gene expression patterns and protein levels in various cultured cell models or animals. However, very little is known about the effect of altered gravity on the responses of cells to the treatment of drugs, especially chemotherapy drugs. To test the hypothesis that zero gravity would result in altered regulations of cells in response to antineoplastic agents, we cultured LNCaP cells in either a High Aspect Ratio Vessel (HARV) bioreactor at the rotating condition to model microgravity in space or in the static condition as control, and treated the cells with mitoxantrone. Cell growth, as well as expressions of oxidative stress related genes, were analyzed after the drug treatment. Compared to static 1g controls, the cells cultured in the simulated microgravity environment did not present significant differences in cell viability, growth rate, or cell cycle distribution. However, after mitoxantrone treatment, a significant proportion of bioreactor cultured cells became apoptotic or was arrested in G2. Several oxidative stress related genes also showed a higher expression level post mitoxantrone treatment. Our results indicate that simulated microgravity may alter the response of LNCaP cells to mitoxantrone treatment. Understanding the mechanisms by which cells respond to drugs differently in an altered gravity environment will be useful for the improvement of cancer treatment on

  7. Personalized Circulating Tumor DNA Biomarkers Dynamically Predict Treatment Response and Survival In Gynecologic Cancers.

    PubMed

    Pereira, Elena; Camacho-Vanegas, Olga; Anand, Sanya; Sebra, Robert; Catalina Camacho, Sandra; Garnar-Wortzel, Leopold; Nair, Navya; Moshier, Erin; Wooten, Melissa; Uzilov, Andrew; Chen, Rong; Prasad-Hayes, Monica; Zakashansky, Konstantin; Beddoe, Ann Marie; Schadt, Eric; Dottino, Peter; Martignetti, John A

    2015-01-01

    High-grade serous ovarian and endometrial cancers are the most lethal female reproductive tract malignancies worldwide. In part, failure to treat these two aggressive cancers successfully centers on the fact that while the majority of patients are diagnosed based on current surveillance strategies as having a complete clinical response to their primary therapy, nearly half will develop disease recurrence within 18 months and the majority will die from disease recurrence within 5 years. Moreover, no currently used biomarkers or imaging studies can predict outcome following initial treatment. Circulating tumor DNA (ctDNA) represents a theoretically powerful biomarker for detecting otherwise occult disease. We therefore explored the use of personalized ctDNA markers as both a surveillance and prognostic biomarker in gynecologic cancers and compared this to current FDA-approved surveillance tools. Tumor and serum samples were collected at time of surgery and then throughout treatment course for 44 patients with gynecologic cancers, representing 22 ovarian cancer cases, 17 uterine cancer cases, one peritoneal, three fallopian tube, and one patient with synchronous fallopian tube and uterine cancer. Patient/tumor-specific mutations were identified using whole-exome and targeted gene sequencing and ctDNA levels quantified using droplet digital PCR. CtDNA was detected in 93.8% of patients for whom probes were designed and levels were highly correlated with CA-125 serum and computed tomography (CT) scanning results. In six patients, ctDNA detected the presence of cancer even when CT scanning was negative and, on average, had a predictive lead time of seven months over CT imaging. Most notably, undetectable levels of ctDNA at six months following initial treatment was associated with markedly improved progression free and overall survival. Detection of residual disease in gynecologic, and indeed all cancers, represents a diagnostic dilemma and a potential critical inflection

  8. Calcitriol restores antiestrogen responsiveness in estrogen receptor negative breast cancer cells: a potential new therapeutic approach.

    PubMed

    Santos-Martínez, Nancy; Díaz, Lorenza; Ordaz-Rosado, David; García-Quiroz, Janice; Barrera, David; Avila, Euclides; Halhali, Ali; Medina-Franco, Heriberto; Ibarra-Sánchez, María J; Esparza-López, José; Camacho, Javier; Larrea, Fernando; García-Becerra, Rocío

    2014-03-29

    Approximately 30% of breast tumors do not express the estrogen receptor (ER) α, which is necessary for endocrine therapy approaches. Studies are ongoing in order to restore ERα expression in ERα-negative breast cancer. The aim of the present study was to determine if calcitriol induces ERα expression in ER-negative breast cancer cells, thus restoring antiestrogen responses. Cultured cells derived from ERα-negative breast tumors and an ERα-negative breast cancer cell line (SUM-229PE) were treated with calcitriol and ERα expression was assessed by real time PCR and western blots. The ERα functionality was evaluated by prolactin gene expression analysis. In addition, the effects of antiestrogens were assessed by growth assay using the XTT method. Gene expression of cyclin D1 (CCND1), and Ether-à-go-go 1 (EAG1) was also evaluated in cells treated with calcitriol alone or in combination with estradiol or ICI-182,780. Statistical analyses were determined by one-way ANOVA. Calcitriol was able to induce the expression of a functional ERα in ER-negative breast cancer cells. This effect was mediated through the vitamin D receptor (VDR), since it was abrogated by a VDR antagonist. Interestingly, the calcitriol-induced ERα restored the response to antiestrogens by inhibiting cell proliferation. In addition, calcitriol-treated cells in the presence of ICI-182,780 resulted in a significant reduction of two important cell proliferation regulators CCND1 and EAG1. Calcitriol induced the expression of ERα and restored the response to antiestrogens in ERα-negative breast cancer cells. The combined treatment with calcitriol and antiestrogens could represent a new therapeutic strategy in ERα-negative breast cancer patients.

  9. Drug Intervention Response Predictions with PARADIGM (DIRPP) identifies drug resistant cancer cell lines and pathway mechanisms of resistance.

    PubMed

    Brubaker, Douglas; Difeo, Analisa; Chen, Yanwen; Pearl, Taylor; Zhai, Kaide; Bebek, Gurkan; Chance, Mark; Barnholtz-Sloan, Jill

    2014-01-01

    The revolution in sequencing techniques in the past decade has provided an extensive picture of the molecular mechanisms behind complex diseases such as cancer. The Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Project (CGP) have provided an unprecedented opportunity to examine copy number, gene expression, and mutational information for over 1000 cell lines of multiple tumor types alongside IC50 values for over 150 different drugs and drug related compounds. We present a novel pipeline called DIRPP, Drug Intervention Response Predictions with PARADIGM7, which predicts a cell line's response to a drug intervention from molecular data. PARADIGM (Pathway Recognition Algorithm using Data Integration on Genomic Models) is a probabilistic graphical model used to infer patient specific genetic activity by integrating copy number and gene expression data into a factor graph model of a cellular network. We evaluated the performance of DIRPP on endometrial, ovarian, and breast cancer related cell lines from the CCLE and CGP for nine drugs. The pipeline is sensitive enough to predict the response of a cell line with accuracy and precision across datasets as high as 80 and 88% respectively. We then classify drugs by the specific pathway mechanisms governing drug response. This classification allows us to compare drugs by cellular response mechanisms rather than simply by their specific gene targets. This pipeline represents a novel approach for predicting clinical drug response and generating novel candidates for drug repurposing and repositioning.

  10. Metastatic colorectal cancer responsive to regorafenib for 2 years: a case report.

    PubMed

    Yoshino, Kenji; Manaka, Dai; Kudo, Ryo; Kanai, Shunpei; Mitsuoka, Eisei; Kanto, Satoshi; Hamasu, Shinya; Konishi, Sayuri; Nishitai, Ryuta

    2017-08-18

    Regorafenib is an oral multikinase inhibitor that has been demonstrated as clinically effective in patients with metastatic colorectal cancer in phase III studies. Although disease control was achieved in 40% of the pretreated patients with metastatic colorectal cancer in the pivotal studies, radiological response has rarely been reported. Severe adverse events associated with regorafenib are known to occur during the first and second courses of treatment. We present a case of a 62-year-old Japanese patient whose metastatic colorectal cancer has been responding to treatment with regorafenib for 2 years. A 54-year-old Japanese man visited our institute exhibiting general malaise, and he was diagnosed with ascending colon cancer in April 2006. He underwent right hemicolectomy, and the final staging was T3N0M0, stage II. After 19 months, pulmonary metastasis and anastomotic recurrences were detected, and a series of operations were performed to resect both metastatic lesions. After that, liver metastasis, a duodenal metastasis with right renal invasion, right adrenal metastasis, and para-aortic lymph node metastases were observed during follow-up, and chemotherapy and resection were performed. The patient had metastatic para-aortic lymph nodes after the fifth tumor resection and underwent multiple lines of chemotherapy in April 2014. Regorafenib monotherapy was started at 80 mg/day. Then, regorafenib was increased to 120 mg/day in the second cycle. Regorafenib monotherapy led to 60% tumor shrinkage within the initial 2 months, and the tumor further decreased in size over 4 months until it became unrecognizable on imaging studies. The clinical effects of regorafenib monotherapy have shown a partial response according to Response Evaluation Criteria in Solid Tumors criteria. No severe adverse events were observed, except for mild fatigue and hand-foot syndrome. The patient has received 24 courses of regorafenib over 2 years without exhibiting tumor progression. To the

  11. Effects of artemisinin and its derivatives on growth inhibition and apoptosis of oral cancer cells.

    PubMed

    Nam, Woong; Tak, Jungae; Ryu, Ju-Kyoung; Jung, Mankil; Yook, Jong-In; Kim, Hyung-Jun; Cha, In-Ho

    2007-04-01

    Artemisinin is of special biological interest because of its outstanding antimalarial activity. Recently, it was reported that artemisinin has antitumor activity. Its derivatives, artesunate, arteether, and artemeter, also have antitumor activity against melanoma, breast, ovarian, prostate, CNS, and renal cancer cell lines. Recently, monomer, dimer, and trimer derivatives were synthesized from deoxoartemisinin, and the dimers and the trimers were found to have much more potent antitumor activity than the monomers. We evaluated the antitumor activity of artemisinin and its various derivatives (dihydroartemisinin, dihydroartemisinin 12-benzoate, 12-(2'-hydroxyethyl) deoxoartemisinin, 12-(2'-ethylthio) deoxoartemisinin dimer, deoxoartemisinin trimer) in comparison with paclitaxel (Taxol), 5-fluorouracil (5-FU), cisplatin in vitro. In this study, the deoxoartemisinin trimer had the most potent antitumor effect (IC(50) = 6.0 microM), even better than paclitaxel (IC(50) = 13.1 microM), on oral cancer cell line (YD-10B). In addition, it induced apoptosis through a caspase-3-dependent mechanism. The deoxoartemisinin trimer was found to have greater antitumor effect on tumor cells than other commonly used chemotherapeutic drugs, such as 5-FU, cisplatin, and paclitaxel. Furthermore, the ability of artemisinin and its derivatives to induce apoptosis highlights their potential as chemotherapeutic agents, for many anticancer drugs achieve their antitumor effects by inducing apoptosis in tumor cells. (c) 2006 Wiley Periodicals, Inc.

  12. Long-term survival based on pathologic response to neoadjuvant therapy in esophageal cancer.

    PubMed

    Tiesi, Gregory; Park, Wungki; Gunder, Meredith; Rubio, Gustavo; Berger, Michael; Ardalan, Bach; Livingstone, Alan; Franceschi, Dido

    2017-08-01

    Neoadjuvant treatment is standard for locally advanced esophageal cancer. However, whether the addition of radiation to neoadjuvant regimen improves survival remains unclear. The aim of this study was to compare survival in locally advanced esophageal cancer treated with neoadjuvant chemotherapy versus chemoradiation. A prospectively maintained database of esophagectomies (1999-2012) was analyzed. We identified 297 patients with locally advanced esophageal cancer that underwent either neoadjuvant chemotherapy (n = 231) or chemoradiation (n = 66) followed by esophagectomy. Pretreatment and pathologic staging were compared to assess response. Overall survival was recorded. Most patients in the chemotherapy and chemoradiation groups had pretreatment stage III disease (66.7% versus 65.2%; P = 0.44). Median follow-up was 79.3 and 64.9 mo for chemotherapy and chemoradiation cohorts, respectively. Complete response rate was higher in chemoradiation than chemotherapy groups (30.3% versus 13.8%; P < 0.001). Overall survival was similar between complete responders in both groups (median not reached versus 121.1 mo; chemotherapy versus chemoradiation). However, partial responders in the chemotherapy cohort had improved median survival (147.2 mo) versus those in the chemoradiation cohort (83.7 mo, P < 0.03). Within the chemotherapy-only group, partial responders had improved survival compared with nonresponders (P = 0.041); however, there was no difference in survival between partial and complete responders (P = 0.36). In patients undergoing esophagectomy for locally advanced esophageal cancer, neoadjuvant chemotherapy was associated with an equivalent overall survival, when compared with neoadjuvant chemoradiotherapy. Adding neoadjuvant radiation may enhance complete response rates but does not appear to be associated with improved survival. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Individual response to neoadjuvant chemotherapy assessed with optical mammography in patients with breast cancer

    NASA Astrophysics Data System (ADS)

    Anderson, Pamela G.; Krishnamurthy, Nishanth; Kalli, Sirishma; Sassaroli, Angelo; Makim, Shital S.; Graham, Roger A.; Fantini, Sergio

    2017-02-01

    We report an optical mammography study on eight patients with breast cancer who underwent neoadjuvant chemotherapy. Of these eight patients, six were responders (tumor size decreased by more than 50%) and two were nonresponders (tumor size decreased by less than 50%). The goals of this study are (1) to characterize the temporal evolution of the hemoglobin concentration ([HbT]) and saturation (SO2) in breast tissue during the course of treatment in responders and non-responders, and (2) to define a quantitative index that is capable of identifying responders and nonresponders during treatment. We found that both [HbT] and SO2 decreased by a greater amount in responders than in non-responders during therapy. This result applied to both cancerous and healthy breast, but the discrimination of responders and non-responders was more significant with SO2 measurements in the cancerous breast. A cumulative response index defined in terms of SO2 measurements in the cancerous breast achieved a 100% sensitivity and 100% specificity for the identification of responders and non-responders at therapy midpoint. These results confirm the potential of optical mammography in assessing response to neoadjuvant chemotherapy during treatment, thus offering the opportunity to consider alternative options to ineffective treatment regimens.

  14. 3D culture of Her2+ breast cancer cells promotes AKT to MAPK switching and a loss of therapeutic response.

    PubMed

    Gangadhara, Sharath; Smith, Chris; Barrett-Lee, Peter; Hiscox, Stephen

    2016-06-01

    The Her2 receptor is overexpressed in up to 25 % of breast cancers and is associated with a poor prognosis. Around half of Her2+ breast cancers also express the estrogen receptor and treatment for such tumours can involve both endocrine and Her2-targeted therapies. However, despite preclinical data supporting the effectiveness of these agents, responses can vary widely in the clinical setting. In light of the increasing evidence pointing to the interplay between the tumour and its extracellular microenvironment as a significant determinant of therapeutic sensitivity and response here we investigated the impact of 3D matrix culture of breast cancer cells on their therapeutic sensitivity. A 3D Matrigel-based culture system was established and optimized for the growth of ER+/Her2+ breast cancer cell models. Growth of cells in response to trastuzumab and endocrine agents in 3D culture versus routine monolayer culture were assessed using cell counting and Ki67 staining. Endogenous and trastuzumab-modulated signalling pathway activity in 2D and 3D cultures were assessed using Western blotting. Breast cancer cells in 3D culture displayed an attenuated response to both endocrine agents and trastuzumab compared with cells cultured in traditional 2D monolayers. Underlying this phenomenon was an apparent matrix-induced shift from AKT to MAPK signalling; consequently, suppression of MAPK in 3D cultures restores therapeutic response. These data suggest that breast cancer cells in 3D culture display a reduced sensitivity to therapeutic agents which may be mediated by internal MAPK-mediated signalling. Targeting of adaptive pathways that maintain growth in 3D culture may represent an effective strategy to improve therapeutic response clinically.

  15. Stimuli-Responsive NO Release for On-Demand Gas-Sensitized Synergistic Cancer Therapy.

    PubMed

    Fan, Wenpei; Yung, Bryant C; Chen, Xiaoyuan

    2018-03-08

    Featuring high biocompatibility, the emerging field of gas therapy has attracted extensive attention in the medical and scientific communities. Currently, considerable research has focused on the gasotransmitter nitric oxide (NO) owing to its unparalleled dual roles in directly killing cancer cells at high concentrations and cooperatively sensitizing cancer cells to other treatments for synergistic therapy. Of particular note, recent state-of-the-art studies have turned our attention to the chemical design of various endogenous/exogenous stimuli-responsive NO-releasing nanomedicines and their biomedical applications for on-demand NO-sensitized synergistic cancer therapy, which are discussed in this Minireview. Moreover, the potential challenges regarding NO gas therapy are also described, aiming to advance the development of NO nanomedicines as well as usher in new frontiers in this fertile research area. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Chromatin Configuration Determines Cell Responses to Hormone Stimuli | Center for Cancer Research

    Cancer.gov

    Ever since selective gene expression was established as the central driver of cell behavior, researchers have been working to understand the forces that control gene transcription. Aberrant gene expression can cause or promote many diseases, including cancer, and alterations in gene expression are the goal of many therapeutic agents. Recent work has focused on the potential role of chromatin structure as a contributor to gene regulation. Chromatin can exist in a tightly packed/inaccessible or loose/accessible configuration depending on the interactions between DNA and its associated proteins. Patterns of chromatin structure can differ between cell types and can also change within cells in response to certain signals. Cancer researchers are particularly interested in the role of chromatin in gene regulation because many of the genomic regions found to be associated with cancer risk are in open chromatin structures.

  17. Heightened cortisol responses to daily stress in working women at familial risk for breast cancer.

    PubMed

    Dettenborn, Lucia; James, Gary D; van Berge-Landry, Helene; Valdimarsdottir, Heiddis B; Montgomery, Guy H; Bovbjerg, Dana H

    2005-05-01

    Consistent with animal models and experimental studies with humans facing other 'background' stressors, women at familial risk for breast cancer have been reported to have stronger cortisol responses to laboratory stressors. To explore the relevance of these findings to daily life, we compared work-stress cortisol responses in women with >or=1 first-degree relative with breast cancer (FH+, n = 74) to women without this risk factor (FH-, n = 141). Repeated-measures ANOVA revealed a group by time interaction (p responses of FH+ women also apply to daily life stressors, and suggest the need for additional research to explore the possibility that accentuated hypothalamic-pituitary-axis responses to such stressors may increase health risk for these women.

  18. STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia.

    PubMed

    Bonetto, Andrea; Aydogdu, Tufan; Kunzevitzky, Noelia; Guttridge, Denis C; Khuri, Sawsan; Koniaris, Leonidas G; Zimmers, Teresa A

    2011-01-01

    Cachexia, or weight loss despite adequate nutrition, significantly impairs quality of life and response to therapy in cancer patients. In cancer patients, skeletal muscle wasting, weight loss and mortality are all positively associated with increased serum cytokines, particularly Interleukin-6 (IL-6), and the presence of the acute phase response. Acute phase proteins, including fibrinogen and serum amyloid A (SAA) are synthesized by hepatocytes in response to IL-6 as part of the innate immune response. To gain insight into the relationships among these observations, we studied mice with moderate and severe Colon-26 (C26)-carcinoma cachexia. Moderate and severe C26 cachexia was associated with high serum IL-6 and IL-6 family cytokines and highly similar patterns of skeletal muscle gene expression. The top canonical pathways up-regulated in both were the complement/coagulation cascade, proteasome, MAPK signaling, and the IL-6 and STAT3 pathways. Cachexia was associated with increased muscle pY705-STAT3 and increased STAT3 localization in myonuclei. STAT3 target genes, including SOCS3 mRNA and acute phase response proteins, were highly induced in cachectic muscle. IL-6 treatment and STAT3 activation both also induced fibrinogen in cultured C2C12 myotubes. Quantitation of muscle versus liver fibrinogen and SAA protein levels indicates that muscle contributes a large fraction of serum acute phase proteins in cancer. These results suggest that the STAT3 transcriptome is a major mechanism for wasting in cancer. Through IL-6/STAT3 activation, skeletal muscle is induced to synthesize acute phase proteins, thus establishing a molecular link between the observations of high IL-6, increased acute phase response proteins and muscle wasting in cancer. These results suggest a mechanism by which STAT3 might causally influence muscle wasting by altering the profile of genes expressed and translated in muscle such that amino acids liberated by increased proteolysis in cachexia are

  19. STAT3 Activation in Skeletal Muscle Links Muscle Wasting and the Acute Phase Response in Cancer Cachexia

    PubMed Central

    Kunzevitzky, Noelia; Guttridge, Denis C.; Khuri, Sawsan; Koniaris, Leonidas G.; Zimmers, Teresa A.

    2011-01-01

    Background Cachexia, or weight loss despite adequate nutrition, significantly impairs quality of life and response to therapy in cancer patients. In cancer patients, skeletal muscle wasting, weight loss and mortality are all positively associated with increased serum cytokines, particularly Interleukin-6 (IL-6), and the presence of the acute phase response. Acute phase proteins, including fibrinogen and serum amyloid A (SAA) are synthesized by hepatocytes in response to IL-6 as part of the innate immune response. To gain insight into the relationships among these observations, we studied mice with moderate and severe Colon-26 (C26)-carcinoma cachexia. Methodology/Principal Findings Moderate and severe C26 cachexia was associated with high serum IL-6 and IL-6 family cytokines and highly similar patterns of skeletal muscle gene expression. The top canonical pathways up-regulated in both were the complement/coagulation cascade, proteasome, MAPK signaling, and the IL-6 and STAT3 pathways. Cachexia was associated with increased muscle pY705-STAT3 and increased STAT3 localization in myonuclei. STAT3 target genes, including SOCS3 mRNA and acute phase response proteins, were highly induced in cachectic muscle. IL-6 treatment and STAT3 activation both also induced fibrinogen in cultured C2C12 myotubes. Quantitation of muscle versus liver fibrinogen and SAA protein levels indicates that muscle contributes a large fraction of serum acute phase proteins in cancer. Conclusions/Significance These results suggest that the STAT3 transcriptome is a major mechanism for wasting in cancer. Through IL-6/STAT3 activation, skeletal muscle is induced to synthesize acute phase proteins, thus establishing a molecular link between the observations of high IL-6, increased acute phase response proteins and muscle wasting in cancer. These results suggest a mechanism by which STAT3 might causally influence muscle wasting by altering the profile of genes expressed and translated in muscle such

  20. Cancer Chemoprevention by Traditional Chinese Herbal Medicine and Dietary Phytochemicals: Targeting Nrf2-Mediated Oxidative Stress/Anti-Inflammatory Responses, Epigenetics, and Cancer Stem Cells

    PubMed Central

    Hun Lee, Jong; Shu, Limin; Fuentes, Francisco; Su, Zheng-Yuan; Tony Kong, Ah-Ng

    2013-01-01

    Excessive oxidative stress induced by reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive metabolites of carcinogens alters cellular homeostasis, leading to genetic/epigenetic changes, genomic instability, neoplastic transformation, and cancer initiation/progression. As a protective mechanism against oxidative stress, antioxidant/detoxifying enzymes reduce these reactive species and protect normal cells from endo-/exogenous oxidative damage. The transcription factor nuclear factor-erythroid 2 p45 (NF-E2)-related factor 2 (Nrf2), a master regulator of the antioxidative stress response, plays a critical role in the expression of many cytoprotective enzymes, including NAD(P)H:quinine oxidoreductase (NQO1), heme oxygenase-1 (HO-1), UDP-glucuronosyltransferase (UGT), and glutathione S-transferase (GST). Recent studies demonstrated that many dietary phytochemicals derived from various vegetables, fruits, spices, and herbal medicines induce Nrf2-mediated antioxidant/detoxifying enzymes, restore aberrant epigenetic alterations, and eliminate cancer stem cells (CSCs). The Nrf2-mediated antioxidant response prevents many age-related diseases, including cancer. Owing to their fundamental contribution to carcinogenesis, epigenetic modifications and CSCs are novel targets of dietary phytochemicals and traditional Chinese herbal medicine (TCHM). In this review, we summarize cancer chemoprevention by dietary phytochemicals, including TCHM, which have great potential as a safer and more effective strategy for preventing cancer. PMID:24716158

  1. Cancer chemoprevention by traditional chinese herbal medicine and dietary phytochemicals: targeting nrf2-mediated oxidative stress/anti-inflammatory responses, epigenetics, and cancer stem cells.

    PubMed

    Hun Lee, Jong; Shu, Limin; Fuentes, Francisco; Su, Zheng-Yuan; Tony Kong, Ah-Ng

    2013-01-01

    Excessive oxidative stress induced by reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive metabolites of carcinogens alters cellular homeostasis, leading to genetic/epigenetic changes, genomic instability, neoplastic transformation, and cancer initiation/progression. As a protective mechanism against oxidative stress, antioxidant/detoxifying enzymes reduce these reactive species and protect normal cells from endo-/exogenous oxidative damage. The transcription factor nuclear factor-erythroid 2 p45 (NF-E2)-related factor 2 (Nrf2), a master regulator of the antioxidative stress response, plays a critical role in the expression of many cytoprotective enzymes, including quinine oxidoreductase (NQO1), heme oxygenase-1 (HO-1), UDP-glucuronosyltransferase (UGT), and glutathione S-transferase (GST). Recent studies demonstrated that many dietary phytochemicals derived from various vegetables, fruits, spices, and herbal medicines induce Nrf2-mediated antioxidant/detoxifying enzymes, restore aberrant epigenetic alterations, and eliminate cancer stem cells (CSCs). The Nrf2-mediated antioxidant response prevents many age-related diseases, including cancer. Owing to their fundamental contribution to carcinogenesis, epigenetic modifications and CSCs are novel targets of dietary phytochemicals and traditional Chinese herbal medicine (TCHM). In this review, we summarize cancer chemoprevention by dietary phytochemicals, including TCHM, which have great potential as a safer and more effective strategy for preventing cancer.

  2. Association between dietary vitamin C intake and risk of esophageal cancer: A dose-response meta-analysis.

    PubMed

    Bo, Yacong; Lu, Yan; Zhao, Yan; Zhao, Erjiang; Yuan, Ling; Lu, Weiquan; Cui, Lingling; Lu, Quanjun

    2016-04-15

    While several epidemiological studies have investigated the association between vitamin C and risk of esophageal cancer, the results remain inconsistent. In the present study, a meta-analysis was conducted to assess the impact of dietary vitamin C intake on esophageal cancer risk. Online databases were searched up to March 29, 2015, for studies on the association between dietary vitamin C intake and esophageal cancer risk. Pooled risk ratios (RRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Dose-response analyses were performed using the method of restricted cubic splines with four knots at percentiles of 5, 35, 65 and 95% of the distribution. Publication bias was estimated using Egger's tests and funnel plots. In all, 15 articles were included in this meta-analysis, including 20 studies, containing 7063 controls and 3955 cases of esophageal cancer. By comparing the highest vs. the lowest categories of vitamin C intake, we found that vitamin C was inversely associated with the risk of esophageal cancer [overall OR = 0.58, 95% CI = 0.49-0.68, I(2) = 56%]. A linear dose-response relationship was found. With an increase in dietary vitamin C intake of 50 mg/day, the risk of esophageal cancer statistically decreased by 13% (OR = 0.87, 95% CI = 0.80-0.93, p(linearity) = 0.0002). In conclusion, our analysis suggested that the higher intake of dietary vitamin C might have a protective effect against esophageal cancer. © 2015 UICC.

  3. Lottery ticket was more effective than a prize draw in increasing questionnaire response among cancer survivors.

    PubMed

    Drummond, Frances J; O'Leary, Eamonn; Sharp, Linda

    2015-07-01

    Compare the effect of financial incentives on response to a cancer survivors' postal questionnaire. Prostate cancer survivors in Ireland, 1.5-18 years after diagnosis, were randomized to the (1) "lottery" arm [a € 1 lottery scratch card sent with the questionnaire (n = 2,413)] or (2) "prize" arm [entry into a draw on return of a completed questionnaire (n = 2,407)]. Impact of interventions on response overall and by survival period ("short term": < 5 years after diagnosis; "long term": ≥ 5 years after diagnosis) was compared as was cost-effectiveness. Adjusted response rate was 54.4%. Response was higher among younger men (P < 0.001) and those with earlier stage disease (P = 0.002). A modest 2.6% higher response rate was observed in the lottery compared with the prize arm [multivariate relative risk (RR) = 1.06; 95% confidence interval (CI): 1.00, 1.11]. When stratified by survival period, higher response in the lottery arm was only observed among long-term survivors (multivariate RR = 1.10; 95% CI: 1.02, 1.19; short-term survivors: RR = 1.01; 95% CI: 0.94, 1.09). Costs per completed questionnaire were € 4.54 and € 3.57 for the lottery and prize arms, respectively. Compared with the prize arm, cost per additional questionnaire returned in the lottery arm was € 25.65. Although more expensive, to optimize response to postal questionnaires among cancer survivors, researchers might consider inclusion of a lottery scratch card. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. PRX1 knockdown potentiates vitamin K3 toxicity in cancer cells: a potential new therapeutic perspective for an old drug.

    PubMed

    He, Tiantian; Hatem, Elie; Vernis, Laurence; Lei, Ming; Huang, Meng-Er

    2015-12-21

    Many promising anticancer molecules are abandoned during the course from bench to bedside due to lack of clear-cut efficiency and/or severe side effects. Vitamin K3 (vitK3) is a synthetic naphthoquinone exhibiting significant in vitro and in vivo anticancer activity against multiple human cancers, and has therapeutic potential when combined with other anticancer molecules. The major mechanism for the anticancer activity of vitK3 is the generation of cytotoxic reactive oxygen species (ROS). We thus reasoned that a rational redox modulation of cancer cells could enhance vitK3 anticancer efficiency. Cancer cell lines with peroxiredoxin 1 (PRX1) gene transiently or stably knocked-down and corresponding controls were exposed to vitK3 as well as a set of anticancer molecules, including vinblastine, taxol, doxorubicin, daunorubicin, actinomycin D and 5-fluorouracil. Cytotoxic effects and cell death events were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-based assay, cell clonogenic assay, measurement of mitochondrial membrane potential and annexin V/propidium iodide double staining. Global ROS accumulation and compartment-specific H2O2 generation were determined respectively by a redox-sensitive chemical probe and H2O2-sensitive sensor HyPer. Oxidation of endogenous antioxidant proteins including TRX1, TRX2 and PRX3 was monitored by redox western blot. We observed that the PRX1 knockdown in HeLa and A549 cells conferred enhanced sensitivity to vitK3, reducing substantially the necessary doses to kill cancer cells. The same conditions (combination of vitK3 and PRX1 knockdown) caused little cytotoxicity in non-cancerous cells, suggesting a cancer-cell-selective property. Increased ROS accumulation had a crucial role in vitK3-induced cell death in PRX1 knockdown cells. The use of H2O2-specific sensors HyPer revealed that vitK3 lead to immediate accumulation of H2O2 in the cytosol, nucleus, and mitochondrial matrix. PRX1 silencing

  5. The impact of EpCAM expression on response to chemotherapy and clinical outcomes in patients with epithelial ovarian cancer.

    PubMed

    Tayama, Shingo; Motohara, Takeshi; Narantuya, Dashdemberel; Li, Chenyan; Fujimoto, Koichi; Sakaguchi, Isao; Tashiro, Hironori; Saya, Hideyuki; Nagano, Osamu; Katabuchi, Hidetaka

    2017-07-04

    Epithelial ovarian cancer is a highly lethal malignancy; moreover, overcoming chemoresistance is the major challenging in treating ovarian cancer patients. The cancer stem cell (CSC) hypothesis considers CSCs to be the main culprits in driving tumor initiation, metastasis, and resistance to conventional therapy. Although growing evidence suggest that CSCs are responsible for chemoresistance, the contribution of CSC marker EpCAM to resistance to chemotherapy remains unresolved.Here we have demonstrated that ovarian cancers containing high levels of EpCAM have a significantly much lower probability of achieving overall responsive rates after first-line chemotherapy. In addition, multivariate analysis revealed that EpCAM expression is an independent risk factor for chemoresistance, indicating that EpCAM expression is a predictive biomarker of chemotherapeutic response. Consistent with these clinical observations, in vitro assays, we found that the subpopulation of EpCAM-positive ovarian cancer cells shows a significantly higher viability compared with EpCAM-negative cells in response to cisplatin treatment by preventing chemotherapy-induced apoptosis, which is regulated by EpCAM-Bcl-2 axis. Furthermore, in an in vivo mouse model, platinum agents preferentially eliminated EpCAM-negative cells in comparison with EpCAM-positive cells, suggesting that the remaining subpopulation of EpCAM-positive cells contributes to tumor recurrence after chemotherapy. Finally, we also found that an increased expression of EpCAM is associated with poor prognosis in ovarian cancer patients.Our findings highlight the clinical significance of EpCAM in the resistance to chemotherapy and provide a rationale for EpCAM-targeted therapy to improve chemoresistance. Targeting EpCAM should be a promising approach to effectively extirpate the CSCs as the putative root of ovarian cancer.

  6. Tectorigenin sensitizes paclitaxel-resistant human ovarian cancer cells through downregulation of the Akt and NFκB pathway.

    PubMed

    Yang, Yeong-In; Lee, Kyung-Tae; Park, Hee-Juhn; Kim, Tae Jin; Choi, Youn Seok; Shih, Ie-Ming; Choi, Jung-Hye

    2012-12-01

    Paclitaxel (Taxol) is currently used as the front-line chemotherapeutic agent for several cancers including ovarian carcinoma; however, the drug frequently induces drug resistance through multiple mechanisms. The new strategy of using natural compounds in combination therapies is highly attractive because those compounds may enhance the efficacy of chemotherapy. In this study, we found that tectorigenin, an isoflavonoid isolated from flower of Pueraria thunbergiana, enhanced the growth-inhibitory effect of paclitaxel in paclitaxel-resistant ovarian cancer cells (MPSC1(TR), A2780(TR) and SKOV3(TR)) as well as their naive counterparts. The combination of tectorigenin with paclitaxel resulted in a synergistic apoptosis compared with either agent alone through activation of caspases-3, -8 and -9. Treatment with tectorigenin inhibited the nuclear translocation of NFκB and the expression of NFκB-dependent genes such as FLIP, XIAP, Bcl-2, Bcl-xL and COX-2, which are known to be associated with chemoresistance. In addition, the tectorigenin-paclitaxel combination inhibited the phosphorylation of IκB and IKK and the activation of Akt in paclitaxel-resistant cancer cells. Moreover, tectorigenin-paclitaxel-induced cell growth inhibition was enhanced by pretreatment with the Akt inhibitor LY294002 or overexpression of the dominant negative Akt (Akt-DN), but reduced by overexpression of constitutively activated Akt (Akt-Myr). Furthermore, we found that Akt-Myr, at least in part, reversed tectorigenin-paclitaxel-induced nuclear translocation of NFκB and the phosphorylation of IκB and IKK. These data suggest that tectorigenin could sensitize paclitaxel-resistant human ovarian cancer cells through inactivation of the Akt/IKK/IκB/NFκB signaling pathway, and promise a new intervention to chemosensitize paclitaxel-induced cytotoxicity in ovarian cancer.

  7. "What Made Me Unhappy". Experiences of, and Responses to, Lifestyle Changes in Breast Cancer Patients

    ERIC Educational Resources Information Center

    Bitsika, Vicki; Sharpley, Christopher F.; Christie, David R. H.

    2010-01-01

    Sixteen breast cancer patients were interviewed about any lifestyle changes they had experienced and their reactions to those changes. Data were collected and analysed via content analysis and then summary tabulations of patient responses until replication of responses was verified across patients. Results indicated that most patients suffered a…

  8. Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer.

    PubMed

    Eritja, Núria; Chen, Bo-Juen; Rodríguez-Barrueco, Ruth; Santacana, Maria; Gatius, Sònia; Vidal, August; Martí, Maria Dolores; Ponce, Jordi; Bergadà, Laura; Yeramian, Andree; Encinas, Mario; Ribera, Joan; Reventós, Jaume; Boyd, Jeff; Villanueva, Alberto; Matias-Guiu, Xavier; Dolcet, Xavier; Llobet-Navàs, David

    2017-03-04

    Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC.

  9. Predicting pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a systematic review.

    PubMed

    Ryan, J E; Warrier, S K; Lynch, A C; Ramsay, R G; Phillips, W A; Heriot, A G

    2016-03-01

    Approximately 20% of patients treated with neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer achieve a pathological complete response (pCR) while the remainder derive the benefit of improved local control and downstaging and a small proportion show a minimal response. The ability to predict which patients will benefit would allow for improved patient stratification directing therapy to those who are likely to achieve a good response, thereby avoiding ineffective treatment in those unlikely to benefit. A systematic review of the English language literature was conducted to identify pathological factors, imaging modalities and molecular factors that predict pCR following chemoradiotherapy. PubMed, MEDLINE and Cochrane Database searches were conducted with the following keywords and MeSH search terms: 'rectal neoplasm', 'response', 'neoadjuvant', 'preoperative chemoradiation', 'tumor response'. After review of title and abstracts, 85 articles addressing the prediction of pCR were selected. Clear methods to predict pCR before chemoradiotherapy have not been defined. Clinical and radiological features of the primary cancer have limited ability to predict response. Molecular profiling holds the greatest potential to predict pCR but adoption of this technology will require greater concordance between cohorts for the biomarkers currently under investigation. At present no robust markers of the prediction of pCR have been identified and the topic remains an area for future research. This review critically evaluates existing literature providing an overview of the methods currently available to predict pCR to nCRT for locally advanced rectal cancer. The review also provides a comprehensive comparison of the accuracy of each modality. Colorectal Disease © 2015 The Association of Coloproctology of Great Britain and Ireland.

  10. A Prospective Study of Bone Tumor Response Assessment in Metastatic Breast Cancer

    PubMed Central

    Hayashi, Naoki; Costelloe, Colleen M.; Hamaoka, Tsuyoshi; Wei, Caimiao; Niikura, Naoki; Theriault, Richard L.; Hortobagyi, Gabriel N.; Madewell, John E.; Ueno, Naoto T.

    2013-01-01

    In this pilot study, we prospectively compared the response of bone metastasis assessed by our MD Anderson (MDA) bone tumor response criteria (computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) with the response assessed by the World Health Organization (WHO) criteria (XR and SS). Both MDA and WHO criteria predicted progression-free survival (PFS) of patients at 6 months but not at an earlier time point. Background In our previous study, new MD Anderson (MDA) bone tumor response criteria (based on computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) predicted progression-free survival (PFS) better than did World Health Organization (WHO) bone tumor response criteria (plain radiography [XR] and SS) among patients with breast cancer and bone-only metastases. In this pilot study, we tested whether MDA criteria could reveal bone metastasis response earlier than WHO criteria in patients with newly diagnosed breast cancer with osseous and measurable nonosseous metastases. Methods We prospectively analyzed bone metastasis response using each imaging modality and set of bone response criteria to distinguish progressive disease (PD) from non-PD and their association with PFS and overall survival (OS). We also compared the response of osseous metastases assessed by both criteria with the response of nonosseous measurable lesions. Results The median follow-up period was 26.7 months (range, 6.1–53.3 months) in 29 patients. PFS rates differed at 6 months based on the classification of PD or non-PD using either set of criteria (MDA, P = .002; WHO, P = .014), but these rates, as well as OS, did not differ at 3 months. Response in osseous metastases by either set of criteria did not correlate with the response in nonosseous metastases. Conclusion MDA and WHO criteria predicted PFS of patients with osseous metastases at 6 months but not at an earlier time point. We plan a well-powered study to determine the role of MDA

  11. QUANTITATION OF MOLECULAR ENDPOINTS FOR THE DOSE-RESPONSE COMPONENT OF CANCER RISK ASSESSMENT

    EPA Science Inventory

    Cancer risk assessment involves the steps of hazard identification, dose-response assessment, exposure assessment and risk characterization. The rapid advances in the use of molecular biology approaches has had an impact on all four components, but the greatest overall current...

  12. Target-oriented discovery of a new esterase-producing strain Enterobacter sp. ECU1107 for whole cell-catalyzed production of (2S,3R)-3-phenylglycidate as a chiral synthon of Taxol.

    PubMed

    Zhou, Dong-Jie; Pan, Jiang; Yu, Hui-Lei; Zheng, Gao-Wei; Xu, Jian-He

    2013-07-01

    A new strain, Enterobacter sp. ECU1107, was identified among over 200 soil isolates using a two-step screening strategy for the enantioselective synthesis of (2S,3R)-3-phenylglycidate methyl ester (PGM), a key intermediate for production of a potent anticancer drug Taxol®. An organic-aqueous biphasic system was employed to reduce spontaneous hydrolysis of the substrate PGM and isooctane was found to be the most suitable organic solvent. The temperature and pH optima of the whole cell-mediated bioreaction were 40 °C and 6.0, respectively. Under these reaction conditions, the enantiomeric excess (ee(s)) of (2S,3R)-PGM recovered was greater than 99 % at approximately 50 % conversion. The total substrate loading in batch reaction could reach 600 mM. By using whole cells of Enterobacter sp. ECU1107, (2S,3R)-PGM was successfully prepared in decagram scale in a 1.0-l mechanically stirred reactor, affording the chiral epoxy ester in >99 % ee s and 43.5 % molar yield based on the initial load of racemic substrate.

  13. In Vitro-In Vivo Dose Response of Ursolic Acid, Sulforaphane, PEITC, and Curcumin in Cancer Prevention.

    PubMed

    Ramirez, Christina N; Li, Wenji; Zhang, Chengyue; Wu, Renyi; Su, Shan; Wang, Chao; Gao, Linbo; Yin, Ran; Kong, Ah-Ng

    2017-12-20

    According to the National Center of Health Statistics, cancer was the culprit of nearly 600,000 deaths in 2016 in the USA. It is by far one of the most heterogeneous diseases to treat. Treatment for metastasized cancers remains a challenge despite modern diagnostics and treatment regimens. For this reason, alternative approaches are needed. Chemoprevention using dietary phytochemicals such as triterpenoids, isothiocyanates, and curcumin in the prevention of initiation and/or progression of cancer poses a promising alternative strategy. However, significant challenges exist in the extrapolation of in vitro cell culture data to in vivo efficacy in animal models and to humans. In this review, the dose at which these phytochemicals elicit a response in vitro and in vivo of a multitude of cellular signaling pathways will be reviewed highlighting Nrf2-mediated antioxidative stress, anti-inflammation, epigenetics, cytoprotection, differentiation, and growth inhibition. The in vitro-in vivo dose response of phytochemicals can vary due, in part, to the cell line/animal model used, the assay system of the biomarker used for the readout, chemical structure of the functional analog of the phytochemical, and the source of compounds used for the treatment study. While the dose response varies across different experimental designs, the chemopreventive efficacy appears to remain and demonstrate the therapeutic potential of triterpenoids, isothiocyanates, and curcumin in cancer prevention and in health in general.

  14. Coping response following a diagnosis of breast cancer: A systematic review.

    PubMed

    Mehrabi, Esmat; Hajian, Sepideh; Simbar, Masoomeh; Hoshyari, Mohammad; Zayeri, Farid

    2015-12-01

    Coping with breast cancer is an important health issue that results in adjustments to the disease in survivors. The present systematic review aims to synthesize the evidence about the coping strategies used by women who are primary breast cancer survivors to adjust to their new situations in their lives. Searches were conducted using Google Scholar, PubMed, Scopus, Wiley Online Library, and PsycINFO, using the terms "breast cancer," "breast malignancy," "coping strategies," "coping behaviors," and "adjustment" from January 2000 to July 2015. Only relevant studies in English were selected at the end of the search. Only those papers were selected that focused on coping strategies/behaviors that were used by breast cancer survivors. Searching the electronic databases resulted in 2390 articles. Ultimately, 20 studies met the inclusion criteria of the present study and were included in the review. Two reviewers independently reviewed all relevant articles using the same inclusion criteria. The reviewers completed a quality assessment using the Newcastle-Ottawa Quality Assessment scales for observational studies. The more frequent coping strategies that patients with breast cancer used in the studies were 1) seeking social support (9 studies), 2) positive reframing and reappraisal behaviors as problem focused strategies (7 studies), 3) religious/spirituality-focused efforts (8 studies), 4) emotional expression as positive emotion-focused strategies (3 studies), and 5) avoidance and distraction as avoidance orientated strategies (6 studies). Women with different ethnicities and educational levels used different coping strategies with breast cancer, and they used different strategies in different phases of the disease. This systematic review revealed that seeking social support and emotion-focused efforts were the main coping strategies that women with breast cancer diagnosis used, especially in the early phase of breast cancer diagnosis. This information about the coping

  15. Service of Remembrance: a comprehensive cancer center's response to bereaved family members.

    PubMed

    Knight, Louise; Cooper, Rhonda S; Hypki, Cinder

    2012-01-01

    Comprehensive cancer centers that offer an array of clinical trials and treatment options often experience significant patient mortality rates. Bereavement resources may not be routinely incorporated into the service delivery model in these specialty hospitals. In response, an interdisciplinary team at one cancer center proposed, planned, and implemented an annual Service of Remembrance. The incorporation of music, poetry, and visual arts was important in designing a program that would provide a meaningful, spiritual experience. A community artist who designed an interactive memorial art piece played a pivotal role. This article outlines the process of institutional culture change and describes future challenges in the implementation of this type of bereavement service.

  16. Paclitaxel-resistant HeLa cells have up-regulated levels of reactive oxygen species and increased expression of taxol resistance gene 1.

    PubMed

    Bi, Wenxiang; Wang, Yuxia; Sun, Gaoying; Zhang, Xiaojin; Wei, Yongqing; Li, Lu; Wang, Xiaoyuan

    2014-07-01

    This study is to establish a paclitaxel (PTX)-resistant human cervical carcinoma HeLa cell line (HeLa/PTX) and to investigate its redox characteristics and the expression of taxol resistance gene 1 (Txr1). HeLa cells were treated with PTX and effects of PTX on cell proliferation were detected through cell counting and the MTT assay. Levels of cellular reactive oxygen species (ROS), reduced glutathione (GSH), and oxidized glutathione (GSSG) as well as the ratio of GSH to GSSG were measured by the 2,7-difluorescein diacetate (DCFH-DA) method and the 5,5'dithiobis(2-nitrobenzoic acid) (DTNB) method. Activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were determined by the nitrite formation method, the molybdate colorimetric method, and the DTNB colorimetric method, respectively. The level of Txr1 mRNA was determined by real-time PCR. Compared with the regular HeLa cells, HeLa/PTX cells were larger in size and had more cytoplasmic granules. The population doubling time for HeLa/PTX cells was 1.32 times of that of HeLa cells (P<0.01). HeLa/PTX cells showed stronger resistance to PTX than HeLa cells with a resistance index of 122.69. HeLa/PTX cells had higher levels of ROS (P<0.01) and Txr1 mRNA (P<0.01), lower level of GSH (P < 0.05), and lower activities of SOD (P<0.01) and GPx (P < 0.05) than HeLa cells. HeLa/PTX cells, with higher levels of ROS and Txr1 mRNA expression, are more resistant to PTX than HeLa cells.

  17. Changes in Cervical Cancer FDG Uptake During Chemoradiation and Association With Response

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kidd, Elizabeth A., E-mail: ekidd@stanford.edu; Thomas, Maria; Siegel, Barry A.

    2013-01-01

    Purpose: Previous research showed that pretreatment uptake of F-18 fluorodeoxyglucose (FDG), as assessed by the maximal standardized uptake value (SUV{sub max}) and the variability of uptake (FDG{sub hetero}), predicted for posttreatment response in cervical cancer. In this pilot study, we evaluated the changes in SUV{sub max} and FDG{sub hetero} during concurrent chemoradiation for cervical cancer and their association with post-treatment response. Methods and Materials: Twenty-five patients with stage Ib1-IVa cervical cancer were enrolled. SUV{sub max}, FDG{sub hetero}, and metabolic tumor volume (MTV) were recorded from FDG-positron emission tomography (PET)/computed tomography (CT) scans performed pretreatment and during weeks 2 and 4more » of treatment and were evaluated for changes and association with response assessed on 3-month post-treatment FDG-PET/CT. Results: For all patients, the average pretreatment SUV{sub max} was 17.8, MTV was 55.4 cm{sup 3}, and FDG{sub hetero} was -1.33. A similar decline in SUV{sub max} was seen at week 2 compared with baseline and week 4 compared with week 2 (34%). The areas of highest FDG uptake in the tumor remained relatively consistent on serial scans. Mean FDG{sub hetero} decreased during treatment. For all patients, MTV decreased more from week 2 to week 4 than from pretreatment to week 2. By week 4, the average SUV{sub max} had decreased by 57% and the MTV had decreased by 30%. Five patients showed persistent or new disease on 3-month post-treatment PET. These poor responders showed a higher average SUV{sub max}, larger MTV, and greater heterogeneity at all 3 times. Week 4 SUV{sub max} (P=.037), week 4 FDG{sub hetero} (P=.005), pretreatment MTV (P=.008), and pretreatment FDG{sub hetero} (P=.008) were all significantly associated with post-treatment PET response. Conclusions: SUV{sub max} shows a consistent rate of decline during treatment and declines at a faster rate than MTV regresses. Based on this pilot study

  18. Facilitating a culture of responsible and effective sharing of cancer genome data.

    PubMed

    Siu, Lillian L; Lawler, Mark; Haussler, David; Knoppers, Bartha Maria; Lewin, Jeremy; Vis, Daniel J; Liao, Rachel G; Andre, Fabrice; Banks, Ian; Barrett, J Carl; Caldas, Carlos; Camargo, Anamaria Aranha; Fitzgerald, Rebecca C; Mao, Mao; Mattison, John E; Pao, William; Sellers, William R; Sullivan, Patrick; Teh, Bin Tean; Ward, Robyn L; ZenKlusen, Jean Claude; Sawyers, Charles L; Voest, Emile E

    2016-05-05

    Rapid and affordable tumor molecular profiling has led to an explosion of clinical and genomic data poised to enhance the diagnosis, prognostication and treatment of cancer. A critical point has now been reached at which the analysis and storage of annotated clinical and genomic information in unconnected silos will stall the advancement of precision cancer care. Information systems must be harmonized to overcome the multiple technical and logistical barriers to data sharing. Against this backdrop, the Global Alliance for Genomic Health (GA4GH) was established in 2013 to create a common framework that enables responsible, voluntary and secure sharing of clinical and genomic data. This Perspective from the GA4GH Clinical Working Group Cancer Task Team highlights the data-aggregation challenges faced by the field, suggests potential collaborative solutions and describes how GA4GH can catalyze a harmonized data-sharing culture.

  19. Predominance of TH1 response in tumor-bearing mice and cancer patients treated with AS101.

    PubMed

    Sredni, B; Tichler, T; Shani, A; Catane, R; Kaufman, B; Strassmann, G; Albeck, M; Kalechman, Y

    1996-09-18

    Several studies have recently suggested that the immune response to malignant growths is regulated by distinct patterns of type 2 cytokine production. These cytokines, regulating the cytotoxic T-lymphocyte response in patients with advanced cancers, may be associated with disease progression. Evidence suggests that the T Helper 1 (TH1) and T Helper 2 (TH2) types of reaction are reciprocally regulated in vivo. The immunomodulator AS101 (ammonium trichloro[dioxoethylene-O,O']tellurate) was found to stimulate mouse and human cells to proliferate and secrete a variety of cytokines. Clinical trials using AS101 on cancer patients are now in progress. The aim of this study was to evaluate the ability of AS101 to modulate TH1 and TH2 responses in tumor-bearing mice and in patients with advanced cancer. In addition, we investigated the association between the predominance of each type of response with the antitumoral effects of AS101. Mice into which Lewis lung carcinoma (3LL) had been transplanted (n = 221) and cancer patients (n = 13) were treated with AS101 on alternate days, at 10 micrograms/mouse intraperitoneally, or for the patients, at 3 mg/m2 intravenously. The types were sarcoma, melanoma, and colon, lung, ovarian, and renal cancers. Cytokine levels were determined by immunoassay kits and compared with the paired Student's t test: in mice, they were tested in spleen cell supernatants; in humans, in sera and mononuclear cell supernatants. The chi-squared test was used to compare tumor volumes. All P values represent two-sided tests of statistical significance. Our results show that treatment of mice and patients with AS101 results in a clear predominance in TH1 responses, with a concomitant decrease in the TH2-type response. This was reflected by a significant enhancement in interleukin 2 (IL-2) and interferon gamma (IFN gamma) levels (P < .01) paralleled by a substantial decrease in IL-4 and IL-10 (P < .01). Moreover, the concentration of IL-12 was significantly

  20. Adjuvant therapy sparing in rectal cancer achieving complete response after chemoradiation

    PubMed Central

    García-Albéniz, Xabier; Gallego, Rosa; Hofheinz, Ralf Dieter; Fernández-Esparrach, Gloria; Ayuso-Colella, Juan Ramón; Bombí, Josep Antoni; Conill, Carles; Cuatrecasas, Miriam; Delgado, Salvadora; Ginés, Angels; Miquel, Rosa; Pagés, Mario; Pineda, Estela; Pereira, Verónica; Sosa, Aarón; Reig, Oscar; Victoria, Iván; Feliz, Luis; María de Lacy, Antonio; Castells, Antoni; Burkholder, Iris; Hochhaus, Andreas; Maurel, Joan

    2014-01-01

    AIM: To evaluate the long-term results of conventional chemoradiotherapy and laparoscopic mesorectal excision in rectal adenocarcinoma patients without adjuvant therapy. METHODS: Patients with biopsy-proven adenocarcinoma of the rectum staged cT3-T4 by endoscopic ultrasound or magnetic resonance imaging received neoadjuvant continuous infusion of 5-fluorouracil for five weeks and concomitant radiotherapy. Laparoscopic surgery was planned after 5-8 wk. Patients diagnosed with ypT0N0 stage cancer were not treated with adjuvant therapy according to the protocol. Patients with ypT1-2N0 or ypT3-4 or N+ were offered 5-fluorouracil-based adjuvant treatment on an individual basis. An external cohort was used as a reference for the findings. RESULTS: One hundred and seventy six patients were treated with induction chemoradiotherapy and 170 underwent total mesorectal excision. Cancer staging of ypT0N0 was achieved in 26/170 (15.3%) patients. After a median follow-up of 58.3 mo, patients with ypT0N0 had five-year disease-free and overall survival rates of 96% (95%CI: 77-99) and 100%, respectively. We provide evidence about the natural history of patients with localized rectal cancer achieving a complete response after preoperative chemoradiation. The inherent good prognosis of these patients will have implications for clinical trial design and care of patients. CONCLUSION: Withholding adjuvant chemotherapy after complete response following standard neoadjuvant chemoradiotherapy and laparoscopic mesorectal excision might be safe within an experienced multidisciplinary team. PMID:25400468

  1. Lung cancer treatment costs, including patient responsibility, by disease stage and treatment modality, 1992 to 2003.

    PubMed

    Cipriano, Lauren E; Romanus, Dorothy; Earle, Craig C; Neville, Bridget A; Halpern, Elkan F; Gazelle, G Scott; McMahon, Pamela M

    2011-01-01

    The objective of this analysis was to estimate costs for lung cancer care and evaluate trends in the share of treatment costs that are the responsibility of Medicare beneficiaries. The Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 1991-2003 for 60,231 patients with lung cancer were used to estimate monthly and patient-liability costs for clinical phases of lung cancer (prediagnosis, staging, initial, continuing, and terminal), stratified by treatment, stage, and non-small- versus small-cell lung cancer. Lung cancer-attributable costs were estimated by subtracting each patient's own prediagnosis costs. Costs were estimated as the sum of Medicare reimbursements (payments from Medicare to the service provider), co-insurance reimbursements, and patient-liability costs (deductibles and "co-payments" that are the patient's responsibility). Costs and patient-liability costs were fit with regression models to compare trends by calendar year, adjusting for age at diagnosis. The monthly treatment costs for a 72-year-old patient, diagnosed with lung cancer in 2000, in the first 6 months ranged from $2687 (no active treatment) to $9360 (chemo-radiotherapy); costs varied by stage at diagnosis and histologic type. Patient liability represented up to 21.6% of care costs and increased over the period 1992-2003 for most stage and treatment categories, even when care costs decreased or remained unchanged. The greatest monthly patient liability was incurred by chemo-radiotherapy patients, which ranged from $1617 to $2004 per month across cancer stages. Costs for lung cancer care are substantial, and Medicare is paying a smaller proportion of the total cost over time. Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  2. Autonomous parvoviruses neither stimulate nor are inhibited by the type I interferon response in human normal or cancer cells.

    PubMed

    Paglino, Justin C; Andres, Wells; van den Pol, Anthony N

    2014-05-01

    Members of the genus Parvovirus are small, nonenveloped single-stranded DNA viruses that are nonpathogenic in humans but have potential utility as cancer therapeutics. Because the innate immune response to parvoviruses has received relatively little attention, we compared the response to parvoviruses to that of several other types of viruses in human cells. In normal human glia, fibroblasts, or melanocytes, vesicular stomatitis virus evoked robust beta interferon (IFN-β) responses. Cytomegalovirus, pseudorabies virus, and Sindbis virus all evoked a 2-log-unit or greater upregulation of IFN-β in glia; in contrast, LuIII and MVMp parvoviruses did not evoke a detectable IFN-β or interferon-stimulated gene (ISG; MX1, oligoadenylate synthetase [OAS], IFIT-1) response in the same cell types. The lack of response raised the question of whether parvoviral infection can be attenuated by IFN; interestingly, we found that IFN did not decrease parvovirus (MVMp, LuIII, and H-1) infectivity in normal human glia, fibroblasts, or melanocytes. The same was true in human cancers, including glioma, sarcoma, and melanoma. Similarly, IFN failed to attenuate transduction by the dependovirus vector adeno-associated virus type 2. Progeny production of parvoviruses was also unimpaired by IFN in both glioma and melanoma, whereas vesicular stomatitis virus replication was blocked. Sarcoma cells with upregulated IFN signaling that show high levels of resistance to other viruses showed strong infection by LuIII. Unlike many other oncolytic viruses, we found no evidence that impairment of innate immunity in cancer cells plays a role in the oncoselectivity of parvoviruses in human cells. Parvoviral resistance to the effects of IFN in cancer cells may constitute an advantage in the virotherapy of some tumors. Understanding the interactions between oncolytic viruses and the innate immune system will facilitate employing these viruses as therapeutic agents in cancer patients. The cancer

  3. Autonomous Parvoviruses neither Stimulate nor Are Inhibited by the Type I Interferon Response in Human Normal or Cancer Cells

    PubMed Central

    Paglino, Justin C.; Andres, Wells

    2014-01-01

    ABSTRACT Members of the genus Parvovirus are small, nonenveloped single-stranded DNA viruses that are nonpathogenic in humans but have potential utility as cancer therapeutics. Because the innate immune response to parvoviruses has received relatively little attention, we compared the response to parvoviruses to that of several other types of viruses in human cells. In normal human glia, fibroblasts, or melanocytes, vesicular stomatitis virus evoked robust beta interferon (IFN-β) responses. Cytomegalovirus, pseudorabies virus, and Sindbis virus all evoked a 2-log-unit or greater upregulation of IFN-β in glia; in contrast, LuIII and MVMp parvoviruses did not evoke a detectable IFN-β or interferon-stimulated gene (ISG; MX1, oligoadenylate synthetase [OAS], IFIT-1) response in the same cell types. The lack of response raised the question of whether parvoviral infection can be attenuated by IFN; interestingly, we found that IFN did not decrease parvovirus (MVMp, LuIII, and H-1) infectivity in normal human glia, fibroblasts, or melanocytes. The same was true in human cancers, including glioma, sarcoma, and melanoma. Similarly, IFN failed to attenuate transduction by the dependovirus vector adeno-associated virus type 2. Progeny production of parvoviruses was also unimpaired by IFN in both glioma and melanoma, whereas vesicular stomatitis virus replication was blocked. Sarcoma cells with upregulated IFN signaling that show high levels of resistance to other viruses showed strong infection by LuIII. Unlike many other oncolytic viruses, we found no evidence that impairment of innate immunity in cancer cells plays a role in the oncoselectivity of parvoviruses in human cells. Parvoviral resistance to the effects of IFN in cancer cells may constitute an advantage in the virotherapy of some tumors. IMPORTANCE Understanding the interactions between oncolytic viruses and the innate immune system will facilitate employing these viruses as therapeutic agents in cancer patients

  4. Tumor response estimation in radar-based microwave breast cancer detection.

    PubMed

    Kurrant, Douglas J; Fear, Elise C; Westwick, David T

    2008-12-01

    Radar-based microwave imaging techniques have been proposed for early stage breast cancer detection. A considerable challenge for the successful implementation of these techniques is the reduction of clutter, or components of the signal originating from objects other than the tumor. In particular, the reduction of clutter from the late-time scattered fields is required in order to detect small (subcentimeter diameter) tumors. In this paper, a method to estimate the tumor response contained in the late-time scattered fields is presented. The method uses a parametric function to model the tumor response. A maximum a posteriori estimation approach is used to evaluate the optimal values for the estimates of the parameters. A pattern classification technique is then used to validate the estimation. The ability of the algorithm to estimate a tumor response is demonstrated by using both experimental and simulated data obtained with a tissue sensing adaptive radar system.

  5. mTOR inhibition elicits a dramatic response in PI3K-dependent colon cancers.

    PubMed

    Deming, Dustin A; Leystra, Alyssa A; Farhoud, Mohammed; Nettekoven, Laura; Clipson, Linda; Albrecht, Dawn; Washington, Mary Kay; Sullivan, Ruth; Weichert, Jamey P; Halberg, Richard B

    2013-01-01

    The phosphatidylinositide-3-kinase (PI3K) signaling pathway is critical for multiple cellular functions including metabolism, proliferation, angiogenesis, and apoptosis, and is the most commonly altered pathway in human cancers. Recently, we developed a novel mouse model of colon cancer in which tumors are initiated by a dominant active PI3K (FC PIK3ca). The cancers in these mice are moderately differentiated invasive mucinous adenocarcinomas of the proximal colon that develop by 50 days of age. Interestingly, these cancers form without a benign intermediary or aberrant WNT signaling, indicating a non-canonical mechanism of tumorigenesis. Since these tumors are dependent upon the PI3K pathway, we investigated the potential for tumor response by the targeting of this pathway with rapamycin, an mTOR inhibitor. A cohort of FC PIK3ca mice were treated with rapamycin at a dose of 6 mg/kg/day or placebo for 14 days. FDG dual hybrid PET/CT imaging demonstrated a dramatic tumor response in the rapamycin arm and this was confirmed on necropsy. The tumor tissue remaining after treatment with rapamycin demonstrated increased pERK1/2 or persistent phosphorylated ribosomal protein S6 (pS6), indicating potential resistance mechanisms. This unique model will further our understanding of human disease and facilitate the development of therapeutics through pharmacologic screening and biomarker identification.

  6. A Database of Reaction Monitoring Mass Spectrometry Assays for Elucidating Therapeutic Response in Cancer

    PubMed Central

    Remily-Wood, Elizabeth R.; Liu, Richard Z.; Xiang, Yun; Chen, Yi; Thomas, C. Eric; Rajyaguru, Neal; Kaufman, Laura M.; Ochoa, Joana E.; Hazlehurst, Lori; Pinilla-Ibarz, Javier; Lancet, Jeffrey; Zhang, Guolin; Haura, Eric; Shibata, David; Yeatman, Timothy; Smalley, Keiran S.M.; Dalton, William S.; Huang, Emina; Scott, Ed; Bloom, Gregory C.; Eschrich, Steven A.; Koomen, John M.

    2012-01-01

    Purpose The Quantitative Assay Database (QuAD), http://proteome.moffitt.org/QUAD/, facilitates widespread implementation of quantitative mass spectrometry in cancer biology and clinical research through sharing of methods and reagents for monitoring protein expression and modification. Experimental Design Liquid chromatography coupled to multiple reaction monitoring mass spectrometry (LC-MRM) assays are developed using SDS-PAGE fractionated lysates from cancer cell lines. Pathway maps created using GeneGO Metacore provide the biological relationships between proteins and illustrate concepts for multiplexed analysis; each protein can be selected to examine assay development at the protein and peptide level. Results The coupling of SDS-PAGE and LC-MRM screening has been used to detect 876 peptides from 218 cancer-related proteins in model systems including colon, lung, melanoma, leukemias, and myeloma, which has led to the development of 95 quantitative assays including stable-isotope labeled peptide standards. Methods are published online and peptide standards are made available to the research community. Protein expression measurements for heat shock proteins, including a comparison with ELISA and monitoring response to the HSP90 inhibitor, 17-DMAG, are used to illustrate the components of the QuAD and its potential utility. Conclusions and Clinical Relevance This resource enables quantitative assessment of protein components of signaling pathways and biological processes and holds promise for systematic investigation of treatment responses in cancer. PMID:21656910

  7. cAMP-response-element-binding protein positively regulates breast cancer metastasis and subsequent bone destruction

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Son, Jieun; Lee, Jong-Ho; Kim, Ha-Neui

    2010-07-23

    Research highlights: {yields} CREB is highly expressed in advanced breast cancer cells. {yields} Tumor-related factors such as TGF-{beta} further elevate CREB expression. {yields} CREB upregulation stimulates metastatic potential of breast cancer cells. {yields} CREB signaling is required for breast cancer-induced bone destruction. -- Abstract: cAMP-response-element-binding protein (CREB) signaling has been reported to be associated with cancer development and poor clinical outcome in various types of cancer. However, it remains to be elucidated whether CREB is involved in breast cancer development and osteotropism. Here, we found that metastatic MDA-MB-231 breast cancer cells exhibited higher CREB expression than did non-metastatic MCF-7 cellsmore » and that CREB expression was further increased by several soluble factors linked to cancer progression, such as IL-1, IGF-1, and TGF-{beta}. Using wild-type CREB and a dominant-negative form (K-CREB), we found that CREB signaling positively regulated the proliferation, migration, and invasion of MDA-MB-231 cells. In addition, K-CREB prevented MDA-MB-231 cell-induced osteolytic lesions in a mouse model of cancer metastasis. Furthermore, CREB signaling in cancer cells regulated the gene expression of PTHrP, MMPs, and OPG, which are closely involved in cancer metastasis and bone destruction. These results indicate that breast cancer cells acquire CREB overexpression during their development and that this CREB upregulation plays an important role in multiple steps of breast cancer bone metastasis.« less

  8. Genetic polymorphisms in 5-Fluorouracil-related enzymes predict pathologic response after neoadjuvant chemoradiation for rectal cancer.

    PubMed

    Nelson, Bailey; Carter, Jane V; Eichenberger, Maurice R; Netz, Uri; Galandiuk, Susan

    2016-11-01

    Many patients with rectal cancer undergo preoperative neoadjuvant chemoradiation, with approximately 70% exhibiting pathologic downstaging in response to treatment. Currently, there is no accurate test to predict patients who are likely to be complete responders to therapy. 5-Fluorouracil is used regularly in the neoadjuvant treatment of rectal cancer. Genetic polymorphisms affect the activity of thymidylate synthase, an enzyme involved in 5-Fluorouracil metabolism, which may account for observed differences in response to neoadjuvant treatment between patients. Detection of genetic polymorphisms might identify patients who are likely to have a complete response to neoadjuvant therapy and perhaps allow them to avoid operation. DNA was isolated from whole blood taken from patients with newly diagnosed rectal cancer who received neoadjuvant therapy (n = 50). Response to therapy was calculated with a tumor regression score based on histology from the time of operation. Polymerase chain reaction was performed targeting the promoter region of thymidylate synthase. Polymerase chain reaction products were separated using electrophoresis to determine whether patients were homozygous for a double-tandem repeat (2R), a triple-tandem repeat (3R), or were heterozygous (2R/3R). A single nucleotide polymorphism, 3G or 3C, also may be present in the second repeat unit of the triple-tandem repeat allele. Restriction fragment length polymorphism assays were performed in patients with at least one 3R allele using HaeIII. Patients with at least 1 thymidylate synthase 3G allele were more likely to have a complete or partial pathologic response to 5-Fluorouracil neoadjuvant therapy (odds ratio 10.4; 95% confidence interval, 1.3-81.6; P = .01) than those without at least one 3G allele. Identification of rectal cancer patients with specific genetic polymorphisms in enzymes involved in 5-Fluorouracil metabolism seems to predict the likelihood of complete or partial pathologic response

  9. Clinical Usefulness of the Histoculture Drug Response Assay for Prostate Cancer and Benign Prostate Hypertrophy (BPH).

    PubMed

    Hoffman, Robert M

    2018-01-01

    The histoculture drug response assay (HDRA) has been adapted to determine androgen sensitivity in Gelfoam histoculture of human benign prostatic tissue as well as prostate cancer. Gelfoam histoculture was used to measure androgen-independent and androgen-dependent growth of benign and malignant prostate tissue. The androgen-sensitivity index was significantly higher in 23 paired specimens of prostate cancer compared to benign prostate hypertrophy (BPH). Genistein decreased the androgen-sensitivity index of BPH and prostate cancer in Gelfoam ® histoculture in a dose-dependent manner.

  10. Exposure–Response Analyses of Asbestos and Lung Cancer Subtypes in a Pooled Analysis of Case–Control Studies

    PubMed Central

    Vermeulen, Roel; Schüz, Joachim; Kromhout, Hans; Pesch, Beate; Peters, Susan; Behrens, Thomas; Portengen, Lützen; Mirabelli, Dario; Gustavsson, Per; Kendzia, Benjamin; Almansa, Josue; Luzon, Veronique; Vlaanderen, Jelle; Stücker, Isabelle; Guida, Florence; Consonni, Dario; Caporaso, Neil; Landi, Maria Teresa; Field, John; Brüske, Irene; Wichmann, Heinz-Erich; Siemiatycki, Jack; Parent, Marie-Elise; Richiardi, Lorenzo; Merletti, Franco; Jöckel, Karl-Heinz; Ahrens, Wolfgang; Pohlabeln, Hermann; Plato, Nils; Tardón, Adonina; Zaridze, David; McLaughlin, John; Demers, Paul; Szeszenia-Dabrowska, Neonila; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Stanescu Dumitru, Rodica; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Boffetta, Paolo; Bueno-de-Mesquita, Bas; Forastiere, Francesco; Brüning, Thomas; Straif, Kurt

    2017-01-01

    Background: Evidence is limited regarding risk and the shape of the exposure–response curve at low asbestos exposure levels. We estimated the exposure–response for occupational asbestos exposure and assessed the joint effect of asbestos exposure and smoking by sex and lung cancer subtype in general population studies. Methods: We pooled 14 case–control studies conducted in 1985–2010 in Europe and Canada, including 17,705 lung cancer cases and 21,813 controls with detailed information on tobacco habits and lifetime occupations. We developed a quantitative job-exposure-matrix to estimate job-, time period-, and region-specific exposure levels. Fiber-years (ff/ml-years) were calculated for each subject by linking the matrix with individual occupational histories. We fit unconditional logistic regression models to estimate odds ratios (ORs), 95% confidence intervals (CIs), and trends. Results: The fully adjusted OR for ever-exposure to asbestos was 1.24 (95% CI, 1.18, 1.31) in men and 1.12 (95% CI, 0.95, 1.31) in women. In men, increasing lung cancer risk was observed with increasing exposure in all smoking categories and for all three major lung cancer subtypes. In women, lung cancer risk for all subtypes was increased in current smokers (ORs ~two-fold). The joint effect of asbestos exposure and smoking did not deviate from multiplicativity among men, and was more than additive among women. Conclusions: Our results in men showed an excess risk of lung cancer and its subtypes at low cumulative exposure levels, with a steeper exposure–response slope in this exposure range than at higher, previously studied levels. (See video abstract at, http://links.lww.com/EDE/B161.) PMID:28141674

  11. Exposure-Response Analyses of Asbestos and Lung Cancer Subtypes in a Pooled Analysis of Case-Control Studies.

    PubMed

    Olsson, Ann C; Vermeulen, Roel; Schüz, Joachim; Kromhout, Hans; Pesch, Beate; Peters, Susan; Behrens, Thomas; Portengen, Lützen; Mirabelli, Dario; Gustavsson, Per; Kendzia, Benjamin; Almansa, Josue; Luzon, Veronique; Vlaanderen, Jelle; Stücker, Isabelle; Guida, Florence; Consonni, Dario; Caporaso, Neil; Landi, Maria Teresa; Field, John; Brüske, Irene; Wichmann, Heinz-Erich; Siemiatycki, Jack; Parent, Marie-Elise; Richiardi, Lorenzo; Merletti, Franco; Jöckel, Karl-Heinz; Ahrens, Wolfgang; Pohlabeln, Hermann; Plato, Nils; Tardón, Adonina; Zaridze, David; McLaughlin, John; Demers, Paul; Szeszenia-Dabrowska, Neonila; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Stanescu Dumitru, Rodica; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Boffetta, Paolo; Bueno-de-Mesquita, Bas; Forastiere, Francesco; Brüning, Thomas; Straif, Kurt

    2017-03-01

    Evidence is limited regarding risk and the shape of the exposure-response curve at low asbestos exposure levels. We estimated the exposure-response for occupational asbestos exposure and assessed the joint effect of asbestos exposure and smoking by sex and lung cancer subtype in general population studies. We pooled 14 case-control studies conducted in 1985-2010 in Europe and Canada, including 17,705 lung cancer cases and 21,813 controls with detailed information on tobacco habits and lifetime occupations. We developed a quantitative job-exposure-matrix to estimate job-, time period-, and region-specific exposure levels. Fiber-years (ff/ml-years) were calculated for each subject by linking the matrix with individual occupational histories. We fit unconditional logistic regression models to estimate odds ratios (ORs), 95% confidence intervals (CIs), and trends. The fully adjusted OR for ever-exposure to asbestos was 1.24 (95% CI, 1.18, 1.31) in men and 1.12 (95% CI, 0.95, 1.31) in women. In men, increasing lung cancer risk was observed with increasing exposure in all smoking categories and for all three major lung cancer subtypes. In women, lung cancer risk for all subtypes was increased in current smokers (ORs ~two-fold). The joint effect of asbestos exposure and smoking did not deviate from multiplicativity among men, and was more than additive among women. Our results in men showed an excess risk of lung cancer and its subtypes at low cumulative exposure levels, with a steeper exposure-response slope in this exposure range than at higher, previously studied levels. (See video abstract at, http://links.lww.com/EDE/B161.).

  12. Assessing Tumor Response to Treatment in Patients with Lung Cancer Using Dynamic Contrast-Enhanced CT.

    PubMed

    Strauch, Louise S; Eriksen, Rie Ø; Sandgaard, Michael; Kristensen, Thomas S; Nielsen, Michael B; Lauridsen, Carsten A

    2016-07-21

    The aim of this study was to provide an overview of the literature available on dynamic contrast-enhanced computed tomography (DCE-CT) as a tool to evaluate treatment response in patients with lung cancer. This systematic review was compiled according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only original research articles concerning treatment response in patients with lung cancer assessed with DCE-CT were included. To assess the validity of each study we implemented Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). The initial search yielded 651 publications, and 16 articles were included in this study. The articles were divided into groups of treatment. In studies where patients were treated with systemic chemotherapy with or without anti-angiogenic drugs, four out of the seven studies found a significant decrease in permeability after treatment. Four out of five studies that measured blood flow post anti-angiogenic treatments found that blood flow was significantly decreased. DCE-CT may be a useful tool in assessing treatment response in patients with lung cancer. It seems that particularly permeability and blood flow are important perfusion values for predicting treatment outcome. However, the heterogeneity in scan protocols, scan parameters, and time between scans makes it difficult to compare the included studies.

  13. Radiation Dose-Response Model for Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Appelt, Ane L., E-mail: ane.lindegaard.appelt@slb.regionsyddanmark.dk; University of Southern Denmark, Odense; Ploen, John

    2013-01-01

    Purpose: Preoperative chemoradiation therapy (CRT) is part of the standard treatment of locally advanced rectal cancers. Tumor regression at the time of operation is desirable, but not much is known about the relationship between radiation dose and tumor regression. In the present study we estimated radiation dose-response curves for various grades of tumor regression after preoperative CRT. Methods and Materials: A total of 222 patients, treated with consistent chemotherapy and radiation therapy techniques, were considered for the analysis. Radiation therapy consisted of a combination of external-beam radiation therapy and brachytherapy. Response at the time of operation was evaluated from themore » histopathologic specimen and graded on a 5-point scale (TRG1-5). The probability of achieving complete, major, and partial response was analyzed by ordinal logistic regression, and the effect of including clinical parameters in the model was examined. The radiation dose-response relationship for a specific grade of histopathologic tumor regression was parameterized in terms of the dose required for 50% response, D{sub 50,i}, and the normalized dose-response gradient, {gamma}{sub 50,i}. Results: A highly significant dose-response relationship was found (P=.002). For complete response (TRG1), the dose-response parameters were D{sub 50,TRG1} = 92.0 Gy (95% confidence interval [CI] 79.3-144.9 Gy), {gamma}{sub 50,TRG1} = 0.982 (CI 0.533-1.429), and for major response (TRG1-2) D{sub 50,TRG1} and {sub 2} = 72.1 Gy (CI 65.3-94.0 Gy), {gamma}{sub 50,TRG1} and {sub 2} = 0.770 (CI 0.338-1.201). Tumor size and N category both had a significant effect on the dose-response relationships. Conclusions: This study demonstrated a significant dose-response relationship for tumor regression after preoperative CRT for locally advanced rectal cancer for tumor dose levels in the range of 50.4-70 Gy, which is higher than the dose range usually considered.« less

  14. Letrozole: a review of its use in the treatment of postmenopausal women with hormone-responsive early breast cancer.

    PubMed

    Keating, Gillian M

    2009-08-20

    Letrozole (Femara) is a third-generation, nonsteroidal aromatase inhibitor. Adjuvant therapy with letrozole is more effective than tamoxifen in postmenopausal women with hormone-responsive early breast cancer, and extended adjuvant therapy with letrozole after the completion of adjuvant tamoxifen therapy is more effective than placebo in this patient population; letrozole is generally well tolerated. Ongoing trials will help answer outstanding questions regarding the optimal duration of letrozole therapy in early breast cancer and its efficacy compared with other third-generation aromatase inhibitors such as anastrozole. In the meantime, letrozole should be considered a valuable option in the treatment of postmenopausal women with hormone-responsive early breast cancer, both as adjuvant and extended adjuvant therapy.

  15. Prediction of response to preoperative chemoradiotherapy and establishment of individualized therapy in advanced rectal cancer.

    PubMed

    Nakao, Toshihiro; Iwata, Takashi; Hotchi, Masanori; Yoshikawa, Kozo; Higashijima, Jun; Nishi, Masaaki; Takasu, Chie; Eto, Shohei; Teraoku, Hiroki; Shimada, Mitsuo

    2015-10-01

    Preoperative chemoradiotherapy (CRT) has become the standard treatment for patients with locally advanced rectal cancer. However, no specific biomarker has been identified to predict a response to preoperative CRT. The aim of the present study was to assess the gene expression patterns of patients with advanced rectal cancer to predict their responses to preoperative CRT. Fifty-nine rectal cancer patients were subjected to preoperative CRT. Patients were randomly assigned to receive CRT with tegafur/gimeracil/oteracil (S-1 group, n=30) or tegafur-uracil (UFT group, n=29). Gene expression changes were studied with cDNA and miRNA microarray. The association between gene expression and response to CRT was evaluated. cDNA microarray showed that 184 genes were significantly differentially expressed between the responders and the non‑responders in the S-1 group. Comparatively, 193 genes were significantly differentially expressed in the responders in the UFT group. TBX18 upregulation was common to both groups whereas BTNL8, LOC375010, ADH1B, HRASLS2, LOC284232, GCNT3 and ALDH1A2 were significantly differentially lower in both groups when compared with the non-responders. Using miRNA microarray, we found that 7 and 16 genes were significantly differentially expressed between the responders and non-responders in the S-1 and UFT groups, respectively. miR-223 was significantly higher in the responders in the S-1 group and tended to be higher in the responders in the UFT group. The present study identified several genes likely to be useful for establishing individualized therapies for patients with rectal cancer.

  16. [Interindividual variation of pharmacokinetic disposition of and clinical responses to opioid analgesics in cancer pain patients].

    PubMed

    Naito, Takafumi; Kawakami, Junichi

    2015-01-01

    Use of prescription opioids for cancer pain according to the World Health Organization analgesic ladder has been accepted in Japan. Although oxycodone and fentanyl are commonly used as first-line analgesics, a few clinical reports have been published on interindividual variations in their pharmacokinetics and clinical responses in cancer patients. (1) Some factors relating to CYP2D6, CYP3A, ATP-binding cassette sub-family B member 1 (ABCB1), and opioid receptor mu 1 (OPRM1) involve oxycodone pharmacokinetics and sensitivity in humans. The relations between their genetic variations and clinical responses to oxycodone are being revealed in limited groups. In our study, the impact of genetic variants and pharmacokinetics on clinical responses to oxycodone were evaluated in Japanese populations. (2) Opioid switching improves the opioid tolerance related to the balance between analgesia and adverse effects. Some patients have difficulty in obtaining better opioid tolerance in recommended conversion ratios. The activities of CYP3A, ABCB1, and OPRM1 contribute to the interindividual variations in clinical responses to fentanyl in cancer patients. However, the variations in opioid switching remain to be clarified in clinical settings. In our study, genetic factors related to interindividual variations in clinical responses in opioid switching to fentanyl were revealed in Japanese populations. In this symposium review, the possibility of approaches to personalized palliative care using opioids based on genetic variants of CYP2D6, CYP3A5, ABCB1, and OPRM1 is discussed.

  17. Plerixafor Improves Primary Tumor Response and Reduces Metastases in Cervical Cancer Treated with Radio-Chemotherapy.

    PubMed

    Chaudary, Naz; Pintilie, Melania; Jelveh, Salomeh; Lindsay, Patricia; Hill, Richard P; Milosevic, Michael

    2017-03-01

    Purpose: There is an important need to improve the effectiveness of radio-chemotherapy (RTCT) for cervical cancer. The CXCL12/CXCR4 pathway can influence RT response by recruiting normal myeloid cells to the tumor microenvironment that in turn can exert radioprotective effects, and may promote metastases. The objective of this study was to explore the efficacy and toxicity of combining RTCT with CXCL12/CXCR4 inhibition in cervical cancer. Experimental Design: CXCR4 expression was measured in 115 patients with cervical cancer. Two primary orthotopic cervical cancer xenografts (OCICx) with different levels of CXCR4 expression were treated with RT (30 Gy: 15 daily fractions) and weekly cisplatin (4 mg/kg), with or without the CXCR4 inhibitor Plerixafor (5 mg/kg/day). The endpoints were tumor growth delay and lymph node metastases. Acute intestinal toxicity was assessed using a crypt cell assay. Results: There was a fivefold variation in CXCR4 mRNA expression in the patient samples, and good correlation between the expression in patients and in the xenografts. The combination of RTCT and Plerixafor produced substantial tumor growth delay and reduced lymph node metastases compared with RTCT alone in both of the xenograft models. There was a trend toward reduced acute intestinal toxicity with the addition of Plerixafor to RTCT. There were no changes in normal organ morphology to suggest increased late toxicity. Conclusions: This study demonstrates that the addition of Plerixafor to standard RTCT improves primary tumor response and reduces metastases in cervical cancer with no increase in toxicity. This combination warrants further investigation in phase I/II clinical trials. Clin Cancer Res; 23(5); 1242-9. ©2016 AACR . ©2016 American Association for Cancer Research.

  18. A meta-analysis including dose-response relationship between night shift work and the risk of colorectal cancer.

    PubMed

    Wang, Xiao; Ji, Alin; Zhu, Yi; Liang, Zhen; Wu, Jian; Li, Shiqi; Meng, Shuai; Zheng, Xiangyi; Xie, Liping

    2015-09-22

    A meta-analysis was conducted to quantitatively evaluate the correlation between night shift work and the risk of colorectal cancer. We searched for publications up to March 2015 using PubMed, Web of Science, Cochrane Library, EMBASE and the Chinese National Knowledge Infrastructure databases, and the references of the retrieved articles and relevant reviews were also checked. OR and 95% CI were used to assess the degree of the correlation between night shift work and risk of colorectal cancer via fixed- or random-effect models. A dose-response meta-analysis was performed as well. The pooled OR estimates of the included studies illustrated that night shift work was correlated with an increased risk of colorectal cancer (OR = 1.318, 95% CI 1.121-1.551). No evidence of publication bias was detected. In the dose-response analysis, the rate of colorectal cancer increased by 11% for every 5 years increased in night shift work (OR = 1.11, 95% CI 1.03-1.20). In conclusion, this meta-analysis indicated that night shift work was associated with an increased risk of colorectal cancer. Further researches should be conducted to confirm our findings and clarify the potential biological mechanisms.

  19. Advanced glycation end products increase carbohydrate responsive element binding protein expression and promote cancer cell proliferation.

    PubMed

    Chen, Hanbei; Wu, Lifang; Li, Yakui; Meng, Jian; Lin, Ning; Yang, Dianqiang; Zhu, Yemin; Li, Xiaoyong; Li, Minle; Xu, Ye; Wu, Yuchen; Tong, Xuemei; Su, Qing

    2014-09-01

    Diabetic patients have increased levels of advanced glycation end products (AGEs) and the role of AGEs in regulating cancer cell proliferation is unclear. Here, we found that treating colorectal and liver cancer cells with AGEs promoted cell proliferation. AGEs stimulated both the expression and activation of a key transcription factor called carbohydrate responsive element binding protein (ChREBP) which had been shown to promote glycolytic and anabolic activity as well as proliferation of colorectal and liver cancer cells. Using siRNAs or the antagonistic antibody for the receptor for advanced glycation end-products (RAGE) blocked AGEs-induced ChREBP expression or cell proliferation in cancer cells. Suppressing ChREBP expression severely impaired AGEs-induced cancer cell proliferation. Taken together, these results demonstrate that AGEs-RAGE signaling enhances cancer cell proliferation in which AGEs-mediated ChREBP induction plays an important role. These findings may provide new explanation for increased cancer progression in diabetic patients. Copyright © 2014. Published by Elsevier Ireland Ltd.

  20. Wnt-Responsive Cancer Stem Cells Are Located Close to Distorted Blood Vessels and Not in Hypoxic Regions in a p53-Null Mouse Model of Human Breast Cancer

    PubMed Central

    Landua, John D.; Bu, Wen; Wei, Wei; Li, Fuhai; Wong, Stephen T.C.; Dickinson, Mary E.; Rosen, Jeffrey M.; Lewis, Michael T.

    2014-01-01

    Cancer stem cells (CSCs, or tumor-initiating cells) may be responsible for tumor formation in many types of cancer, including breast cancer. Using high-resolution imaging techniques, we analyzed the relationship between a Wnt-responsive, CSC-enriched population and the tumor vasculature using p53-null mouse mammary tumors transduced with a lentiviral Wnt signaling reporter. Consistent with their localization in the normal mammary gland, Wnt-responsive cells in tumors were enriched in the basal/myoepithelial population and generally located in close proximity to blood vessels. The Wnt-responsive CSCs did not colocalize with the hypoxia-inducible factor 1α-positive cells in these p53-null basal-like tumors. Average vessel diameter and vessel tortuosity were increased in p53-null mouse tumors, as well as in a human tumor xenograft as compared with the normal mammary gland. The combined strategy of monitoring the fluorescently labeled CSCs and vasculature using high-resolution imaging techniques provides a unique opportunity to study the CSC and its surrounding vasculature. PMID:24797826

  1. New Agents for Taxol-Resistant Breast Adenocarcinoma

    DTIC Science & Technology

    2004-07-01

    mg/ mi2 (14) using 3 hr infusion schedules failed to demonstrate marked improvement in disease response or survival, despite incurring severe sensory...analyzed immediately by flow cytometry. Immunoblotting The anti-human HER-2/neu mouse monoclonal antibody , clone 3B5, isotype IgGI, was obtained from...carboxyl domain of the human c-neu gene product. An affinity-purified sheep anti-mouse IgG whole antibody preparation conjugated to horseradish peroxidase

  2. Tumor Response and Survival Predicted by Post-Therapy FDG-PET/CT in Anal Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Schwarz, Julie K.; Siegel, Barry A.; Dehdashti, Farrokh

    2008-05-01

    Purpose: To evaluate the response to therapy for anal carcinoma using post-therapy imaging with positron emission tomography (PET)/computed tomography and F-18 fluorodeoxyglucose (FDG) and to compare the metabolic response with patient outcome. Patients and Methods: This was a prospective cohort study of 53 consecutive patients with anal cancer. All patients underwent pre- and post-treatment whole-body FDG-PET/computed tomography. Patients had been treated with external beam radiotherapy and concurrent chemotherapy. Whole-body FDG-PET was performed 0.9-5.4 months (mean, 2.1) after therapy completion. Results: The post-therapy PET scan did not show any abnormal FDG uptake (complete metabolic response) in 44 patients. Persistent abnormal FDGmore » uptake (partial metabolic response) was found in the anal tumor in 9 patients. The 2-year cause-specific survival rate was 94% for patients with a complete vs. 39% for patients with a partial metabolic response in the anal tumor (p = 0.0008). The 2-year progression-free survival rate was 95% for patients with a complete vs. 22% for patients with a partial metabolic response in the anal tumor (p < 0.0001). A Cox proportional hazards model of survival outcome indicated that a complete metabolic response was the most significant predictor of progression-free survival in our patient population (p = 0.0003). Conclusions: A partial metabolic response in the anal tumor as determined by post-therapy FDG-PET is predictive of significantly decreased progression-free and cause-specific survival after chemoradiotherapy for anal cancer.« less

  3. Evaluation of Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy

    DTIC Science & Technology

    2012-07-01

    Mediated by Listeria -Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy PRINCIPAL INVESTIGATOR: David J. Chung, M D , Ph D...CONTRACT NUMBER Evaluation of Immune Responses Mediated by Listeria -Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy 5b...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The purpose of this project is to study the immunomodulatory effect of Listeria on

  4. Evaluation of Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy

    DTIC Science & Technology

    2014-07-01

    and J.W. Young, Human dendritic cells : potent antigen-presenting cells at the crossroads of innate and adaptive immunity. J Immunol, 2005. 175(3): p...by Listeria-Stimulated Human Dendritic Cells : Implications for Cancer Vaccine Therapy PRINCIPAL INVESTIGATOR: David J. Chung, MD, PhD...5a. CONTRACT NUMBER Evaluation of Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells : Implications for Cancer Vaccine

  5. Chemical and Biological Studies of Nakiterpiosin and Nakiterpiosinone

    PubMed Central

    Gao, Shuanhu; Wang, Qiaoling; Huang, Lily Jun-Shen; Lum, Lawrence; Chen, Chuo

    2009-01-01

    Nakiterpiosin and nakiterpiosinone are two related C-nor-D-homosteroids isolated from the sponge Terpios hoshinota that show promise as anti-cancer agents. We have previously described the asymmetric synthesis and the revision of the relative configuration of nakiterpiosin. We now provide detailed information on the stereochemical analysis that supports our structure revision and the synthesis of the originally proposed and revised nakiterpiosin. In addition, we herein describe a refined approach for the synthesis of nakiterpiosin, the first synthesis of nakiterpiosinone, and preliminary mechanistic studies of nakiterpiosin's action in mammalian cells. Cells treated with nakiterpiosin exhibit compromised formation of the primary cilium, an organelle that functions as an assembly point for components of the Hedgehog signal transduction pathway. We provide evidence that the biological effects exhibited by nakiterpiosin are mechanistically distinct from those of well-established anti-mitotic agents such as taxol. Nakiterpiosin may be useful as an anti-cancer agent in those tumors resistant to existing anti-mitotic agents and those dependent on Hedgehog pathway responses for growth. PMID:20000429

  6. Lysosome-controlled efficient ROS overproduction against cancer cells with a high pH-responsive catalytic nanosystem

    NASA Astrophysics Data System (ADS)

    Fu, Jingke; Shao, Yiran; Wang, Liyao; Zhu, Yingchun

    2015-04-01

    Excess reactive oxygen species (ROS) have been proved to damage cancer cells efficiently. ROS overproduction is thus greatly desirable for cancer therapy. To date, ROS production is generally uncontrollable and outside cells, which always bring severe side-effects in the vasculature. Since most ROS share a very short half-life and primarily react close to their site of formation, it would be more efficient if excess ROS are controllably produced inside cancer cells. Herein, we report an efficient lysosome-controlled ROS overproduction via a pH-responsive catalytic nanosystem (FeOx-MSNs), which catalyze the decomposition of H2O2 to produce considerable ROS selectively inside the acidic lysosomes (pH 5.0) of cancer cells. After a further incorporation of ROS-sensitive TMB into the nanosystem (FeOx-MSNs-TMB), both a distinct cell labeling and an efficient death of breast carcinoma cells are obtained. This lysosome-controlled efficient ROS overproduction suggests promising applications in cancer treatments.Excess reactive oxygen species (ROS) have been proved to damage cancer cells efficiently. ROS overproduction is thus greatly desirable for cancer therapy. To date, ROS production is generally uncontrollable and outside cells, which always bring severe side-effects in the vasculature. Since most ROS share a very short half-life and primarily react close to their site of formation, it would be more efficient if excess ROS are controllably produced inside cancer cells. Herein, we report an efficient lysosome-controlled ROS overproduction via a pH-responsive catalytic nanosystem (FeOx-MSNs), which catalyze the decomposition of H2O2 to produce considerable ROS selectively inside the acidic lysosomes (pH 5.0) of cancer cells. After a further incorporation of ROS-sensitive TMB into the nanosystem (FeOx-MSNs-TMB), both a distinct cell labeling and an efficient death of breast carcinoma cells are obtained. This lysosome-controlled efficient ROS overproduction suggests

  7. Dose-Response Relationship between Inorganic Arsenic Exposure and Lung Cancer among Arseniasis Residents with Low Methylation Capacity.

    PubMed

    Hsu, Kuang-Hung; Tsui, Ke-Hung; Hsu, Ling-I; Chiou, Hung-Yi; Chen, Chien-Jen

    2017-05-01

    Background: Exposure to inorganic arsenic (InAs) has been documented as a risk factor for lung cancer. This study examined the association between InAs exposure, its metabolism, and lung cancer occurrence. Methods: We followed 1,300 residents from an arseniasis area in Taiwan, determined urinary InAs metabolites, and identified 39 lung cancer cases. Cox proportional hazards model was performed. Results: The results demonstrated that participants with either the primary methylation index [monomethylarsonic acid (MMA)/InAs] or the secondary methylation index [dimethylarsenic acid (DMA)/MMA] lower than their respective median values were at a higher risk of lung cancer (HRs from 3.41 to 4.66) than those with high methylation capacity. The incidence density of lung cancer increased from 79.9/100,000 (year -1 ) to 467.4/100,000 (year -1 ) for residents with low methylation capacity and from 0 to 158.5/100,000 (year -1 ) for residents with high methylation capacity when the arsenic exposure dose increased from 2 to 10 ppb to ≥200 ppb, respectively. The analyses revealed a dose-response relationship between lung cancer occurrence and increasing arsenic concentrations in drinking water as well as cumulative arsenic exposure (monotonic trend test; P < 0.05 and P < 0.05, respectively) among the residents with low methylation capacity. The relationship between arsenic exposure and lung cancer among high methylators was not statistically significant. Conclusions: Hypomethylation responses to InAs exposure may dose dependently increase lung cancer occurrence. Impact: The high-risk characteristics observed among those exposed should be considered in future preventive medicine and research on arsenic carcinogenesis. Cancer Epidemiol Biomarkers Prev; 26(5); 756-61. ©2016 AACR . ©2016 American Association for Cancer Research.

  8. Circulating leptin and inflammatory response in esophageal cancer, esophageal cancer-related cachexia-anorexia syndrome (CAS) and non-malignant CAS of the alimentary tract.

    PubMed

    Diakowska, Dorota; Krzystek-Korpacka, Malgorzata; Markocka-Maczka, Krystyna; Diakowski, Witold; Matusiewicz, Malgorzata; Grabowski, Krzysztof

    2010-08-01

    We investigated the association between esophageal cancer and cachexia-anorexia syndrome (CAS) of the alimentary tract and leptin, an adipocytokine crucial for body weight regulation, a modulator of inflammatory/immune response, implication of which in cancer and CAS development remains debatable. Circulating leptin was measured in 135 esophageal cancer patients (51 non-cachectic and 84 cachectic) and 83 controls (63 non-cachectic and 20 cachectic) and referred to cancer stage, CAS, and inflammatory and nutritional indices. Leptin was down-regulated in cancer patients and cachectic controls as compared to non-cachectic controls, with more pronounced hypoleptinemia in advanced cancers. Leptin correlated directly with BMI, TNF-alpha, albumin, and hemoglobin and indirectly with IL-6, IL-8, and hsCRP. The correlations, except for hsCRP, were more pronounced in females. BMI alone (females) and BMI and hsCRP (males) were independent predictors of leptin explaining over 60% of its variability. Following adjustment for BMI and gender, cancer-related CAS but not cancer itself negatively affected leptin. Leptin and BMI were independently associated with cancer-related and non-malignant CAS with diagnostic accuracy of 93% in identifying subjects with CAS. Pro-inflammatory, angiogenic and mitogenic properties of leptin do not seem to be important for esophageal cancer development but hypoleptinemia, independently from co-occurring reduction of adiposity, appears to be strongly associated with esophageal cancer-related CAS and non-malignant CAS of the alimentary tract. Copyright 2010 Elsevier Ltd. All rights reserved.

  9. Stimuli-responsive nanotherapeutics for precision drug delivery and cancer therapy.

    PubMed

    Qiao, Yiting; Wan, Jianqin; Zhou, Liqian; Ma, Wen; Yang, Yuanyuan; Luo, Weixuan; Yu, Zhiqiang; Wang, Hangxiang

    2018-05-04

    Cancer remains one of the world's leading causes of death. However, most conventional chemotherapeutic drugs only show a narrow therapeutic window in patients because of their inability to discriminate cancer cells from healthy cells. Nanoparticle-based therapeutics (termed nanotherapeutics) have emerged as potential solutions to mitigate many obstacles posed by these free drugs. Deep insights into knowledge of the tumor microenvironment and materials science make it possible to construct nanotherapeutics that are able to release cargoes in response to a variety of internal stimuli and external triggers. Therefore, such highly sophisticated nanosystems could help impede the premature release of toxic drugs in the blood circulation or healthy tissues, thus enhancing the safety profiles of encapsulated drugs. In this context, this review offers a comprehensive overview of several specific stimuli, including internal stimuli (e.g., pH, temperature, enzyme, redox, and H 2 O 2 ) and external stimuli (e.g., magnetic, photo, and ultrasound). We envision that applications of these smart nanotherapeutics can benefit cancer patients and provide a good chance for clinical translation of many nanoparticle formulas. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > in vitro Nanoparticle-Based Sensing. © 2018 Wiley Periodicals, Inc.

  10. Red and processed meat consumption and the risk of lung cancer: a dose-response meta-analysis of 33 published studies

    PubMed Central

    Xue, Xiu-Juan; Gao, Qing; Qiao, Jian-Hong; Zhang, Jie; Xu, Cui-Ping; Liu, Ju

    2014-01-01

    This meta-analysis was to summarize the published studies about the association between red/processed meat consumption and the risk of lung cancer. 5 databases were systematically reviewed, and random-effect model was used to pool the study results and to assess dose-response relationships. Results shown that six cohort studies and twenty eight case-control studies were included in this meat-analysis. The pooled Risk Radios (RR) for total red meat and processed meat were 1.44 (95% CI, 1.29-1.61) and 1.23 (95% CI, 1.10-1.37), respectively. Dose-response analysis revealed that for every increment of 120 grams red meat per day the risk of lung cancer increases 35% and for every increment of 50 grams red meat per day the risk of lung cancer increases 20%. The present dose-response meta-analysis suggested that both red and processed meat consumption showed a positive effect on lung cancer risk. PMID:25035778

  11. Nomograms Predicting Response to Therapy and Outcomes After Bladder-Preserving Trimodality Therapy for Muscle-Invasive Bladder Cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Coen, John J., E-mail: jcoen@harthosp.org; Paly, Jonathan J.; Niemierko, Andrzej

    2013-06-01

    Purpose: Selective bladder preservation by use of trimodality therapy is an established management strategy for muscle-invasive bladder cancer. Individual disease features have been associated with response to therapy, likelihood of bladder preservation, and disease-free survival. We developed prognostic nomograms to predict the complete response rate, disease-specific survival, and likelihood of remaining free of recurrent bladder cancer or cystectomy. Methods and Materials: From 1986 to 2009, 325 patients were managed with selective bladder preservation at Massachusetts General Hospital (MGH) and had complete data adequate for nomogram development. Treatment consisted of a transurethral resection of bladder tumor followed by split-course chemoradiation. Patientsmore » with a complete response at midtreatment cystoscopic assessment completed radiation, whereas those with a lesser response underwent a prompt cystectomy. Prognostic nomograms were constructed predicting complete response (CR), disease-specific survival (DSS), and bladder-intact disease-free survival (BI-DFS). BI-DFS was defined as the absence of local invasive or regional recurrence, distant metastasis, bladder cancer-related death, or radical cystectomy. Results: The final nomograms included information on clinical T stage, presence of hydronephrosis, whether a visibly complete transurethral resection of bladder tumor was performed, age, sex, and tumor grade. The predictive accuracy of these nomograms was assessed. For complete response, the area under the receiving operating characteristic curve was 0.69. The Harrell concordance index was 0.61 for both DSS and BI-DFS. Conclusions: Our nomograms allow individualized estimates of complete response, DSS, and BI-DFS. They may assist patients and clinicians making important treatment decisions.« less

  12. Glutathione responsive micelles incorporated with semiconducting polymer dots and doxorubicin for cancer photothermal-chemotherapy

    NASA Astrophysics Data System (ADS)

    Cai, Zhixiong; Zhang, Da; Lin, Xinyi; Chen, Yunzhu; Wu, Ming; Wei, Zuwu; Zhang, Zhenxi; Liu, Xiaolong; Yao, Cuiping

    2017-10-01

    Nanoplatform integrated with photothermal therapy (PTT) and chemotherapy has been recognized a promising agent for enhancing cancer therapeutic outcomes, but still suffer from less controllability for optimizing their synergistic effects. We fabricated glutathione (GSH) responsive micelles incorporated with semiconducting polymer dots and doxorubicin (referred as SPDOX NPs) for combining PTT with chemotherapy to enhance cancer therapeutic efficiency. These micelles, with excellent water dispersibility, comprises of three distinct functional components: (1) the monomethoxy-poly(ethylene glycol)-S-S-hexadecyl (mPEG-S-S-C16), which forms the micelles, can render hydrophobic substances water-soluble and improve the colloidal stability; (2) disulfide linkages can be cleaved in a reductive environment for tumor specific drug release due to the high GSH concentrations of tumor micro-environment; (3) PCPDTBT dots and anti-cancer drug DOX that are loaded inside the hydrophobic core of the micelle can be applied to simultaneously perform PTT and chemotherapy to achieve significantly enhanced tumor killing efficiency both in vitro and in vivo. In summary, our studies demonstrated that our SPDOX NPs with simultaneous photothermal-chemotherapy functions could be a promising platform for a tumor specific responsive drug delivery system.

  13. Immunological tumor status may predict response to neoadjuvant chemotherapy and outcome after radical cystectomy in bladder cancer.

    PubMed

    Tervahartiala, Minna; Taimen, Pekka; Mirtti, Tuomas; Koskinen, Ilmari; Ecke, Thorsten; Jalkanen, Sirpa; Boström, Peter J

    2017-10-04

    Bladder cancer (BC) is the ninth most common cancer worldwide. Radical cystectomy (RC) with neoadjuvant chemotherapy (NAC) is recommended for muscle-invasive BC. The challenge of the neoadjuvant approach relates to challenges in selection of patients to chemotherapy that are likely to respond to the treatment. To date, there are no validated molecular markers or baseline clinical characteristics to identify these patients. Different inflammatory markers, including tumor associated macrophages with their plastic pro-tumorigenic and anti-tumorigenic functions, have extensively been under interests as potential prognostic and predictive biomarkers in different cancer types. In this immunohistochemical study we evaluated the predictive roles of three immunological markers, CD68, MAC387, and CLEVER-1, in response to NAC and outcome of BC. 41% of the patients had a complete response (pT0N0) to NAC. Basic clinicopathological variables did not predict response to NAC. In contrast, MAC387 + cells and CLEVER-1 + macrophages associated with poor NAC response, while CLEVER-1 + vessels associated with more favourable response to NAC. Higher counts of CLEVER-1 + macrophages associated with poorer overall survival and CD68 + macrophages seem to have an independent prognostic value in BC patients treated with NAC. Our findings point out that CD68, MAC387, and CLEVER-1 may be useful prognostic and predictive markers in BC.

  14. Comprehensive Analysis of the Unfolded Protein Response in Breast Cancer Subtypes.

    PubMed

    Jiang, Dadi; Turner, Brandon; Song, Jie; Li, Ruijiang; Diehn, Maximilian; Le, Quynh-Thu; Khatri, Purvesh; Koong, Albert C

    2017-01-01

    Triple-negative breast cancers (TNBCs) are associated with a worse prognosis and patients with TNBC have fewer therapeutic options than patients with non-TNBC. Recently, the IRE1α-XBP1 branch of the unfolded protein response (UPR) was implicated in TNBC prognosis on the basis of a relatively small patient population, suggesting the diagnostic and therapeutic value of this pathway in TNBCs. In addition, the IRE1α-XBP1 and hypoxia-induced factor 1 α (HIF1α) pathways have been identified as interacting partners in TNBC, suggesting a novel mechanism of regulation. To comprehensively evaluate and validate these findings, we investigated the relative activities and relevance to patient survival of the UPR and HIF1α pathways in different breast cancer subtypes in large populations of patients. We performed a comprehensive analysis of gene expression and survival data from large cohorts of patients with breast cancer. The patients were stratified based on the average expression of the UPR or HIF1α gene signatures. We identified a strong positive association between the XBP1 gene signature and estrogen receptor-positive status or the HIF1α gene signature, as well as the predictive value of the XBP1 gene signature for survival of patients who are estrogen receptor negative, or have TNBC or HER2 + . In contrast, another important UPR branch, the ATF4/CHOP pathway, lacks prognostic value in breast cancer in general. Activity of the HIF1α pathway is correlated with patient survival in all the subtypes evaluated. These findings clarify the relevance of the UPR pathways in different breast cancer subtypes and underscore the potential therapeutic importance of the IRE1α-XBP1 branch in breast cancer treatment.

  15. Influence of Methylenetetrahydrofolate Reductase C677T Polymorphism on the Risk of Lung Cancer and the Clinical Response to Platinum-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer: An Updated Meta-Analysis

    PubMed Central

    Zhu, Ning; Gong, Yi; He, Jian; Xia, Jingwen

    2013-01-01

    Purpose Methylenetetrahydrofolate reductase (MTHFR) has been implicated in lung cancer risk and response to platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). However, the results are controversial. We performed meta-analysis to investigate the effect of MTHFR C677T polymorphism on lung cancer risk and response to platinum-based chemotherapy in advanced NSCLC. Materials and Methods The databases of PubMed, Ovid, Wanfang and Chinese Biomedicine were searched for eligible studies. Nineteen studies on MTHFR C677T polymorphism and lung cancer risk and three articles on C677T polymorphism and response to platinum-based chemotherapy in advanced NSCLC, were identified. Results The results indicated that the allelic contrast, homozygous contrast and recessive model of the MTHFR C677T polymorphism were associated significantly with increased lung cancer risk. In the subgroup analysis, the C677T polymorphism was significantly correlated with an increased risk of NSCLC, with the exception of the recessive model. The dominant model and the variant T allele showed a significant association with lung cancer susceptibility of ever smokers. Male TT homozygote carriers had a higher susceptibility, but the allelic contrast and homozygote model had a protective effect in females. No relationship was observed for SCLC in any comparison model. In addition, MTHFR 677TT homozygote carriers had a better response to platinum-based chemotherapy in advanced NSCLC in the recessive model. Conclusion The MTHFR C677T polymorphism might be a genetic marker for lung cancer risk or response to platinum-based chemotherapy in advanced NSCLC. However, our results require further verification. PMID:24142642

  16. Experimental Treatment of Prostate Cancer Models with Rh2, an Isolated Ginsenoside Compound

    DTIC Science & Technology

    2003-03-01

    ppendices ......................................................................................... 8 3 Annual Summary of Research Project...20%/- 0% 0 5 10 15 20 25 30 35 Days Figure 2. Body weight changes of nude mice in toxicology study Based on the findings of the acute toxicity study...test, pɘ.01 **). Key Research Accomplishments 1) Acute toxicity study showed that 4 weeks’ treatment with Rh2 (50 mg/kg p.o. 5 days/week) + Taxol (6

  17. Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer

    PubMed Central

    Knickelbein, Kyle; Zhang, Lin

    2014-01-01

    Mutations in the KRAS oncogene represent one of the most prevalent genetic alterations in colorectal cancer (CRC), the third leading cause of cancer-related death in the US. In addition to their well-characterized function in driving tumor progression, KRAS mutations have been recognized as a critical determinant of the therapeutic response of CRC. Recent studies demonstrate that KRAS-mutant tumors are intrinsically insensitive to clinically-used epidermal growth factor receptor (EGFR) targeting antibodies, including cetuximab and panitumumab. Acquired resistance to the anti-EGFR therapy was found to be associated with enrichment of KRAS-mutant tumor cells. However, the underlying molecular mechanism of mutant-KRAS-mediated therapeutic resistance has remained unclear. Despite intensive efforts, directly targeting mutant KRAS has been largely unsuccessful. This review summarizes the recent advances in understanding the biological function of KRAS mutations in determining the therapeutic response of CRC, highlighting several recently developed agents and strategies for targeting mutant KRAS, such as synthetic lethal interactions. PMID:25815366

  18. Raman spectroscopy identifies radiation response in human non-small cell lung cancer xenografts

    NASA Astrophysics Data System (ADS)

    Harder, Samantha J.; Isabelle, Martin; Devorkin, Lindsay; Smazynski, Julian; Beckham, Wayne; Brolo, Alexandre G.; Lum, Julian J.; Jirasek, Andrew

    2016-02-01

    External beam radiation therapy is a standard form of treatment for numerous cancers. Despite this, there are no approved methods to account for patient specific radiation sensitivity. In this report, Raman spectroscopy (RS) was used to identify radiation-induced biochemical changes in human non-small cell lung cancer xenografts. Chemometric analysis revealed unique radiation-related Raman signatures that were specific to nucleic acid, lipid, protein and carbohydrate spectral features. Among these changes was a dramatic shift in the accumulation of glycogen spectral bands for doses of 5 or 15 Gy when compared to unirradiated tumours. When spatial mapping was applied in this analysis there was considerable variability as we found substantial intra- and inter-tumour heterogeneity in the distribution of glycogen and other RS spectral features. Collectively, these data provide unique insight into the biochemical response of tumours, irradiated in vivo, and demonstrate the utility of RS for detecting distinct radiobiological responses in human tumour xenografts.

  19. Rapid response of breast cancer to neoadjuvant intramammary testosterone-anastrozole therapy: neoadjuvant hormone therapy in breast cancer.

    PubMed

    Glaser, Rebecca L; Dimitrakakis, Constantine

    2014-06-01

    Experimental and clinical data support the inhibitory effect of testosterone on breast tissue and breast cancer. However, testosterone is aromatized to estradiol, which exerts the opposite effect. The aim of this study was to determine the effect of testosterone, combined with the aromatase inhibitor anastrozole, on a hormone receptor positive, infiltrating ductal carcinoma in the neoadjuvant setting. To determine clinical response, we obtained serial ultrasonic measurements and mammograms before and after therapy. Three combination implants-each containing 60 mg of testosterone and 4 mg of anastrozole-were placed anterior, superior, and inferior to a 2.4-cm tumor in the left breast. Three additional testosterone-anastrozole implants were again placed peritumorally 48 days later. By day 46, there was a sevenfold reduction in tumor volume, as measured on ultrasound. By week 13, we documented a 12-fold reduction in tumor volume, demonstrating a rapid logarithmic response to intramammary testosterone-anastrozole implant therapy, equating to a daily response rate of 2.78% and a tumor half-life of 23 days. Therapeutic systemic levels of testosterone were achieved without elevation of estradiol, further demonstrating the efficacy of anastrozole combined with testosterone. This novel therapy, delivered in the neoadjuvant setting, has the potential to identify early responders and to evaluate the effectiveness of therapy in vivo. This may prove to be a new approach to both local and systemic therapies for breast cancer in subgroups of patients. In addition, it can be used to reduce tumor volume, allowing for less surgical intervention and better cosmetic oncoplastic results.

  20. Proteomic profiling reveals DNA damage, nucleolar and ribosomal stress are the main responses to oxaliplatin treatment in cancer cells.

    PubMed

    Ozdian, Tomas; Holub, Dusan; Maceckova, Zuzana; Varanasi, Lakshman; Rylova, Gabriela; Rehulka, Jiri; Vaclavkova, Jana; Slavik, Hanus; Moudry, Pavel; Znojek, Pawel; Stankova, Jarmila; de Sanctis, Juan Bautista; Hajduch, Marian; Dzubak, Petr

    2017-06-06

    Oxaliplatin is widely used to treat colorectal cancer in both palliative and adjuvant settings. It is also being tested for use in treating hematological, esophageal, biliary tract, pancreatic, gastric, and hepatocellular cancers. Despite its routine clinical use, little is known about the responses it induces in cancer cells. Therefore the whole-cell proteomics study was conducted to characterize the cellular response induced by oxaliplatin. Chemosensitive CCRF-CEM cells were treated with oxaliplatin at 29.3μM (5×IC 50 ) for 240min (half-time to caspase activation). The proteomes of un-/treated cells were then compared by high-resolution mass spectrometry, revealing 4049 proteins expressed over 3 biological replicates. Among these proteins, 76 were significantly downregulated and 31 significantly upregulated in at least two replicates. In agreement with the DNA-damaging effects of platinum drugs, proteins involved in DNA damage responses were present in both the upregulated and downregulated groups. The downregulated proteins were divided into three subgroups; i) centrosomal proteins, ii) RNA processing and iii) ribosomal proteins, which indicates nucleolar and ribosomal stress. In conclusion, our data supported by further validation experiments indicate the initial cellular response to oxaliplatin is the activation of DNA damage response, which in turn or in parallel triggers nucleolar and ribosomal stress. We have performed a whole-cell proteomic study of cellular response to oxaliplatin treatment, which is the drug predominantly used in the treatment of colorectal cancer. Compared to its predecessors, cisplatin and carboplatin, there is only a small fraction of studies dedicated to oxaliplatin. From those studies, most of them are focused on modification of treatment regimens or study of oxaliplatin in new cancer diagnoses. Cellular response hasn't been studied deeply and to our best knowledge, this is the first whole-cell proteomics study focused exclusively

  1. GLI1-mediated regulation of side population is responsible for drug resistance in gastric cancer

    PubMed Central

    Yu, Beiqin; Gu, Dongsheng; Zhang, Xiaoli; Li, Jianfang; Liu, Bingya; Xie, Jingwu

    2017-01-01

    Gastric cancer is the third leading cause of cancer-related mortality worldwide. Chemotherapy is frequently used for gastric cancer treatment. Most patients with advanced gastric cancer eventually succumb to the disease despite some patients responded initially to chemotherapy. Thus, identifying molecular mechanisms responsible for cancer relapse following chemotherapy will help design new ways to treat gastric cancer. In this study, we revealed that the residual cancer cells following treatment with chemotherapeutic reagent cisplatin have elevated expression of hedgehog target genes GLI1, GLI2 and PTCH1, suggestive of hedgehog signaling activation. We showed that GLI1 knockdown sensitized gastric cancer cells to CDDP whereas ectopic GLI1 expression decreased the sensitivity. Further analyses indicate elevated GLI1 expression is associated with an increase in tumor sphere formation, side population and cell surface markers for putative cancer stem cells. We have evidence to support that GLI1 is critical for maintenance of putative cancer stem cells through direct regulation of ABCG2. In fact, GLI1 protein was shown to be associated with the promoter fragment of ABCG2 through a Gli-binding consensus site in gastric cancer cells. Disruption of ABCG2 function, through ectopic expression of an ABCG2 dominant negative construct or a specific ABCG2 inhibitor, increased drug sensitivity of cancer cells both in culture and in mice. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high ABCG2 expression was associated with poor survival in the gastric cancer patients who underwent chemotherapy. Taken together, we have identified a molecular mechanism by which gastric cancer cells gain chemotherapy resistance. PMID:28404967

  2. Pre-treatment neutrophil to lymphocyte ratio as a predictive marker for pathological response to preoperative chemoradiotherapy in pancreatic cancer

    PubMed Central

    HASEGAWA, SHINICHIRO; EGUCHI, HIDETOSHI; TOMOKUNI, AKIRA; TOMIMARU, YOSHITO; ASAOKA, TADAFUMI; WADA, HIROSHI; HAMA, NAOKI; KAWAMOTO, KOICHI; KOBAYASHI, SHOGO; MARUBASHI, SHIGERU; KONNNO, MASAMITSU; ISHII, HIDESHI; MORI, MASAKI; DOKI, YUICHIRO; NAGANO, HIROAKI

    2016-01-01

    An elevated neutrophil to lymphocyte ratio (NLR) has been reported to be associated with the pathological response to neoadjuvant therapies in numerous types of cancer. The aim of the current study was to clarify the association between pre-treatment NLR and the pathological response to preoperative chemoradiotherapy in pancreatic cancer patients. This retrospective analysis included data from 56 consecutive patients whose tumors were completely surgically resected. All patients received preoperative therapy, consisting of gemcitabine-based chemotherapy (alone or in combination with S-1) combined with 40 or 50.4 Gy irradiation, prior to surgery. Predictive factors, including NLR, platelet to lymphocyte ratio (PLR), modified Glasgow prognostic score and prognostic nutrition index, were measured prior to treatment. A comparison was made between those who responded well pathologically (good response group, Evans classification IIb/III) and those with a poor response (Evans I/IIa). NLR was determined to be significantly higher in the poor response group. Multivariate analysis identified an elevated NLR as an independent risk factor for the poor pathological response [odds ratio (OR), 5.35; P=0.0257]. The pre-treatment NLR (≥2.2/<2.2) was found to be a statistically significant predictive indicator of pathological response (P=0.00699). The results demonstrate that pre-treatment NLR may be a useful predictive marker for the pathological response to preoperative therapy in pancreatic cancer patients. PMID:26893780

  3. Dynamic contrast-enhanced MR imaging pharmacokinetic parameters as predictors of treatment response of brain metastases in patients with lung cancer.

    PubMed

    Kuchcinski, Grégory; Le Rhun, Emilie; Cortot, Alexis B; Drumez, Elodie; Duhal, Romain; Lalisse, Maxime; Dumont, Julien; Lopes, Renaud; Pruvo, Jean-Pierre; Leclerc, Xavier; Delmaire, Christine

    2017-09-01

    To determine the diagnostic accuracy of pharmacokinetic parameters measured by dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in predicting the response of brain metastases to antineoplastic therapy in patients with lung cancer. Forty-four consecutive patients with lung cancer, harbouring 123 newly diagnosed brain metastases prospectively underwent conventional 3-T MRI at baseline (within 1 month before treatment), during the early (7-10 weeks) and midterm (5-7 months) post-treatment period. An additional DCE MRI sequence was performed during baseline and early post-treatment MRI to evaluate baseline pharmacokinetic parameters (K trans , k ep , v e , v p ) and their early variation (∆K trans , ∆k ep , ∆v e , ∆v p ). The objective response was judged by the volume variation of each metastasis from baseline to midterm MRI. ROC curve analysis determined the best DCE MRI parameter to predict the objective response. Baseline DCE MRI parameters were not associated with the objective response. Early ∆K trans , ∆v e and ∆v p were significantly associated with the objective response (p = 0.02, p = 0.001 and p = 0.02, respectively). The best predictor of objective response was ∆v e with an area under the curve of 0.93 [95% CI = 0.87, 0.99]. DCE MRI and early ∆v e may be a useful tool to predict the objective response of brain metastases in patients with lung cancer. • DCE MRI could predict the response of brain metastases from lung cancer • ∆v e was the best predictor of response • DCE MRI could be used to individualize patients' follow-up.

  4. Suppressive influences in the immune response to cancer.

    PubMed

    Bronte, Vincenzo; Mocellin, Simone

    2009-01-01

    Although much evidence has been gathered demonstrating that immune effectors can play a significant role in controlling tumor growth under natural conditions or in response to therapeutic manipulation, it is clear that malignant cells do evade immune surveillance in most cases. Considering that anticancer active specific immunotherapy seems to have reached a plateau of results and that currently no vaccination regimen is indicated as a standard anticancer therapy, the dissection of the molecular events underlying tumor immune escape is the necessary condition to make anticancer vaccines a therapeutic weapon effective enough to be implemented in the routine clinical setting. Recent years have witnessed significant advances in our understanding of the molecular mechanisms underlying tumor immune escape. These mechanistic insights are fostering the development of rationally designed therapeutics aimed to revert the immunosuppressive circuits that undermine an effective antitumor immune response. In this review, the best characterized mechanisms that allow cancer cells to evade immune surveillance are overviewed and the most debated controversies constellating this complex field are highlighted.

  5. New techniques for assessing response after hypofractionated radiotherapy for lung cancer

    PubMed Central

    Mattonen, Sarah A.; Huang, Kitty; Ward, Aaron D.; Senan, Suresh

    2014-01-01

    Hypofractionated radiotherapy (HFRT) is an effective and increasingly-used treatment for early stage non-small cell lung cancer (NSCLC). Stereotactic ablative radiotherapy (SABR) is a form of HFRT and delivers biologically effective doses (BEDs) in excess of 100 Gy10 in 3-8 fractions. Excellent long-term outcomes have been reported; however, response assessment following SABR is complicated as radiation induced lung injury can appear similar to a recurring tumor on CT. Current approaches to scoring treatment responses include Response Evaluation Criteria in Solid Tumors (RECIST) and positron emission tomography (PET), both of which appear to have a limited role in detecting recurrences following SABR. Novel approaches to assess response are required, but new techniques should be easily standardized across centers, cost effective, with sensitivity and specificity that improves on current CT and PET approaches. This review examines potential novel approaches, focusing on the emerging field of quantitative image feature analysis, to distinguish recurrence from fibrosis after SABR. PMID:24688782

  6. The Significance of the Stromal Response in Breast Cancer: An Immunohistochemical Study of Myofibroblasts in Primary and Metastatic Breast Cancer.

    PubMed

    Roozdar, Alale; Hayes, Malcolm M; Pourseyedei, Bahram; Zeinalinejad, Hamid; Shamsi Meymandi, Manzumeh; Dabiri, Bahram; Dabiri, Shahriar

    2018-05-01

    Gene expression profiling of breast cancer has demonstrated the importance of stromal response in determining the prognosis of invasive breast cancer. The host response to breast cancer is of increasing interest to pathologists and may be a future focus for novel pharmacological treatments. This study describes the pattern of distribution of stromal myofibroblasts using immunostains for CD10 and smooth muscle actin (SMA) in 50 primary breast cancers and their matched nodal metastases (68.6% nodes positive and 31.4% nodes negative). The stroma within the tumor (intratumoral) and at the advancing tumor edge (peri-tumoral) was studied in both primary and nodal sites. A simple quantitative scoring system was employed for both immunostains. The correlation between expression of these markers by stromal cells and standard pathological prognostic factors of stage, grade, hormone receptor and Her-2 status was analysed. SMA-positive stromal cells were more abundant in peri-tumoral stroma compared with intratumoral stroma in both primary and metastatic lesions. SMA expression in the lymph node metastases showed a significant correlation with tumor stage. SMA expression in peri-tumoral stroma correlated with Her-2 status. The results of this study suggest that myofibroblasts, particularly those expressing SMA, might potentiate the progression of the carcinomatous process especially in nodal metastases. Thus these cells may be a potential therapeutic target. © 2018 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

  7. Patient-derived ovarian cancer xenografts re-growing after a cisplatinum treatment are less responsive to a second drug re-challenge: a new experimental setting to study response to therapy.

    PubMed

    Ricci, Francesca; Fratelli, Maddalena; Guffanti, Federica; Porcu, Luca; Spriano, Filippo; Dell'Anna, Tiziana; Fruscio, Robert; Damia, Giovanna

    2017-01-31

    Even if ovarian cancer patients are very responsive to a cisplatinum-based therapy, most will relapse with a resistant disease. New experimental animal models are needed to explore the mechanisms of resistance, to better tailor treatment and improve patient prognosis. To address these aims, seven patient-derived high-grade serous/endometrioid ovarian cancer xenografts were characterized for the antitumor response after one and two cycles of cisplatinum and classified as Very Responsive, Responsive, and Low Responsive to drug treatment. Xenografts re-growing after the first drug cycle were much less responsive to the second one. The expression of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) genes was investigated in cisplatinum-treated and not-treated tumors. We found that different EMT (TCF3, CAMK2N1, EGFR, and IGFBP4) and CSCs (SMO, DLL1, STAT3, and ITGA6) genes were expressed at higher levels in Low Responsive than in Responsive and Very Responsive xenografts. The expression of STAT3 was found to be associated with lower survival (HR = 13.7; p = 0.013) in the TCGA patient data set. MMP9, CD44, DLL4, FOXP1, MERTK, and PTPRC genes were found more expressed in tumors re-growing after cisplatinum treatment than in untreated tumors. We here describe a new in vivo ovarian carcinoma experimental setting that will be instrumental for specific trials of combination therapy to counteract cisplatinum resistance in order to improve the prognosis of ovarian patients.

  8. Genomics, microRNA, epigenetics, and proteomics for future diagnosis, treatment and monitoring response in upper GI cancers.

    PubMed

    Brücher, Björn L D M; Li, Yan; Schnabel, Philipp; Daumer, Martin; Wallace, Timothy J; Kube, Rainer; Zilberstein, Bruno; Steele, Scott; Voskuil, Jan L A; Jamall, Ijaz S

    2016-03-01

    One major objective for our evolving understanding in the treatment of cancers will be to address how a combination of diagnosis and treatment strategies can be used to integrate patient and tumor variables with an outcome-oriented approach. Such an approach, in a multimodal therapy setting, could identify those patients (1) who should undergo a defined treatment (personalized therapy) (2) in whom modifications of the multimodal therapy due to observed responses might lead to an improvement of the response and/or prognosis (individualized therapy), (3) who might not benefit from a particular toxic treatment regimen, and (4) who could be identified early on and thereby be spared the morbidity associated with such treatments. These strategies could lead in the direction of precision medicine and there is hope of integrating translational molecular data to improve cancer classifications. In order to achieve these goals, it is necessary to understand the key issues in different aspects of biotechnology to anticipate future directions of personalized and individualized diagnosis and multimodal treatment strategies. Providing an overview of translational data in cancers proved to be a challenge as different methods and techniques used to obtain molecular data are used and studies are based on different tumor entities with different tumor biology and prognoses as well as vastly different therapeutic approaches. The pros and cons of the available methodologies and the potential response data in genomics, microRNA, epigenetics and proteomics with a focus on upper gastrointestinal cancers are considered herein to allow for an understanding of where these technologies stand with respect to cancer diagnosis, prognosis and treatment.

  9. Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer

    PubMed Central

    Cook, Katherine L.; Wärri, Anni; Soto-Pantoja, David R.; Clarke, Pamela A.G.; Cruz, M. Idalia; Zwart, Alan; Clarke, Robert

    2014-01-01

    Purpose Estrogen receptor-α (ERα) targeted therapies including tamoxifen (TAM) or Faslodex (ICI) are used to treat ER+ breast cancers. Up to 50% of tumors will acquire resistance to these interventions. Autophagy has been implicated as a major driver of antiestrogen resistance. We have explored the ability of hydroxychloroquine (HCQ), which inhibits autophagy, to affect antiestrogen responsiveness. Experimental Design TAM-resistant MCF7-RR and ICI-resistant/TAM cross-resistant LCC9 ER+ breast cancer cells were injected into mammary fat pads of female athymic mice and treated with TAM and/or ICI in combination with oral low-dose HCQ. Results We show HCQ can increase antiestrogen responsiveness in MCF7-RR and LCC9 cells and tumors, likely through the inhibition of autophagy. However, the combination of ICI+HCQ was less effective than HCQ alone in vivo, unlike the TAM+HCQ combination. Antiestrogen treatment stimulated angiogenesis in tumors but did not prevent HCQ effectiveness. The lower efficacy of ICI+HCQ was associated with ICI effects on cell-mediated immunity within the tumor microenvironment. The mouse chemokine KC (CXCL1) and IFNγ were differentially regulated by both TAM and ICI treatments, suggesting a possible effect on macrophage development/activity. Consistent with these observations, TAM+HCQ treatment increased tumor CD68+ cells infiltration, whereas ICI and ICI+HCQ reduced peripheral tumor macrophage content. Moreover, macrophage elimination of breast cancer target cells in vitro was reduced following exposure to ICI. Conclusion HCQ restores antiestrogen sensitivity to resistant tumors. Moreover, the beneficial combination of TAM+HCQ suggests a positive outcome for ongoing neoadjuvant clinical trials using this combination for the treatment of ER+ ductal carcinoma in situ lesions. PMID:24928945

  10. Identifying patterns of adaptation in breast cancer patients with cancer-related fatigue using response shift analyses at subgroup level.

    PubMed

    Salmon, Maxime; Blanchin, Myriam; Rotonda, Christine; Guillemin, Francis; Sébille, Véronique

    2017-11-01

    Fatigue is the most prevalent symptom in breast cancer. It might be perceived differently among patients over time as a consequence of the differing patients' adaptation and psychological adjustment to their cancer experience which can be related to response shift (RS). RS analyses can provide important insights on patients' adaptation to cancer but it is usually assumed that RS occurs in the same way in all individuals which is unrealistic. This study aimed to identify patients' subgroups in which different RS effects on self-reported fatigue could occur over time using a combination of methods for manifest and latent variables. The FATSEIN study comprised 466 breast cancer patients followed over a 2-year period. Fatigue was measured with the Multidimensional Fatigue Inventory questionnaire (MFI-20) during 10 visits. A novel combination of Mixed Models, Growth Mixture Modeling, and Structural Equation Modeling was used to assess the occurrence of RS in fatigue changes to identify subgroups displaying different RS patterns over time. An increase in fatigue was evidenced over the 8-month follow-up, followed by a decrease between the 8- and 24-month. Four latent classes of patients were identified. Different RS patterns were detected in all latent classes between the inclusion and 8 months (last cycle of chemotherapy). No RS was evidenced between 8- and 24-month. Several RS effects were evidenced in different groups of patients. Women seemed to adapt differently to their treatment and breast cancer experience possibly indicating differing needs for medical/psychological support. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  11. Availability of the key metabolic substrates dictates the respiratory response of cancer cells to the mitochondrial uncoupling.

    PubMed

    Zhdanov, Alexander V; Waters, Alicia H C; Golubeva, Anna V; Dmitriev, Ruslan I; Papkovsky, Dmitri B

    2014-01-01

    Active glycolysis and glutaminolysis provide bioenergetic stability of cancer cells in physiological conditions. Under hypoxia, metabolic and mitochondrial disorders, or pharmacological treatment, a deficit of key metabolic substrates may become life-threatening to cancer cells. We analysed the effects of mitochondrial uncoupling by FCCP on the respiration of cells fed by different combinations of Glc, Gal, Gln and Pyr. In cancer PC12 and HCT116 cells, a large increase in O2 consumption rate (OCR) upon uncoupling was only seen when Gln was combined with either Glc or Pyr. Inhibition of glutaminolysis with BPTES abolished this effect. Despite the key role of Gln, addition of FCCP inhibited respiration and induced apoptosis in cells supplied with Gln alone or Gal/Gln. For all substrate combinations, amplitude of respiratory responses to FCCP did not correlate with Akt, Erk and AMPK phosphorylation, cellular ATP, and resting OCR, mitochondrial Ca(2+) or membrane potential. However, we propose that proton motive force could modulate respiratory response to FCCP by regulating mitochondrial transport of Gln and Pyr, which decreases upon mitochondrial depolarisation. As a result, an increase in respiration upon uncoupling is abolished in cells, deprived of Gln or Pyr (Glc). Unlike PC12 or HCT116 cells, mouse embryonic fibroblasts were capable of generating pronounced response to FCCP when deprived of Gln, thus exhibiting lower dependence on glutaminolysis. Overall, the differential regulation of the respiratory response to FCCP by metabolic environment suggests that mitochondrial uncoupling has a potential for substrate-specific inhibition of cell function, and can be explored for selective cancer treatment. © 2013.

  12. A smart drug: a pH-responsive photothermal ablation agent for Golgi apparatus activated cancer therapy.

    PubMed

    Xue, Fengfeng; Wen, Ying; Wei, Peng; Gao, Yilin; Zhou, Zhiguo; Xiao, Shuzhang; Yi, Tao

    2017-06-13

    We report a pH-responsive photothermal ablation agent (pH-PTT) based on cyanine dyes for photothermal therapy (PTT). The nanoparticles formed by BSA and pH-PTT preferentially accumulated in the Golgi apparatus of cancer cells compared to normal cells, and thus can be specifically activated by the acidic Golgi apparatus in cancer cells for effective PTT both ex vivo and in vivo.

  13. T cell Bim levels reflect responses to anti–PD-1 cancer therapy

    PubMed Central

    Dronca, Roxana S.; Liu, Xin; Harrington, Susan M.; Chen, Lingling; Cao, Siyu; Kottschade, Lisa A.; McWilliams, Robert R.; Block, Matthew S.; Nevala, Wendy K.; Thompson, Michael A.; Mansfield, Aaron S.; Park, Sean S.; Markovic, Svetomir N.

    2016-01-01

    Immune checkpoint therapy with PD-1 blockade has emerged as an effective therapy for many advanced cancers; however, only a small fraction of patients achieve durable responses. To date, there is no validated blood-based means of predicting the response to PD-1 blockade. We report that Bim is a downstream signaling molecule of the PD-1 pathway, and its detection in T cells is significantly associated with expression of PD-1 and effector T cell markers. High levels of Bim in circulating tumor-reactive (PD-1+CD11ahiCD8+) T cells were prognostic of poor survival in patients with metastatic melanoma who did not receive anti–PD-1 therapy and were also predictive of clinical benefit in patients with metastatic melanoma who were treated with anti–PD-1 therapy. Moreover, this circulating tumor-reactive T cell population significantly decreased after successful anti–PD-1 therapy. Our study supports a crucial role of Bim in both T cell activation and apoptosis as regulated by PD-1 and PD-L1 interactions in effector CD8+ T cells. Measurement of Bim levels in circulating T cells of patients with cancer may provide a less invasive strategy to predict and monitor responses to anti–PD-1 therapy, although future prospective analyses are needed to validate its utility. PMID:27182556

  14. Machine learning for predicting the response of breast cancer to neoadjuvant chemotherapy

    PubMed Central

    Mani, Subramani; Chen, Yukun; Li, Xia; Arlinghaus, Lori; Chakravarthy, A Bapsi; Abramson, Vandana; Bhave, Sandeep R; Levy, Mia A; Xu, Hua; Yankeelov, Thomas E

    2013-01-01

    Objective To employ machine learning methods to predict the eventual therapeutic response of breast cancer patients after a single cycle of neoadjuvant chemotherapy (NAC). Materials and methods Quantitative dynamic contrast-enhanced MRI and diffusion-weighted MRI data were acquired on 28 patients before and after one cycle of NAC. A total of 118 semiquantitative and quantitative parameters were derived from these data and combined with 11 clinical variables. We used Bayesian logistic regression in combination with feature selection using a machine learning framework for predictive model building. Results The best predictive models using feature selection obtained an area under the curve of 0.86 and an accuracy of 0.86, with a sensitivity of 0.88 and a specificity of 0.82. Discussion With the numerous options for NAC available, development of a method to predict response early in the course of therapy is needed. Unfortunately, by the time most patients are found not to be responding, their disease may no longer be surgically resectable, and this situation could be avoided by the development of techniques to assess response earlier in the treatment regimen. The method outlined here is one possible solution to this important clinical problem. Conclusions Predictive modeling approaches based on machine learning using readily available clinical and quantitative MRI data show promise in distinguishing breast cancer responders from non-responders after the first cycle of NAC. PMID:23616206

  15. MYC Amplification as a Predictive Factor of Complete Pathologic Response to Docetaxel-based Neoadjuvant Chemotherapy for Breast Cancer.

    PubMed

    Pereira, Cynthia Brito Lins; Leal, Mariana Ferreira; Abdelhay, Eliana Saul Furquim Werneck; Demachki, Sâmia; Assumpção, Paulo Pimentel; de Souza, Mirian Carvalho; Moreira-Nunes, Caroline Aquino; Tanaka, Adriana Michiko da Silva; Smith, Marília Cardoso; Burbano, Rommel Rodríguez

    2017-06-01

    Neoadjuvant chemotherapy is a standard treatment for stage II and III breast cancer. The identification of biomarkers that may help in the prediction of response to neoadjuvant therapies is necessary for a more precise definition of the best drug or drug combination to induce a better response. We assessed the role of Ki67, hormone receptors expression, HER2, MYC genes and their protein status, and KRAS codon 12 mutations as predictor factors of pathologic response to anthracycline-cyclophosphamide (AC) followed by taxane docetaxel (T) neoadjuvant chemotherapy (AC+T regimen) in 51 patients with invasive ductal breast cancer. After neoadjuvant chemotherapy, 82.4% of patients showed pathologic partial response, with only 9.8% showing pathologic complete response. In multivariate analysis, MYC immunoreactivity and high MYC gain defined as MYC/nucleus ≥ 5 were significant predictor factors for pathologic partial response. Using the receiver operating characteristic curve analysis, the ratio of 2.5 MYC/CEP8 (sensitivity of 80% and specificity of 89.1%) or 7 MYC/nuclei copies (sensitivity of 80% and specificity of 73.9%) as the best cutoff in predicting a pathologic complete response was identified. Thus, MYC may have a role in chemosensitivity to AC and/or docetaxel drugs. Additionally, MYC amplification may be a predictor factor of pathologic response to the AC+T regimen in patients with breast cancer. Moreover, patients with an increased number of MYC copies showed pathologic complete response to this neoadjuvant treatment more frequently. The analysis of MYC amplification may help in the identification of patients that may have a better response to AC+T treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Role of genetic polymorphisms in NFKB-mediated inflammatory pathways in response to primary chemoradiation therapy for rectal cancer.

    PubMed

    Dzhugashvili, Maia; Luengo-Gil, Ginés; García, Teresa; González-Conejero, Rocío; Conesa-Zamora, Pablo; Escolar, Pedro Pablo; Calvo, Felipe; Vicente, Vicente; Ayala de la Peña, Francisco

    2014-11-01

    To investigate whether polymorphisms of genes related to inflammation are associated with pathologic response (primary endpoint) in patients with rectal cancer treated with primary chemoradiation therapy (PCRT). Genomic DNA of 159 patients with locally advanced rectal cancer treated with PCRT was genotyped for polymorphisms rs28362491 (NFKB1), rs1213266/rs5789 (PTGS1), rs5275 (PTGS2), and rs16944/rs1143627 (IL1B) using TaqMan single nucleotide polymorphism genotyping assays. The association between each genotype and pathologic response (poor response vs complete or partial response) was analyzed using logistic regression models. The NFKB1 DEL/DEL genotype was associated with pathologic response (odds ratio [OR], 6.39; 95% confidence interval [CI], 0.78-52.65; P=.03) after PCRT. No statistically significant associations between other polymorphisms and response to PCRT were observed. Patients with the NFKB1 DEL/DEL genotype showed a trend for longer disease-free survival (log-rank test, P=.096) and overall survival (P=.049), which was not significant in a multivariate analysis that included pathologic response. Analysis for 6 polymorphisms showed that patients carrying the haplotype rs28362491-DEL/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G (13.7% of cases) had a higher response rate to PCRT (OR, 8.86; 95% CI, 1.21-64.98; P=.034) than the reference group (rs28362491-INS/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G). Clinically significant (grade ≥2) acute organ toxicity was also more frequent in patients with that same haplotype (OR, 4.12; 95% CI, 1.11-15.36; P=.037). Our results suggest that genetic variation in NFKB-related inflammatory pathways might influence sensitivity to primary chemoradiation for rectal cancer. If confirmed, an inflammation-related radiogenetic profile might be used to select patients with rectal cancer for preoperative combined-modality treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Is adjuvant chemotherapy of benefit for postmenopausal women who receive endocrine treatment for highly endocrine-responsive, node-positive breast cancer? International Breast Cancer Study Group Trials VII and 12-93.

    PubMed

    Pagani, Olivia; Gelber, Shari; Simoncini, Edda; Castiglione-Gertsch, Monica; Price, Karen N; Gelber, Richard D; Holmberg, Stig B; Crivellari, Diana; Collins, John; Lindtner, Jurij; Thürlimann, Beat; Fey, Martin F; Murray, Elizabeth; Forbes, John F; Coates, Alan S; Goldhirsch, Aron

    2009-08-01

    To compare the efficacy of chemoendocrine treatment with that of endocrine treatment (ET) alone for postmenopausal women with highly endocrine responsive breast cancer. In the International Breast Cancer Study Group (IBCSG) Trials VII and 12-93, postmenopausal women with node-positive, estrogen receptor (ER)-positive or ER-negative, operable breast cancer were randomized to receive either chemotherapy or endocrine therapy or combined chemoendocrine treatment. Results were analyzed overall in the cohort of 893 patients with endocrine-responsive disease, and according to prospectively defined categories of ER, age and nodal status. STEPP analyses assessed chemotherapy effect. The median follow-up was 13 years. Adding chemotherapy reduced the relative risk of a disease-free survival event by 19% (P = 0.02) compared with ET alone. STEPP analyses showed little effect of chemotherapy for tumors with high levels of ER expression (P = 0.07), or for the cohort with one positive node (P = 0.03). Chemotherapy significantly improves disease-free survival for postmenopausal women with endocrine-responsive breast cancer, but the magnitude of the effect is substantially attenuated if ER levels are high.

  18. miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer.

    PubMed

    Corcoran, Claire; Rani, Sweta; Breslin, Susan; Gogarty, Martina; Ghobrial, Irene M; Crown, John; O'Driscoll, Lorraine

    2014-03-24

    While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. We investigated the levels of intra- and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate- or acquired- resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630's regulation of mRNA, proteins and their phosphorylated forms. We established that introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630's regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells

  19. EDA-Fibronectin Originating from Osteoblasts Inhibits the Immune Response against Cancer

    PubMed Central

    Rossnagl, Stephanie; Altrock, Eva; Sens, Carla; Kraft, Sabrina; Rau, Katrin; Giese, Thomas; Samstag, Yvonne; Nakchbandi, Inaam A.

    2016-01-01

    Osteoblasts lining the inner surface of bone support hematopoietic stem cell differentiation by virtue of proximity to the bone marrow. The osteoblasts also modify their own differentiation by producing various isoforms of fibronectin (FN). Despite evidence for immune regulation by osteoblasts, there is limited knowledge of how osteoblasts modulate cells of the immune system. Here, we show that extra domain A (EDA)-FN produced by osteoblasts increases arginase production in myeloid-derived cells, and we identify α5β1 as the mediating receptor. In different mouse models of cancer, osteoblasts or EDA-FN was found to up-regulate arginase-1 expression in myeloid-derived cells, resulting in increased cancer growth. This harmful effect can be reduced by interfering with the integrin α5β1 receptor or inhibiting arginase. Conversely, in tissue injury, the expression of arginase-1 is normally beneficial as it dampens the immune response to allow wound healing. We show that EDA-FN protects against excessive fibrotic tissue formation in a liver fibrosis model. Our results establish an immune regulatory function for EDA-FN originating from the osteoblasts and identify new avenues for enhancing the immune reaction against cancer. PMID:27653627

  20. A meta-analysis including dose-response relationship between night shift work and the risk of colorectal cancer

    PubMed Central

    Wang, Xiao; Ji, Alin; Zhu, Yi; Liang, Zhen; Wu, Jian; Li, Shiqi; Meng, Shuai; Zheng, Xiangyi; Xie, Liping

    2015-01-01

    A meta-analysis was conducted to quantitatively evaluate the correlation between night shift work and the risk of colorectal cancer. We searched for publications up to March 2015 using PubMed, Web of Science, Cochrane Library, EMBASE and the Chinese National Knowledge Infrastructure databases, and the references of the retrieved articles and relevant reviews were also checked. OR and 95% CI were used to assess the degree of the correlation between night shift work and risk of colorectal cancer via fixed- or random-effect models. A dose-response meta-analysis was performed as well. The pooled OR estimates of the included studies illustrated that night shift work was correlated with an increased risk of colorectal cancer (OR = 1.318, 95% CI 1.121–1.551). No evidence of publication bias was detected. In the dose-response analysis, the rate of colorectal cancer increased by 11% for every 5 years increased in night shift work (OR = 1.11, 95% CI 1.03–1.20). In conclusion, this meta-analysis indicated that night shift work was associated with an increased risk of colorectal cancer. Further researches should be conducted to confirm our findings and clarify the potential biological mechanisms. PMID:26208480

  1. Advancing Social Workers' Responsiveness to Health Disparities: The Case of Breast Cancer Screening

    ERIC Educational Resources Information Center

    Altpeter, Mary; Mitchell, James F.; Pennell, Joan

    2005-01-01

    This study provides the basis for customizing culturally responsive social work health promotion programs aimed at eliminating breast cancer screening and mortality disparities between white and African American women. Survey data collected from a random sample of 853 women in rural North Carolina were used to explore the impact of psychosocial…

  2. Semiquantitative visual approach to scoring lung cancer treatment response using computed tomography: a pilot study.

    PubMed

    Gottlieb, Ronald H; Kumar, Prasanna; Loud, Peter; Klippenstein, Donald; Raczyk, Cheryl; Tan, Wei; Lu, Jenny; Ramnath, Nithya

    2009-01-01

    Our objective was to compare a newly developed semiquantitative visual scoring (SVS) method with the current standard, the Response Evaluation Criteria in Solid Tumors (RECIST) method, in the categorization of treatment response and reader agreement for patients with metastatic lung cancer followed by computed tomography. The 18 subjects (5 women and 13 men; mean age, 62.8 years) were from an institutional review board-approved phase 2 study that evaluated a second-line chemotherapy regimen for metastatic (stages III and IV) non-small cell lung cancer. Four radiologists, blinded to the patient outcome and each other's reads, evaluated the change in the patients' tumor burden from the baseline to the first restaging computed tomographic scan using either the RECIST or the SVS method. We compared the numbers of patients placed into the partial response, the stable disease (SD), and the progressive disease (PD) categories (Fisher exact test) and observer agreement (kappa statistic). Requiring the concordance of 3 of the 4 readers resulted in the RECIST placing 17 (100%) of 17 patients in the SD category compared with the SVS placing 9 (60%) of 15 patients in the partial response, 5 (33%) of the 15 patients in the SD, and 1 (6.7%) of the 15 patients in the PD categories (P < 0.0001). Interobserver agreement was higher among the readers using the SVS method (kappa, 0.54; P < 0.0001) compared with that of the readers using the RECIST method (kappa, -0.01; P = 0.5378). Using the SVS method, the readers more finely discriminated between the patient response categories with superior agreement compared with the RECIST method, which could potentially result in large differences in early treatment decisions for advanced lung cancer.

  3. Characterization of Pancreatic Cancer Cell Thermal Response to Heat Ablation or Cryoablation.

    PubMed

    Baumann, Kenneth W; Baust, John M; Snyder, Kristi K; Baust, John G; Van Buskirk, Robert G

    2017-08-01

    One of the most lethal carcinomas is pancreatic cancer. As standard treatment using chemotherapy and radiation has shown limited success, thermal regimens (cryotherapy or heat ablation) are emerging as viable alternatives. Although promising, our understanding of pancreatic cancer response to thermal ablation remains limited. In this study, we investigated the thermal responses of 2 pancreatic cancer cell lines in an effort to identify the minimum lethal temperature needed for complete cell death to provide guidance for in vivo applications. PANC-1 and BxPC-3 were frozen (-10°C to -25°C) or heated (45°C-50°C) in single and repeated exposure regimes. Posttreatment survival and recovery were analyzed using alamarBlue assay over a 7-day interval. Modes of cell death were assessed using fluorescence microscopy (calcein acetoxymethyl ester/propidium iodide) and flow cytometry (YO-PRO-1/propidium iodide). Freezing to -10°C resulted in minimal cell death. Exposure to -15°C had a mild impact on PANC-1 survival (93%), whereas BxPC-3 was more severely damaged (33%). Exposure to -20°C caused a significant reduction in viability (PANC-1 = 23%; BxPC-3 = 2%) whereas -25°C yielded complete death. Double freezing exposure was more effective than single exposure. Repeat exposure to -15°C resulted in complete death of BxPC-3, whereas -20°C severely impacted PANC-1 (7%). Heating to 45°C resulted in minimum cell death. Exposure to 48°C yielded a slight increase in cell loss (PANC-1 = 85%; BxPC-3 = 98%). Exposure to 50°C caused a significant decline (PANC-1 = 70%; BxPC-3 = 9%) with continued deterioration to 0%. Double heating to 45°C resulted in similar effects observed in single exposures, whereas repeated 48°C resulted in significant increases in cell death (PANC-1 = 68%; BxPC-3 = 29%). In conclusion, we observed that pancreatic cancer cells were completely destroyed at temperatures <-25°C or >50°C using single thermal exposures. Repeated exposures resulted in

  4. Evaluation of Radiation Response and Gold Nanoparticle Enhancement in Drug-Resistant Pancreatic Cancer Cells

    NASA Astrophysics Data System (ADS)

    Abourabia, Assya

    Pancreatic cancer is a major cause of cancer-related death worldwide after lung cancer and colorectal cancer Pancreatic treatment modalities consist of surgery, chemotherapy, and radiation therapy or combination of these therapies. These modalities are good to some extents but they do have some limitations. For example, during the chemotherapy, tumor cells can develop some escape mechanisms and become chemoresistant to protect themselves against the chemo drugs and pass on theses escape mechanisms to their offspring, despite the treatment given. Cancer Cells can become chemoresistant by many mechanisms, for example, decreased drug influx mechanisms, decreased of drug transport molecules, decreased drug activation, altered drug metabolism that diminishes the capacity of cytotoxic drugs, and enhanced repair of DNA damage. Given that some of these chemoresistance mechanisms may impact sensitivity to radiation. Therefore, there is a strong need for a new alternative treatment option to amplify the therapeutic efficacy of radiotherapy and eventually increase the overall efficacy of cancer treatment. Nano-radiation therapy is an emerging and promising modality aims to enhance the therapeutic efficacy of radiotherapy through the use of radiosensitizing nanoparticles. The primary goal of using GNP-enhanced radiation is that GNPs are potent radiosensitizer agents that sensitize the tumor cells to radiation, and these agents promote generation of the free radicals produced by Photo- and Auger- electrons emission at the molecular level which can enhance the effectiveness of radiation-induced cancer cell death. The main aim of this research is to analyze and compare the response to radiation of pancreatic cancer cells, PANC-1, and PANC-1 cells that are resistant to oxaliplatin, PANC-1/OR, and investigate the radiation dose enhancement effect attributable to GNP when irradiating the cells with low-energy (220 kVp) beam at various doses. Based on evidence from the existing

  5. Oncolytic Adenovirus With Temozolomide Induces Autophagy and Antitumor Immune Responses in Cancer Patients

    PubMed Central

    Liikanen, Ilkka; Ahtiainen, Laura; Hirvinen, Mari LM; Bramante, Simona; Cerullo, Vincenzo; Nokisalmi, Petri; Hemminki, Otto; Diaconu, Iulia; Pesonen, Sari; Koski, Anniina; Kangasniemi, Lotta; Pesonen, Saila K; Oksanen, Minna; Laasonen, Leena; Partanen, Kaarina; Joensuu, Timo; Zhao, Fang; Kanerva, Anna; Hemminki, Akseli

    2013-01-01

    Oncolytic adenoviruses and certain chemotherapeutics can induce autophagy and immunogenic cancer cell death. We hypothesized that the combination of oncolytic adenovirus with low-dose temozolomide (TMZ) is safe, effective, and capable of inducing antitumor immune responses. Metronomic low-dose cyclophosphamide (CP) was added to selectively reduce regulatory T-cells. Preclinically, combination therapy inhibited tumor growth, increased autophagy, and triggered immunogenic cell death as indicated by elevated calreticulin, adenosine triphosphate (ATP) release, and nuclear protein high-mobility group box-1 (HMGB1) secretion. A total of 41 combination treatments given to 17 chemotherapy-refractory cancer patients were well tolerated. We observed anti- and proinflammatory cytokine release, evidence of virus replication, and induction of neutralizing antibodies. Tumor cells showed increased autophagy post-treatment. Release of HMGB1 into serum—a possible indicator of immune response—increased in 60% of treatments, and seemed to correlate with tumor-specific T-cell responses, observed in 10/15 cases overall (P = 0.0833). Evidence of antitumor efficacy was seen in 67% of evaluable treatments with a trend for increased survival over matched controls treated with virus only. In summary, the combination of oncolytic adenovirus with low-dose TMZ and metronomic CP increased tumor cell autophagy, elicited antitumor immune responses, and showed promising safety and efficacy. PMID:23546299

  6. Cancer patients' expressions of emotional cues and concerns and oncology nurses' responses, in an online patient-nurse communication service.

    PubMed

    Grimsbø, Gro Hjelmeland; Ruland, Cornelia M; Finset, Arnstein

    2012-07-01

    To (1) investigate emotional cues and concerns (C&C) of cancer patients expressed in e-mail communication with oncology nurses in an online patient-nurse communication service (OPNC), and (2) explore how nurses responded to patients' C&C. 283 e-messages sent from 38 breast and 22 prostate cancer patients and 286 e-responses from five oncology nurses were coded with the Verona Coding Definitions of Emotional Sequences. We identified 102 cues and 33 concerns expressed in patients' messages. Cues indicating expression of uncertainty or hope, occurred most frequently (in 38.5% of messages), followed by concerns (in 24.4% of messages). Nurses responded to 85.2% of patients' C&Cs; more than half of patients' C&Cs were met with a mixture of information giving and empathic responses. Patients with breast and prostate cancer express many C&C in e-mail communications with oncology nurses, who demonstrated satisfactory sensitivity to patients' emotions in their responses to patients. Offering e-communication with oncology nurses to cancer patients is a promising and feasible supplement to usual care to address and relieve patients' concerns and emotional distress during illness and recovery. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  7. p53 and PCNA expression in advanced colorectal cancer: response to chemotherapy and long-term prognosis.

    PubMed

    Paradiso, A; Rabinovich, M; Vallejo, C; Machiavelli, M; Romero, A; Perez, J; Lacava, J; Cuevas, M A; Rodriquez, R; Leone, B; Sapia, M G; Simone, G; De Lena, M

    1996-12-20

    In a series of 71 patients with advanced colorectal cancer treated with biochemically modulated 5-fluorouracil (5-FU) and methotrexate (MTX), we investigated the relationship between the proliferating-cell nuclear antigen (PCNA) (PC10) and p53 (Pab1801) primary-tumor immunohistochemical expression with respect to clinical response and long-term prognosis. Nuclear p53 expression was demonstrated in 44% of samples (any number of positive tumor cells) while all tumors showed a certain degree of PCNA immunostaining. PCNA immunostaining was correlated with histopathologic grade and p53 expression, while p53 was not correlated with any of the parameters considered. The probability of clinical response to biochemically modulated 5-FU was independent of p53 and PCNA expression. p53 expression (all cut-off values) was not associated with short- or long-term clinical prognosis, whereas patients with higher PCNA primary-tumor expression showed longer survival from treatment and survival from diagnosis, according to univariate and multivariate analysis, particularly in the sub-set of colon-cancer patients. We conclude that the clinical response of advanced-colorectal-cancer patients to biochemically modulated 5-FU and MTX cannot be predicted by PCNA and p53 primary-tumor expression, but high PCNA expression appears to be independently related to long-term prognosis.

  8. NEGATIVE EMOTIONS IN CANCER CARE: DO ONCOLOGISTS’ RESPONSES DEPEND ON SEVERITY AND TYPE OF EMOTION?

    PubMed Central

    Kennifer, Sarah L.; Alexander, Stewart C.; Pollak, Kathryn I.; Jeffreys, Amy S.; Olsen, Maren K.; Rodriguez, Keri L.; Arnold, Robert M.; Tulsky, James A.

    2009-01-01

    Objective To examine how type and severity of patients’ negative emotions influence oncologists’ responses and subsequent conversations. Methods We analyzed 264 audio-recorded conversations between advanced cancer patients and their oncologists. Conversations were coded for patients’ expressions of negative emotion, which were categorized by type of emotion and severity. Oncologists’ responses were coded as using either empathic language or blocking and distancing approaches. Results Patients presented fear more often than anger or sadness; severity of disclosures was most often moderate. Oncologists responded to 35% of these negative emotional disclosures with empathic language. They were most empathic when patients presented intense emotions. Responding empathically to patients’ emotional disclosures lengthened discussions by an average of only 21 seconds. Conclusion Greater response rates to severe emotions suggest oncologists may recognize negative emotions better when patients express them more intensely. Oncologists were least responsive to patient fear and responded with greatest empathy to sadness. Practice Implications Oncologists may benefit from additional training to recognize negative emotions, even when displayed without intensity. Teaching cancer patients to better articulate their emotional concerns may also enhance patient-oncologist communication. PMID:19041211

  9. EF5 PET of Tumor Hypoxia: A Predictive Imaging Biomarker of Response to Stereotactic Ablative Radiotherapy (SABR) for Early Lung Cancer

    DTIC Science & Technology

    2014-09-01

    Predictive Imaging Biomarker of Response to Stereotactic Ablative Radiotherapy ( SABR ) for Early Lung Cancer PRINCIPAL INVESTIGATOR: Billy W...CONTRACT NUMBER Response to Stereotactic Ablative Radiotherapy ( SABR ) for Early Lung Cancer 5b. GRANT NUMBER W81XWH-12-1-0236 5c...NOTES 14. ABSTRACT Purpose and scope: Stereotactic ablative radiotherapy ( SABR ) has become a new standard of care for early stage lung

  10. In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival.

    PubMed

    Ladoire, Sylvain; Mignot, Grégoire; Dabakuyo, Sandrine; Arnould, Laurent; Apetoh, Lionel; Rébé, Cedric; Coudert, Bruno; Martin, Francois; Bizollon, Marie Hélène; Vanoli, André; Coutant, Charles; Fumoleau, Pierre; Bonnetain, Franck; Ghiringhelli, François

    2011-07-01

    Accumulating preclinical evidence suggests that anticancer immune responses contribute to the success of chemotherapy. However, the predictive value of tumour-infiltrating lymphocytes after neoadjuvant chemotherapy for breast cancer remains unknown. We hypothesized that the nature of the immune infiltrate following neoadjuvant chemotherapy would predict patient survival. In a series of 111 consecutive HER2- and a series of 51 non-HER2-overexpressing breast cancer patients treated by neoadjuvant chemotherapy, we studied by immunohistochemistry tumour infiltration by FOXP3 and CD8 T lymphocytes before and after chemotherapy. Kaplan-Meier analysis and Cox modelling were used to assess relapse-free survival (RFS) and overall survival (OS). A predictive scoring system using American Joint Committee on Cancer (AJCC) pathological staging and immunological markers was created. Association of high CD8 and low FOXP3 cell infiltrates after chemotherapy was significantly associated with improved RFS (p = 0.02) and OS (p = 0.002), and outperformed classical predictive factors in multivariate analysis. A combined score associating CD8/FOXP3 ratio and pathological AJCC staging isolated a subgroup of patients with a long-term overall survival of 100%. Importantly, this score also identified patients with a favourable prognosis in an independent cohort of HER2-negative breast cancer patients. These results suggest that immunological CD8 and FOXP3 cell infiltrate after treatment is an independent predictive factor of survival in breast cancer patients treated with neoadjuvant chemotherapy and provides new insights into the role of the immune milieu and cancer. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  11. Cancer-Specific Stress and Mood Disturbance: Implications for Symptom Perception, Quality of Life, and Immune Response in Women Shortly after Diagnosis of Breast Cancer

    PubMed Central

    Kang, Duck-Hee; Park, Na-Jin; McArdle, Traci

    2012-01-01

    Purpose. To determine the levels of cancer-specific stress and mood disturbance in women shortly after diagnosis of breast cancer and to assess their associations with symptom perception, quality of life, and immune response. Design. Descriptive and correlational. Sample and Setting. One hundred women with newly diagnosed breast cancer were recruited from interdisciplinary breast clinics. Methods. Baseline data were collected using standardized questionnaires and established bioassay prior to the initiation of cancer adjuvant therapy. Blood samples were collected about the same time of day. Results. High cancer-specific stress was significantly correlated with high mood disturbance, which, in turn, was correlated with high symptom perception, poor quality of life, and an immune profile indicating high neutrophils and low lymphocytes. Conclusions. High cancer-specific stress and related mood disturbance show extensive negative relationships with multiple behavioral, clinical, and biological factors. Implications for Nursing. Routine screening for cancer-related stress and mood disturbance should be incorporated into nursing practice for all patients diagnosed with cancer. Given broad negative associations with other biobehavioral factors, early identification of patients at risk and provision and evaluation of stress and mood management programs may have a beneficial effect on subsequent health outcomes over time. PMID:23316388

  12. Longitudinal monitoring of head and neck lymphatics in response to cancer treatment

    NASA Astrophysics Data System (ADS)

    Rasmussen, John C.; Tan, I.-Chih; Naqvi, Syed; Aldrich, Melissa B.; Maus, Erik A.; Blanco, Angel I.; Karni, Ron J.; Sevick-Muraca, Eva M.

    2017-02-01

    Radiation therapy (RT) can promote anti-tumoral responses, but is also known to cause lymphatic endothelial cell apoptosis, loss of dermal lymphatics, and reduction in lymph transport to draining lymph node basins. When combined with lymph node dissection (LND), the radiogenic lymphatic disruption may possibly result in lymph stasis and dermal backflow. If not resolved, this disruption may lead to chronic inflammation, edema, fibrosis, adipose tissue deposition, and ultimately to functional deficits and disfigurement. Because the head and neck (HN) region contains 1/3 of the body's lymph nodes, lymphatic responses to cancer progression and therapy may be significant. Furthermore, it may not be surprising that lymphedema has been estimated to impact as many as 75% of HN cancer survivors three months or more after LND and RT. In this study, we used near-infrared fluorescence imaging to longitudinally assess the lymphatics of 18 patients undergoing treatment for cancer of the oral cavity, oropharynx, and/or larynx following intraoral and intradermal injections of ICG. Patients were imaged before and after surgery, before and after fractionated RT for up to 100 weeks after treatments. Patients who underwent both LND and RT developed lymphatic dermal backflow on treated sides ranging from days after the start of RT to weeks after its completion, while contralateral regions that were not associated with LND but also treated with RT, experienced no such changes in functional lymphatic anatomies. The results show for the first time, the striking reorganization of the lymphatic vasculature and may enable early diagnosis of HN lymphedema.

  13. [A Case of Pathological Complete Response after Neoadjuvant Chemotherapy(S-1 plus Oxaliplatin)and Laparoscopic Low Anterior Resection for Rectal Cancer].

    PubMed

    Ichinohe, Daichi; Morohashi, Hajime; Umetsu, Satoko; Yoshida, Tatsuya; Wakasa, Yusuke; Odagiri, Tadashi; Kimura, Toshirou; Suto, Akiko; Saito, Takeshi; Yoshida, Eri; Akasaka, Harue; Jin, Hiroyuki; Miura, Takuya; Sakamoto, Yoshiyuki; Hakamada, Kenichi

    2016-11-01

    We report a case of pathological complete response after neoadjuvant chemotherapy(NAC)(S-1 plus oxaliplatin)for rectal cancer. The patient was a 50-year-old man who had type 3 circumferential rectal cancer. An abdominal CT scan revealed locally advanced rectal cancer(cT3N2H0P0M0, cStage III b)with severe stenosis and oral-side intestinal dilatation. The patient was treated with NAC after loop-ileostomy. After 3 courses of chemotherapy, a CT scan revealed significant tumor reduction. Laparoscopic low anterior resection and bilateral lymph node dissection were performed 5 weeks after the last course of chemotherapy. The pathological diagnosis was a pathological complete response(no residual cancer cells). This case suggests that laparoscopic low anterior resection after NAC with S-1 plus oxaliplatin for locally advanced rectal cancer is a potentially effective procedure.

  14. The role of positron emission tomography in the diagnosis, staging and response assessment of non-small cell lung cancer

    PubMed Central

    Ali, Jason M.; Tasker, Angela; Peryt, Adam; Aresu, Giuseppe; Coonar, Aman S.

    2018-01-01

    Lung cancer is a common disease and the leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Following diagnosis of lung cancer, accurate staging is essential to guide clinical management and inform prognosis. Positron emission tomography (PET) in conjunction with computed tomography (CT)—as PET-CT has developed as an important tool in the multi-disciplinary management of lung cancer. This article will review the current evidence for the role of 18F-fluorodeoxyglucose (FDG) PET-CT in NSCLC diagnosis, staging, response assessment and follow up. PMID:29666818

  15. Implication from thyroid function decreasing during chemotherapy in breast cancer patients: chemosensitization role of triiodothyronine

    PubMed Central

    2013-01-01

    Background Thyroid hormones have been shown to regulate breast cancer cells growth, the absence or reduction of thyroid hormones in cells could provoke a proliferation arrest in G0-G1 or weak mitochondrial activity, which makes cells insensitive to therapies for cancers through transforming into low metabolism status. This biological phenomenon may help explain why treatment efficacy and prognosis vary among breast cancer patients having hypothyroid, hyperthyroid and normal function. Nevertheless, the abnormal thyroid function in breast cancer patients has been considered being mainly caused by thyroid diseases, few studied influence of chemotherapy on thyroid function and whether its alteration during chemotherapy can influence the respose to chemotherapy is still unclear. So, we aimed to find the alterations of thyroid function and non-thyroidal illness syndrome (NTIS) prevalence druing chemotherapy in breast cancer patients, and investigate the influence of thyroid hormones on chemotherapeutic efficacy. Methods Thyroid hormones and NTIS prevalence at initial diagnosis and during chemotherapy were analyzed in 685 breast diseases patients (369 breast cancer, 316 breast benign lesions). The influence of thyroid hormones on chemotherapeutic efficacy was evaluated by chemosensitization test, to compare chemotherapeutic efficacy between breast cancer cells with chemotherapeutics plus triiodothyronine (T3) and chemotherapeutics only. Results In breast cancer, NTIS prevalence at the initial diagnosis was higher and increased during chemotherapy, but declined before the next chemotherapeutic course. Thyroid hormones decreased signigicantly during chemotherapy. T3 can enhance the chemosensitivity of MCF-7 to 5-Fu and taxol, with progression from G0-G1 phase to S phase. The similar chemosensitization role of T3 were found in MDA-MB-231. We compared chemotherapeutic efficacy among groups with different usage modes of T3, finding pretreatment with lower dose of T3, using

  16. Parental consanguineous marriages and clinical response to chemotherapy in locally advanced breast cancer patients.

    PubMed

    Saadat, Mostafa; Khalili, Maryam; Omidvari, Shahpour; Ansari-Lari, Maryam

    2011-03-28

    The main aim of the present study was investigating the association between parental consanguinity and clinical response to chemotherapy in females affected with locally advanced breast cancer. A consecutive series of 92 patients were prospectively included in this study. Clinical assessment of treatment was accomplished by comparing initial tumor size with preoperative tumor size using revised RECIST guideline (version 1.1). Clinical response defined as complete response, partial response and no response. The Kaplan-Meier survival analysis were used to evaluate the association of parental marriages (first cousin vs unrelated marriages) and clinical response to chemotherapy (complete and partial response vs no response). Number of courses of chemotherapy was considered as time, in the analysis. Kaplan-Meier analysis revealed that offspring of unrelated marriages had poorer response to chemotherapy (log rank statistic=5.10, df=1, P=0.023). Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  17. Positron emission tomography using [18F]fluorotamoxifen to evaluate therapeutic responses in patients with breast cancer: preliminary study.

    PubMed

    Inoue, T; Kim, E E; Wallace, S; Yang, D J; Wong, F C; Bassa, P; Cherif, A; Delpassand, E; Buzdar, A; Podoloff, D A

    1996-08-01

    Positron emission tomography (PET) was used to assess the biodistribution and clinical usefulness of [18F]fluorotamoxifen (FTX) in 10 patients with estrogen-receptor(ER)-positive breast tumors. Ten patients with ER-positive breast cancer were prospectively studied, and the consecutive PET imagings (each takes 15 or 20 min) were obtained for 60 or 80 min after the injection of 88.8-392.2 MBq (2.4-10.6 mCi) of [18F]FTX. Twenty three suspected primary or metastatic lesions in 10 patients were evaluated and the tumor uptakes of [18F]FTX in nineteen tumor lesions were correlated to the response of tamoxifen therapy. Three lesions in three patients were considered to be truly negative for breast cancer on the bases of biopsy specimens and/or clinical course. Five (71.4%) of seven patients and 16 (80.0%) of 20 lesions were interpreted to be truly positive for breast cancer. The mean standardized uptake value (SUV) of the radiotracer in tumor was 3.0 on delayed images. There was no significant correlation between the standardized uptake values of [18F]FTX and the ER concentrations in primary lesions. Nineteen tumor lesions in six patients were evaluable to compare the [18F]FTX uptake with responses to tamoxifen therapy after the PET study. Three patients who had a good response to tamoxifen therapy showed positive lesions on PET images, whereas two of three patients who had a poor response showed negative lesions and one showed mixed results. There was no significant difference of [18F]FTX uptake in bone lesions between good and poor responders. However, when bone lesions were excluded, [18F]FTX uptakes in tumors with good responses were significantly higher than those with poor responses (mean and standard deviation of SUV: 2.46 +/- 0.62 vs 1.37 +/- 0.59, P < 0.05). PET imaging using [18F]FTX provides useful information in predicting the effect of tamoxifen therapy in patients with ER-positive breast cancer. Further study is warranted to confirm the clinical utility of

  18. Use of mode of action data to inform a dose-response assessment for bladder cancer following exposure to inorganic arsenic.

    PubMed

    Gentry, P R; Yager, J W; Clewell, R A; Clewell, H J

    2014-10-01

    In the recent National Research Council report on conducting a dose-response assessment for inorganic arsenic, the committee remarked that mode of action data should be used, to the extent possible, to extrapolate below the observed range for epidemiological studies to inform the shape of the dose-response curve. Recent in vitro mode of action studies focused on understanding the development of bladder cancer following exposure to inorganic arsenic provide data to inform the dose-response curve. These in vitro data, combined with results of bladder cancer epidemiology studies, inform the dose-response curve in the low-dose region, and include values for both pharmacokinetic and pharmacodynamic variability. Integration of these data provides evidence of a range of concentrations of arsenic for which no effect on the bladder would be expected. Specifically, integration of these results suggest that arsenic exposures in the range of 7-43 ppb in drinking water are exceedingly unlikely to elicit changes leading to key events in the development of cancer or noncancer effects in bladder tissue. These findings are consistent with the lack of evidence for bladder cancer following chronic ingestion of arsenic water concentrations <100 ppb in epidemiological studies. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. GDNF-RET signaling in ER-positive breast cancers is a key determinant of response and resistance to aromatase inhibitors

    PubMed Central

    Morandi, Andrea; Martin, Lesley-Ann; Gao, Qiong; Pancholi, Sunil; Mackay, Alan; Robertson, David; Zvelebil, Marketa; Dowsett, Mitch; Plaza-Menacho, Ivan; Isacke, Clare M.

    2013-01-01

    Most breast cancers at diagnosis are estrogen receptor (ER)-positive and depend on estrogen for growth and survival. Blocking estrogen biosynthesis by aromatase inhibitors (AI) has therefore become a first-line endocrine therapy for post-menopausal women with ER-positive breast cancers. Despite providing substantial improvements in patient outcome, AI resistance remains a major clinical challenge. The receptor tyrosine kinase RET and its co-receptor GFRα1 are upregulated in a subset of ER-positive breast cancers, and the RET ligand, glial-derived neurotrophic factor (GDNF) is upregulated by inflammatory cytokines. Here we report the findings of a multidisciplinary strategy to address the impact of GDNF-RET signaling in the response to AI treatment. In breast cancer cells in 2D and 3D culture, GDNF-mediated RET signaling is enhanced in a model of AI resistance. Further, GDNF-RET signaling promoted the survival of AI-resistant cells and elicited resistance in AI-sensitive cells. Both these effects were selectively reverted by the RET kinase inhibitor NVP-BBT594. Gene expression profiling in ER-positive cancers defined a proliferation-independent GDNF-response signature that prognosed poor patient outcome and, more importantly, predicted poor response to AI treatment with the development of resistance. We validated these findings by demonstrating increased RET protein expression levels in an independent cohort of AI-resistant patient specimens. Together, our results establish GDNF-RET signaling as a rational therapeutic target to combat or delay the onset of AI resistance in breast cancer. PMID:23650283

  20. Preclinical testing of an Atr inhibitor demonstrates improved response to standard therapies for esophageal cancer.

    PubMed

    Leszczynska, Katarzyna B; Dobrynin, Greg; Leslie, Rhea E; Ient, Jonathan; Boumelha, Adam J; Senra, Joana M; Hawkins, Maria A; Maughan, Tim; Mukherjee, Somnath; Hammond, Ester M

    2016-11-01

    Esophageal cancer has a persistently low 5-year survival rate and has recently been classified as a cancer of unmet need by Cancer Research UK. Consequently, new approaches to therapy are urgently required. Here, we tested the hypothesis that an ATR inhibitor, VX-970, used in combination with standard therapies for esophageal cancer could improve treatment outcome. Using esophageal cancer cell lines we evaluated the efficacy of combining VX-970 with cisplatin and carboplatin in vitro and with radiation in vitro and in vivo. Radiation experiments were also carried out in hypoxic conditions to mimic the tumor microenvironment. Combining VX-970 with cisplatin, carboplatin and radiation increased tumor cell kill in vitro. A significant tumor growth delay was observed when VX-970 was combined with radiotherapy in vivo. VX-970 is an effective chemo/radiosensitizer which could be readily integrated in the current treatment paradigm to improve the treatment response in esophageal cancer and we plan to test it prospectively in the forthcoming phase I dose escalation safety study combining the ATR inhibitor VX-970 with chemoradiotherapy in esophageal cancer (EudraCT number: 2015-003965-27). Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  1. Late Stage Cancer Patients: Age Differences in Their Psychophysical Status and Response to Counseling.

    ERIC Educational Resources Information Center

    Linn, Bernard S.; Linn, Margaret W.

    1981-01-01

    Studied (N=120) terminally ill cancer patients over several months on quality of life variables, functional status and survival. Counseled patients changed significantly more than controls by three months. Overall, response to counseling was similar in young and old patients, with both improving. (Author/JAC)

  2. Association between dietary fiber and endometrial cancer: a dose-response meta-analysis123

    PubMed Central

    Bandera, Elisa V; Kushi, Lawrence H; Moore, Dirk F; Gifkins, Dina M; McCullough, Marjorie L

    2008-01-01

    Background Endometrial cancer is the most common female gynecologic cancer in the United States. Excessive and prolonged exposure of the endometrium to estrogens unopposed by progesterone and a high body mass are well-established risk factors for endometrial cancer. Although dietary fiber has been shown to beneficially reduce estrogen concentrations and prevent obesity, its role in endometrial cancer has received relatively little attention. Objective The objective was to summarize and quantify the current evidence of a role of dietary fiber consumption in endometrial cancer risk and to identify research gaps in this field. Design We conducted a systematic literature review of articles published through February 2007 to summarize the current evidence of a relation between dietary fiber consumption and endometrial cancer risk and to quantify the magnitude of the association by conducting a dose-response meta-analysis. Results Ten articles representing 1 case-cohort study and 9 case-control studies that evaluated several aspects of fiber consumption and endometrial cancer risk were identified through searches in various databases. On the basis of 7 case-control studies, the random-effects summary risk estimate was 0.82 (95% CI: 0.75, 0.90) per 5 g/1000 kcal dietary fiber, with no evidence of heterogeneity (I2: 0%, P for heterogeneity: 0.55). The random-effects summary estimate was 0.71 (95% CI: 0.59, 0.85) for the comparison of the highest with the lowest dietary fiber intake in 8 case-control studies, with little evidence of heterogeneity (I2: 20.8%, P for heterogeneity: 0.26). In contrast, the only prospective study that evaluated this association did not find an association. Conclusions Although the current evidence, based on data from case-control studies, supports an inverse association between dietary fiber and endometrial cancer, additional population-based studies, particularly cohort studies, are needed before definitive conclusions can be drawn. PMID

  3. Response monitoring of breast cancer patients receiving neoadjuvant chemotherapy using quantitative ultrasound, texture, and molecular features

    PubMed Central

    Gangeh, Mehrdad; Tadayyon, Hadi; Sadeghi-Naini, Ali; Gandhi, Sonal; Wright, Frances C.; Slodkowska, Elzbieta; Curpen, Belinda; Tran, William; Czarnota, Gregory J.

    2018-01-01

    Background Pathological response of breast cancer to chemotherapy is a prognostic indicator for long-term disease free and overall survival. Responses of locally advanced breast cancer in the neoadjuvant chemotherapy (NAC) settings are often variable, and the prediction of response is imperfect. The purpose of this study was to detect primary tumor responses early after the start of neoadjuvant chemotherapy using quantitative ultrasound (QUS), textural analysis and molecular features in patients with locally advanced breast cancer. Methods The study included ninety six patients treated with neoadjuvant chemotherapy. Breast tumors were scanned with a clinical ultrasound system prior to chemotherapy treatment, during the first, fourth and eighth week of treatment, and prior to surgery. Quantitative ultrasound parameters and scatterer-based features were calculated from ultrasound radio frequency (RF) data within tumor regions of interest. Additionally, texture features were extracted from QUS parametric maps. Prior to therapy, all patients underwent a core needle biopsy and histological subtypes and biomarker ER, PR, and HER2 status were determined. Patients were classified into three treatment response groups based on combination of clinical and pathological analyses: complete responders (CR), partial responders (PR), and non-responders (NR). Response classifications from QUS parameters, receptors status and pathological were compared. Discriminant analysis was performed on extracted parameters using a support vector machine classifier to categorize subjects into CR, PR, and NR groups at all scan times. Results Of the 96 patients, the number of CR, PR and NR patients were 21, 52, and 23, respectively. The best prediction of treatment response was achieved with the combination mean QUS values, texture and molecular features with accuracies of 78%, 86% and 83% at weeks 1, 4, and 8, after treatment respectively. Mean QUS parameters or clinical receptors status alone

  4. Breast cancer cell-associated endopeptidase EC 24.11 modulates proliferative response to bombesin

    PubMed Central

    Burns, D M; Walker, B; Gray, J; Nelson, J

    1999-01-01

    We have investigated the production, growth and inactivation of gastrin-releasing peptide (GRP)-like peptides in human breast cancer cell lines. Radioimmunoassay detected GRP-like immunoreactivity (GRP-LI) in T47D breast cancer cells but not in the conditioned medium, indicating rapid clearance. No GRP-LI was found in the ZR-75-1 or MDA-MB-436 cells or their conditioned medium. High-performance liquid chromatography (HPLC) analysis of the GRP-LI in the T47D cells revealed a major peak, which co-eluted with GRP18–27, and a minor more hydrophilic peak. In vitro stimulation of T47D cell growth by bombesin (BN) was enhanced to 138% of control levels (bombesin alone) by the addition of the selective endopeptidase EC 3.4.24.11 inhibitor phosphoramidon (0.1 ng ml−;1). Fluorogenic analysis using whole cells confirmed low levels of this phosphoramidon-sensitive enzyme on the T47D cells. This enzyme, previously unreported in human breast cancer cells, significantly modulates both T47D growth and its response to BN-induced growth. © 1999 Cancer Research Campaign PMID:9888460

  5. TUSC3 Loss Alters the ER Stress Response and Accelerates Prostate Cancer Growth in vivo

    NASA Astrophysics Data System (ADS)

    Horak, Peter; Tomasich, Erwin; Vaňhara, Petr; Kratochvílová, Kateřina; Anees, Mariam; Marhold, Maximilian; Lemberger, Christof E.; Gerschpacher, Marion; Horvat, Reinhard; Sibilia, Maria; Pils, Dietmar; Krainer, Michael

    2014-01-01

    Prostate cancer is the most prevalent cancer in males in developed countries. Tumor suppressor candidate 3 (TUSC3) has been identified as a putative tumor suppressor gene in prostate cancer, though its function has not been characterized. TUSC3 shares homologies with the yeast oligosaccharyltransferase (OST) complex subunit Ost3p, suggesting a role in protein glycosylation. We provide evidence that TUSC3 is part of the OST complex and affects N-linked glycosylation in mammalian cells. Loss of TUSC3 expression in DU145 and PC3 prostate cancer cell lines leads to increased proliferation, migration and invasion as well as accelerated xenograft growth in a PTEN negative background. TUSC3 downregulation also affects endoplasmic reticulum (ER) structure and stress response, which results in increased Akt signaling. Together, our findings provide first mechanistic insight in TUSC3 function in prostate carcinogenesis in general and N-glycosylation in particular.

  6. An application of a Hill-based response surface model for a drug combination experiment on lung cancer.

    PubMed

    Ning, Shaoyang; Xu, Hongquan; Al-Shyoukh, Ibrahim; Feng, Jiaying; Sun, Ren

    2014-10-30

    Combination chemotherapy with multiple drugs has been widely applied to cancer treatment owing to enhanced efficacy and reduced drug resistance. For drug combination experiment analysis, response surface modeling has been commonly adopted. In this paper, we introduce a Hill-based global response surface model and provide an application of the model to a 512-run drug combination experiment with three chemicals, namely AG490, U0126, and indirubin-3  ' -monoxime (I-3-M), on lung cancer cells. The results demonstrate generally improved goodness of fit of our model from the traditional polynomial model, as well as the original Hill model on the basis of fixed-ratio drug combinations. We identify different dose-effect patterns between normal and cancer cells on the basis of our model, which indicates the potential effectiveness of the drug combination in cancer treatment. Meanwhile, drug interactions are analyzed both qualitatively and quantitatively. The distinct interaction patterns between U0126 and I-3-M on two types of cells uncovered by the model could be a further indicator of the efficacy of the drug combination. Copyright © 2014 John Wiley & Sons, Ltd.

  7. Molecular analysis of urothelial cancer cell lines for modeling tumor biology and drug response.

    PubMed

    Nickerson, M L; Witte, N; Im, K M; Turan, S; Owens, C; Misner, K; Tsang, S X; Cai, Z; Wu, S; Dean, M; Costello, J C; Theodorescu, D

    2017-01-05

    The utility of tumor-derived cell lines is dependent on their ability to recapitulate underlying genomic aberrations and primary tumor biology. Here, we sequenced the exomes of 25 bladder cancer (BCa) cell lines and compared mutations, copy number alterations (CNAs), gene expression and drug response to BCa patient profiles in The Cancer Genome Atlas (TCGA). We observed a mutation pattern associated with altered CpGs and APOBEC-family cytosine deaminases similar to mutation signatures derived from somatic alterations in muscle-invasive (MI) primary tumors, highlighting a major mechanism(s) contributing to cancer-associated alterations in the BCa cell line exomes. Non-silent sequence alterations were confirmed in 76 cancer-associated genes, including mutations that likely activate oncogenes TERT and PIK3CA, and alter chromatin-associated proteins (MLL3, ARID1A, CHD6 and KDM6A) and established BCa genes (TP53, RB1, CDKN2A and TSC1). We identified alterations in signaling pathways and proteins with related functions, including the PI3K/mTOR pathway, altered in 60% of lines; BRCA DNA repair, 44%; and SYNE1-SYNE2, 60%. Homozygous deletions of chromosome 9p21 are known to target the cell cycle regulators CDKN2A and CDKN2B. This loci was commonly lost in BCa cell lines and we show the deletions extended to the polyamine enzyme methylthioadenosine (MTA) phosphorylase (MTAP) in 36% of lines, transcription factor DMRTA1 (27%) and antiviral interferon epsilon (IFNE, 19%). Overall, the BCa cell line genomic aberrations were concordant with those found in BCa patient tumors. We used gene expression and copy number data to infer pathway activities for cell lines, then used the inferred pathway activities to build a predictive model of cisplatin response. When applied to platinum-treated patients gathered from TCGA, the model predicted treatment-specific response. Together, these data and analysis represent a valuable community resource to model basic tumor biology and to study

  8. PTTG1, A novel androgen responsive gene is required for androgen-induced prostate cancer cell growth and invasion

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhang, Zheng; Jin, Bo; Jin, Yaqiong

    Androgens (AR) play an important role in initiation and progression of prostate cancer. It has been shown that AR exert their effects mainly through the androgen-activated AR which binds to androgen response elements (AREs) in the regulatory regions of target genes to regulate the transcription of androgen-responsive genes, thus, identification of AR downstream target gene is critical to understand androgen function in prostate cancer. In this study, our results showed that androgen treatment of LNCaP cells induced PTTG1 expression, which was blocked by the androgen receptor antagonist, Casodex. Bioinformatics analysis and experiments using PTTG1 promoter deletion mutants showed that themore » PTTG1 promoter contains a putative androgen response element (ARE), which localizes in the −851 to −836 region of the promoter. Androgen activated androgen receptor (AR) binding to this ARE was confirmed by Chromatin immunoprecipitation (ChIP) assay. Furthermore, Knockdown of PTTG1 expression using short hairpin RNA significantly reduced androgen-induced LNCaP cell growth and invasion. In addition, we showed PTTG1 is highly expressed in metastasis prostate cancer tissue. These results suggest that PTTG1 is a novel downstream target gene of androgen receptor and take part in prostate cancer proliferation and metastasis. - Highlights: • Androgen treatment of LNCaP cells induced PTTG1 expression. • Knockdown of PTTG1 expression significantly reduced androgen-induced LNCaP cell growth and invasion. • PTTG1 is highly expressed in metastasis prostate cancer tissue. • PTTG1 is a novel downstream target gene of androgen receptor.« less

  9. [An intractable gastric cancer showing an extremely effective response to immunochemotherapy].

    PubMed

    Takashima, S; Komaki, H; Yokota, H; Kiriyama, M; Kinami, Y

    1988-07-01

    Reported herein is the case of a terminal patient with advanced gastric cancer who was shown an extremely effective response to immunochemotherapy. The patient, a 62-year-old female, was determined as having a gastric cancer, Borr. type 2, originating in the pyloric antrum. The tumor was found to be H3P3S2N2 (stage IV), and its histology revealed a mucus-producing papillary adeno-carcinoma, ss gamma, n(+), ly2, and V1. Thus the patient underwent a distal gastrectomy, and was given an operative administration of MMC, followed by postoperative immunochemotherapy with FT 207 and OK 432. Consequently, no ascites were noticed throughout the recuperative course, and repeated CT scannings of the hepatic metastatic lesions, revealed a remarkable regression. Two years after this operation, she resumed normal daily life. Further, her preoperatively elevated tumor markers have returned to normal.

  10. CPTAC Develops Fit-for-Purpose Multiplex Immuno-MRM Assay for Profiling the DNA Damage Response Pathway | Office of Cancer Clinical Proteomics Research

    Cancer.gov

    Ionizing radiation (IR) is a commonly employed cancer treatment that kills cancer cells by damaging their DNA. While the DNA damage response (DDR) pathway may be key to determining tumor responses, radiochemical damage due to IR can target the patients’ healthy dividing cells, leading to the formation of secondary hematologic and solid tumors after DNA-damaging therapy.

  11. The internal and external responsiveness of Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Short Form-12 Health Survey version 2 (SF-12 v2) in patients with prostate cancer.

    PubMed

    Choi, Edmond P H; Wong, Carlos K H; Wan, Eric Y F; Tsu, James H L; Chin, W Y; Kung, Kenny; Yiu, M K

    2016-09-01

    To examine the responsiveness of Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Short Form-12 Health Survey version 2 (SF-12 v2) in prostate cancer patients because there is a lack of evidence to support their responsiveness in this patient population. One hundred sixty-eight subjects with prostate cancer were surveyed at baseline and at 6 months using the SF-12 v2 and FACT-P version 4. Internal responsiveness was assessed using paired t test and generalized estimating equation. External responsiveness was evaluated using receiver operating characteristic curve analysis. The internal responsiveness of the FACT-P and SF-12 v2 to detect positive change was satisfactory. The FACT-P and SF-12 v2 could not detect negative change. The FACT-P and the SF-12 v2 performed the best in distinguishing between improved general health and worsened general health. The FACT-P performed better in distinguishing between unchanged general health and worsened general health. The SF-12 v2 performed better in distinguishing between unchanged general health and improved general health. Positive change detected by these measures should be interpreted with caution as they might be too responsive to detect "noise," which is not clinically significant. The ability of the FACT-P and the SF-12 v2 to detect negative change was disappointing. The internal and external responsiveness of the social well-being of the FACT-P cannot be supported, suggesting that it is not suitable to longitudinally monitor the social component of HRQOL in prostate cancer patients. The study suggested that generic and disease-specific measures should be used together to complement each other.

  12. Humanized Androgen Receptor Mice: A Genetic Model for Differential Response to Prostate Cancer Therapy

    DTIC Science & Technology

    2011-06-01

    tract length to male fertility (Davis-Dao et al., 2007) and in hypogonadal men to response to testosterone replacement (Zitzmann et al., 2004...changing, as occurs in development and aging, or clinically, as when hormone is replaced in hypogonadal men or ablated in prostate cancer treatment

  13. Systems analysis of apoptotic priming in ovarian cancer identifies vulnerabilities and predictors of drug response.

    PubMed

    Zervantonakis, Ioannis K; Iavarone, Claudia; Chen, Hsing-Yu; Selfors, Laura M; Palakurthi, Sangeetha; Liu, Joyce F; Drapkin, Ronny; Matulonis, Ursula; Leverson, Joel D; Sampath, Deepak; Mills, Gordon B; Brugge, Joan S

    2017-08-28

    The lack of effective chemotherapies for high-grade serous ovarian cancers (HGS-OvCa) has motivated a search for alternative treatment strategies. Here, we present an unbiased systems-approach to interrogate a panel of 14 well-annotated HGS-OvCa patient-derived xenografts for sensitivity to PI3K and PI3K/mTOR inhibitors and uncover cell death vulnerabilities. Proteomic analysis reveals that PI3K/mTOR inhibition in HGS-OvCa patient-derived xenografts induces both pro-apoptotic and anti-apoptotic signaling responses that limit cell killing, but also primes cells for inhibitors of anti-apoptotic proteins. In-depth quantitative analysis of BCL-2 family proteins and other apoptotic regulators, together with computational modeling and selective anti-apoptotic protein inhibitors, uncovers new mechanistic details about apoptotic regulators that are predictive of drug sensitivity (BIM, caspase-3, BCL-X L ) and resistance (MCL-1, XIAP). Our systems-approach presents a strategy for systematic analysis of the mechanisms that limit effective tumor cell killing and the identification of apoptotic vulnerabilities to overcome drug resistance in ovarian and other cancers.High-grade serous ovarian cancers (HGS-OvCa) frequently develop chemotherapy resistance. Here, the authors through a systematic analysis of proteomic and drug response data of 14 HGS-OvCa PDXs demonstrate that targeting apoptosis regulators can improve response of these tumors to inhibitors of the PI3K/mTOR pathway.

  14. Mutant MHC class II epitopes drive therapeutic immune responses to cancer.

    PubMed

    Kreiter, Sebastian; Vormehr, Mathias; van de Roemer, Niels; Diken, Mustafa; Löwer, Martin; Diekmann, Jan; Boegel, Sebastian; Schrörs, Barbara; Vascotto, Fulvia; Castle, John C; Tadmor, Arbel D; Schoenberger, Stephen P; Huber, Christoph; Türeci, Özlem; Sahin, Ugur

    2015-04-30

    Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire. Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient's tumour possesses a unique set of mutations ('the mutanome') that must first be identified. Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient's individual tumour-specific mutations. Here we show in three independent murine tumour models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that, unexpectedly, the majority of the immunogenic mutanome is recognized by CD4(+) T cells. Vaccination with such CD4(+) immunogenic mutations confers strong antitumour activity. Encouraged by these findings, we established a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines. We show that vaccination with such polytope mRNA vaccines induces potent tumour control and complete rejection of established aggressively growing tumours in mice. Moreover, we demonstrate that CD4(+) T cell neo-epitope vaccination reshapes the tumour microenvironment and induces cytotoxic T lymphocyte responses against an independent immunodominant antigen in mice, indicating orchestration of antigen spread. Finally, we demonstrate an abundance of mutations predicted to bind to MHC class II in human cancers as well by employing the same predictive algorithm on corresponding human cancer types. Thus, the tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo

  15. Human Pancreatic Cancer Cells Induce a MyD88-Dependent Stromal Response To Promote a Tumor-Tolerant Immune Microenvironment

    PubMed Central

    Delitto, Daniel; Delitto, Andrea E.; DiVita, Bayli B.; Pham, Kien; Han, Song; Hartlage, Emily R.; Newby, Brittney N.; Gerber, Michael H.; Behrns, Kevin E.; Moldawer, Lyle L.; Thomas, Ryan M.; George, Thomas J.; Brusko, Todd M.; Mathews, Clayton E.; Liu, Chen; Trevino, Jose G.; Hughes, Steven J.; Wallet, Shannon M.

    2016-01-01

    Cancer cells exert mastery over the local tumor-associated stroma (TAS) to configure protective immunity within the tumor microenvironment. The immunomodulatory character of pancreatic lysates of patients with cancer differs from those with pancreatitis. In this study, we evaluated the crosstalk between pancreatic cancer (PC) and its TAS in primary human cell culture models. Upon exposure of TAS to PC cell-conditioned media, we documented robust secretion of IL-6 and IL-8. This TAS response was MyD88-dependent and sufficient to directly suppress both CD4+ and CD8+ T cell proliferation, inducing Th17 polarization at the expense of Th1. We found that patients possessed a similar shift in circulating effector memory Th17:Th1 ratios compared to healthy controls. The TAS response also directly suppressed CD8+ T cell-mediated cytotoxicity. Overall, our results demonstrate how TAS contributes to the production of an immunosuppressive tumor microenvironment in pancreatic cancer. PMID:27864347

  16. Blood oxygenation level-dependent (BOLD) contrast magnetic resonance imaging (MRI) for prediction of breast cancer chemotherapy response: a pilot study.

    PubMed

    Jiang, Lan; Weatherall, Paul T; McColl, Roderick W; Tripathy, Debu; Mason, Ralph P

    2013-05-01

    To determine whether a simple noninvasive method of assessing tumor oxygenation is feasible in the clinical setting and can provide useful, potentially predictive information. Tumor microcirculation and oxygenation play critical roles in tumor growth and responsiveness to cytotoxic treatment and may provide prognostic indicators for cancer therapy. Deoxyhemoglobin is paramagnetic and can serve as an endogenous contrast agent causing signal loss in echo planar magnetic resonance imaging (MRI) (blood oxygenation level-dependent [BOLD]-MRI). We used BOLD-MRI to provide early evaluation of response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. MRI was performed on 11 patients with biopsy-proven malignancy. MRI exams were scheduled before, during, and after chemotherapy. The BOLD study applied a 6-minute oxygen breathing challenge. Seven patients successfully completed the exams. Before chemotherapy, BOLD contrast enhancement was observed in all tumors, but the patients, who ultimately had complete pathological response, exhibited a significantly higher BOLD response to oxygen breathing. We have successfully implemented an oxygen-breathing challenge BOLD contrast technique as part of the standard breast MRI exam in patients with locally advanced breast cancer. The preliminary observation that a large BOLD response correlated with better treatment response suggests a predictive capability for BOLD MRI. Copyright © 2012 Wiley Periodicals, Inc.

  17. A priori Prediction of Neoadjuvant Chemotherapy Response and Survival in Breast Cancer Patients using Quantitative Ultrasound

    PubMed Central

    Tadayyon, Hadi; Sannachi, Lakshmanan; Gangeh, Mehrdad J.; Kim, Christina; Ghandi, Sonal; Trudeau, Maureen; Pritchard, Kathleen; Tran, William T.; Slodkowska, Elzbieta; Sadeghi-Naini, Ali; Czarnota, Gregory J.

    2017-01-01

    Quantitative ultrasound (QUS) can probe tissue structure and analyze tumour characteristics. Using a 6-MHz ultrasound system, radiofrequency data were acquired from 56 locally advanced breast cancer patients prior to their neoadjuvant chemotherapy (NAC) and QUS texture features were computed from regions of interest in tumour cores and their margins as potential predictive and prognostic indicators. Breast tumour molecular features were also collected and used for analysis. A multiparametric QUS model was constructed, which demonstrated a response prediction accuracy of 88% and ability to predict patient 5-year survival rates (p = 0.01). QUS features demonstrated superior performance in comparison to molecular markers and the combination of QUS and molecular markers did not improve response prediction. This study demonstrates, for the first time, that non-invasive QUS features in the core and margin of breast tumours can indicate breast cancer response to neoadjuvant chemotherapy (NAC) and predict five-year recurrence-free survival. PMID:28401902

  18. A priori Prediction of Neoadjuvant Chemotherapy Response and Survival in Breast Cancer Patients using Quantitative Ultrasound.

    PubMed

    Tadayyon, Hadi; Sannachi, Lakshmanan; Gangeh, Mehrdad J; Kim, Christina; Ghandi, Sonal; Trudeau, Maureen; Pritchard, Kathleen; Tran, William T; Slodkowska, Elzbieta; Sadeghi-Naini, Ali; Czarnota, Gregory J

    2017-04-12

    Quantitative ultrasound (QUS) can probe tissue structure and analyze tumour characteristics. Using a 6-MHz ultrasound system, radiofrequency data were acquired from 56 locally advanced breast cancer patients prior to their neoadjuvant chemotherapy (NAC) and QUS texture features were computed from regions of interest in tumour cores and their margins as potential predictive and prognostic indicators. Breast tumour molecular features were also collected and used for analysis. A multiparametric QUS model was constructed, which demonstrated a response prediction accuracy of 88% and ability to predict patient 5-year survival rates (p = 0.01). QUS features demonstrated superior performance in comparison to molecular markers and the combination of QUS and molecular markers did not improve response prediction. This study demonstrates, for the first time, that non-invasive QUS features in the core and margin of breast tumours can indicate breast cancer response to neoadjuvant chemotherapy (NAC) and predict five-year recurrence-free survival.

  19. Longitudinal perceptions of the side effects of chemotherapy in patients with gynecological cancer.

    PubMed

    Hsu, Hui-Chun; Tsai, Su-Yu; Wu, Shang-Liang; Jeang, Shiow-Roug; Ho, Mei-Yao; Liou, Wen-Shiung; Chiang, An-Jen; Chang, Tsung-Hsien

    2017-11-01

    This study aimed to assess the incidence and difference of side effects among six courses of chemotherapy (C/T) in gynecological cancer patients. The study period was from Sep. 2010 to Dec. 2011 at the Kaohsiung Veterans General Hospital in Taiwan. The treating protocols, courses, and drugs of C/T in patient were considered according to the different malignant cancers and clinical conditions. The patient data of age, marriage status, education, religion, and experiences of C/T were collected. The patients' or their families' reported side effects of C/T were recorded daily from the beginning of C/T to the 10th day after C/T in each cycle and every course of C/T. Total 89 patients enrolled into the study received total 450 courses of C/T. The mean age was 54.52 ± 11.02. Ovarian cancer was the most common malignant disease (64.0%). The most often combination of drugs used was Taxol and carboplatin (40.9%). Patients complained peripheral numbness of limbs, with the highest incidence of 58.6%. The side effects with incidence about 50% were decreased fatigue (55.0%) and hair loss (49.9%). Other side effects with different levels of incidence were also noticed, such as lack of appetite, changes in taste, and muscle ache. The incidences of peripheral limb numbness and hair loss were increased with following courses of C/T. The high incidence of fatigue did not show variation between different courses of C/T. This study revealed the incidence of side effects and occurrence timing during C/T in patients with gynecological cancer. These data provide substantial information to patients and their families to understand the potential side effects of C/T courses, which might increase their compliance in receiving adjuvant C/T. Relieving the side effects in C/T would be important to improve their quality of daily life and treatment willingness.

  20. Brain responses to erotic and other emotional stimuli in breast cancer survivors with and without distress about low sexual desire: a preliminary fMRI study.

    PubMed

    Versace, Francesco; Engelmann, Jeffrey M; Jackson, Edward F; Slapin, Aurelija; Cortese, Kristin M; Bevers, Therese B; Schover, Leslie R

    2013-12-01

    Many breast cancer survivors report a loss of sexual desire and arousability, consonant with the new DSM-V category of female sexual interest/arousal disorder. The cause of decreased sexual desire and pleasure after treatment for cancer is unknown. One possibility is that cancer, or treatment for cancer, damages brain circuits that are involved in reward-seeking. To test the hypothesis that brain reward systems are involved in decreased sexual desire in breast cancer survivors, we used functional magnetic resonance imaging (fMRI) to compare brain responses to erotica and other emotional stimuli in two groups of women previously treated for breast cancer with chemotherapy: those who were distressed about a perceived loss of sexual desire and those who may have had low desire, but were not distressed about it. Women distressed about their desire had reduced brain responses to erotica in the anterior cingulate and dorsolateral prefrontal cortex, which are part of the brain reward system. This study is the first to demonstrate, in cancer survivors, that problems with sexual desire/arousability are associated with blunted brain responses to erotica in reward systems. Future research is necessary to determine whether brain responses differ as a result of chemotherapy, hormone therapy, and menopausal status. This may contribute to the development of new, evidence-based interventions for one of the most prevalent and enduring side effects of cancer treatment.

  1. Psychometric properties of the Chinese version of resilience scale specific to cancer: an item response theory analysis.

    PubMed

    Ye, Zeng Jie; Liang, Mu Zi; Zhang, Hao Wei; Li, Peng Fei; Ouyang, Xue Ren; Yu, Yuan Liang; Liu, Mei Ling; Qiu, Hong Zhong

    2018-06-01

    Classic theory test has been used to develop and validate the 25-item Resilience Scale Specific to Cancer (RS-SC) in Chinese patients with cancer. This study was designed to provide additional information about the discriminative value of the individual items tested with an item response theory analysis. A two-parameter graded response model was performed to examine whether any of the items of the RS-SC exhibited problems with the ordering and steps of thresholds, as well as the ability of items to discriminate patients with different resilience levels using item characteristic curves. A sample of 214 Chinese patients with cancer diagnosis was analyzed. The established three-dimension structure of the RS-SC was confirmed. Several items showed problematic thresholds or discrimination ability and require further revision. Some problematic items should be refined and a short-form of RS-SC maybe feasible in clinical settings in order to reduce burden on patients. However, the generalizability of these findings warrants further investigations.

  2. Radiation-induced myocardial perfusion abnormalities in breast cancer patients following external beam radiation therapy.

    PubMed

    Eftekhari, Mohammad; Anbiaei, Robabeh; Zamani, Hanie; Fallahi, Babak; Beiki, Davood; Ameri, Ahmad; Emami-Ardekani, Alireza; Fard-Esfahani, Armaghan; Gholamrezanezhad, Ali; Seid Ratki, Kazem Razavi; Roknabadi, Alireza Momen

    2015-01-01

    Radiation therapy for breast cancer can induce myocardial capillary injury and increase cardiovascular morbidity and mortality. A prospective cohort was conducted to study the prevalence of myocardial perfusion abnormalities following radiation therapy of left-sided breast cancer patients as compared to those with right-sided cancer. To minimize potential confounding factors, only those patients with low 10-year risk of coronary artery disease (based on Framingham risk scoring) were included. All patients were initially treated by modified radical mastectomy and then were managed by postoperative 3D Conformal Radiation Therapy (CRT) to the surgical bed with an additional 1-cm margin, delivered by 46-50 Gy (in 2 Gy daily fractions) over a 5-week course. The same dose-adjusted chemotherapy regimen (including anthracyclines, cyclophosphamide and taxol) was given to all patients. Six months after radiation therapy, all patients underwent cardiac SPECT for the evaluation of myocardial perfusion. A total of 71 patients with a mean age of 45.3±7.2 years [35 patients with leftsided breast cancer (exposed) and 36 patients with right-sided cancer (controls)] were enrolled. Dose-volume histogram (DVH) [showing the percentage of the heart exposed to >50% of radiation] was significantly higher in patients with left-sided breast cancer. Visual interpretation detected perfusion abnormalities in 42.9% of cases and 16.7% of controls (P=0.02, Odds ratio=1.46). In semiquantitative segmental analysis, only apical (28.6% versus 8.3%, P=0.03) and anterolateral (17.1% versus 2.8%, P=0.049) walls showed significantly reduced myocardial perfusion in the exposed group. Summed Stress Score (SSS) of>3 was observed in twelve cases (34.3%), while in five of the controls (13.9%),(Odds ratio=1.3). There was no significant difference between the groups regarding left ventricular ejection fraction. The risk of radiation induced myocardial perfusion abnormality in patients treated with CRT on the

  3. miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer

    PubMed Central

    2014-01-01

    Background While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. Methods We investigated the levels of intra- and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate- or acquired- resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630’s regulation of mRNA, proteins and their phosphorylated forms. Results We established that introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630’s regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby

  4. BYSTANDER EFFECTS GENOMIC INSTABILITY, ADAPTIVE RESPONSE AND CANCER RISK ASSESSMENT FOR RADIAION AND CHEMICAL EXPOSURES

    EPA Science Inventory

    BYSTANDER EFFECTS, GENOMIC INSTABILITY, ADAPTIVE RESPONSE AND CANCER RISK ASSESSMENT FOR RADIATION AND CHEMICAL EXPOSURES

    R. Julian Preston
    Environmental Carcinogenesis Division, U.S. Environmental Protection Agency, Research Triangle Park, N.C. 27711, USA

    There ...

  5. Toward patient-centered cancer care: patient perceptions of problematic events, impact, and response.

    PubMed

    Mazor, Kathleen M; Roblin, Douglas W; Greene, Sarah M; Lemay, Celeste A; Firneno, Cassandra L; Calvi, Josephine; Prouty, Carolyn D; Horner, Kathryn; Gallagher, Thomas H

    2012-05-20

    Cancer treatments are complex, involving multiple clinicians, toxic therapies, and uncertain outcomes. Consequently, patients are vulnerable when breakdowns in care occur. This study explored cancer patients' perceptions of preventable, harmful events; the impact of these events; and interactions with clinicians after such events. In-depth telephone interviews were conducted with cancer patients from three clinical sites. Patients were eligible if they believed: something "went wrong" during their cancer care; the event could have been prevented; and the event caused, or could have caused, significant harm. Interviews focused on patients' perceptions of the event, its impact, and clinicians' responses to the event. Ninety-three of 416 patients queried believed something had gone wrong in their care that was preventable and caused or could have caused harm. Seventy-eight patients completed interviews. Of those interviewed, 28% described a problem with medical care, such as a delay in diagnosis or treatment; 47% described a communication problem, including problems with information exchange or manner; and 24% described problems with both medical care and communication. Perceived harms included physical and emotional harm, disruption of life, effect on family members, damaged physician-patient relationship, and financial expense. Few clinicians initiated discussion of the problematic events. Most patients did not formally report their concerns. Cancer patients who believe they experienced a preventable, harmful event during their cancer diagnosis or care often do not formally report their concerns. Systems are needed to encourage patients to report such events and to help physicians and health care systems respond effectively.

  6. Dual-Responsive Metabolic Precursor and Light-Up AIEgen for Cancer Cell Bio-orthogonal Labeling and Precise Ablation.

    PubMed

    Hu, Fang; Yuan, Youyong; Wu, Wenbo; Mao, Duo; Liu, Bin

    2018-06-05

    Metabolic glycoengineering of unnatural glycans with bio-orthogonal chemical groups and a subsequent click reaction with fluorescent probes have been widely used in monitoring various bioprocesses. Herein, we developed a dual-responsive metabolic precursor that could specifically generate unnatural glycans with azide groups on the membrane of targeted cancer cells with high selectivity. Moreover, a water-soluble fluorescent light-up probe with aggregation-induced emission (AIE) was synthesized, which turned its fluorescence on upon a click reaction with azide groups on the cancer cell surface, enabling special cancer cell imaging with low background signal. Furthermore, the probe can generate 1 O 2 upon light irradiation, fulfilling its dual role as an imaging and therapeutic agent for cancer cells. Therefore, the concepts of the cancer-cell-specific metabolic precursor cRGD-S-Ac 3 ManNAz and the AIE light-up probe are promising in bio-orthogonal labeling and cancer-specific imaging and therapy.

  7. let-7d-3p is associated with apoptosis and response to neoadjuvant chemotherapy in ovarian cancer.

    PubMed

    García-Vázquez, Raúl; Gallardo Rincón, Dolores; Ruiz-García, Erika; Meneses García, Abelardo; Hernández De La Cruz, Olga N; Astudillo-De La Vega, Horacio; Isla-Ortiz, David; Marchat, Laurence A; Salinas-Vera, Yarely M; Carlos-Reyes, Ángeles; López-González, Sullivan; Ramos-Payan, Rosalio; López-Camarillo, César

    2018-06-01

    Altered expression of microRNAs contributes to the heterogeneous biological behavior of human malignancies and it may correlate with the clinical pathological features of patients. The let-7 microRNA family is frequently downregulated in human cancers and its aberrant expression may be a useful marker for prediction of the clinical response to therapy in patients. In the present study, we analyzed the expression of three members of the let-7 family (let-7a-3p, let-7d-3p and let-7f), which remains largely uncharacterized in ovarian cancer tissues. We also investigated the function of let-7d-3p in the apoptosis and sensitization to chemotherapy in ovarian cancer cells. Our data from stem-loop quantitative RT-PCR showed that expression of let-7a-3p and let-7d-3p, but not let-7f, was significantly (P<0.04) upregulated in ovarian tumors relative to that noted in normal ovarian tissues. Markedly, an increased expression of let‑7d-3p (also known as let-7d-3*) was associated with positive response to carboplatin/paclitaxel treatment in ovarian cancer patients. To investigate the biological relevance of let‑7d-3p, we knocked down its expression in SKOV-3 ovarian cancer cell line using antagomiRs. Loss of function analysis showed that inhibition of let-7d-3p significantly (P<0.05) impaired cell proliferation and activated apoptosis. In contrast, scratch/wound healing and Transwell chamber assays showed that migration and invasion abilities were not affected in the let-7d-3p-deficient SKOV-3 cancer cells. Notably, Annexin V assays showed a significant (P<0.05) increase in cell death of cancer cells treated with the let-7d-3p inhibitor plus carboplatin indicating a synergistic effect of the drug with antagomiR therapy. Gene ontology classification of predicted targets of let-7d-3p identified a number of genes involved in cellular pathways associated with therapy resistance such as ABC transporters, HIF-1, RAS and ErbB signaling. In summary, our findings showed that

  8. Platelet “First Responders” in Wound Response, Cancer, and Metastasis

    PubMed Central

    Menter, David G.; Kopetz, Scott; Hawk, Ernest; Sood, Anil K.; Loree, Jonathan M; Gresele, Paolo; Honn, Kenneth V.

    2017-01-01

    Platelets serve as “First Responders” during normal wounding and homeostasis. Arising from bone marrow stem cell lineage megakaryocytes, anucleate platelets can influence inflammation and immune regulation. Biophysically, platelets are optimized due to size and discoid morphology to distribute near vessel walls, monitor vascular integrity and initiate quick responses to vascular lesions. Adhesion receptors linked to a highly reactive filopodia-generating cytoskeleton maximizes their vascular surface contact allowing rapid response capabilities. Functionally, platelets normally initiate rapid clotting, vasoconstriction, inflammation and wound biology that leads to sterilization, tissue repair and resolution. Platelets also are among the first to sense, phagocytize, decorate, or react to pathogens in the circulation. These platelet first responder properties are commandeered during chronic inflammation, cancer progression and metastasis. Leaky or inflammatory reaction blood vessel genesis during carcinogenesis provides opportunities for platelet invasion into tumors. Cancer is thought of as a non-healing or chronic wound that can be actively aided by platelet mitogenic properties to stimulate tumor growth. This growth ultimately outstrips circulatory support leads to angiogenesis and intravasation of tumor cells into the blood stream. Circulating tumor cells reengage additional platelets, which facilitates tumor cell adhesion, arrest and extravasation and metastasis. This process, along with the hypercoagulable states associated with malignancy is amplified by IL6 production in tumors that stimulate liver thrombopoietin production and elevates circulating platelet numbers by thrombopoiesis in the bone marrow. These complex interactions and the “First Responder” role of platelets during diverse physiologic stresses provides a useful therapeutic target that deserves further exploration. PMID:28730545

  9. Toll-like receptors in the inflammatory response during open and laparoscopic colectomy for colorectal cancer.

    PubMed

    Tsimogiannis, Konstantinos E; Tellis, Constantinos C; Tselepis, Alexandros D; Pappas-Gogos, George K; Tsimoyiannis, Evangelos C; Basdanis, George

    2012-02-01

    Surgical interventions activate a cascade of reactions that result in an aseptic inflammatory reaction. This inflammatory response initiates the organism's innate immunity. Laparoscopic surgery reduces the trauma, and patients benefit from diminished surgical trauma and maintained immune function. Cytokine levels and C-reactive protein (CRP) are related to the magnitude of surgical trauma and surgical stress. Toll-like receptors (TLRs) 2 and 4 are the first sensor-recognition receptors of the invading pathogens for the innate immune response. This study aimed to compare the inflammatory response and then the stress response during laparoscopic and open colectomy for cancer by calculating TLR-2 and TLR-4 as the first sensor-recognition receptors together with interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high-sensitivity CRP (hsCRP). A total 40 patients with colorectal cancer were randomized in two groups: group A (open colectomy, n = 20) and group B (laparoscopic colectomy, n = 20). An epidural catheter was placed in all patients 1 h preoperatively. Rupivocaine was administered perioperatively and 48 h postoperatively. Blood samples were taken for calculation of IL-6, TNF-α, hsCRP, TLR-2, and TLR-4 preoperatively and 5 min after deflation of pneumoperitoneum (group B) or 5 min after division of the colon (group A), then 6 and 24 h postoperatively. The mean operative time was 115 for group A and 142 min for group B. The mean blood loss was respectively 240 and 105 ml (P < 0.001), and the mean hospital stay was respectively 8 and 5 days (P < 0.05). The IL-6 level was significant higher in group A than in group B at 6 and 24 h postoperatively (P < 0.0001), and the hsCRP level was significant higher in group A than in group B at 24 h postoperatively (P < 0.001). The TNF-α values did not differ between the two groups. The TLR-2 level was significantly higher in group A than in group B at 5 min (P = 0.013) and 24 h (P = 0.007) postoperatively. The TLR-4

  10. Histogram analysis of apparent diffusion coefficient for monitoring early response in patients with advanced cervical cancers undergoing concurrent chemo-radiotherapy.

    PubMed

    Meng, Jie; Zhu, Lijing; Zhu, Li; Ge, Yun; He, Jian; Zhou, Zhengyang; Yang, Xiaofeng

    2017-11-01

    Background Apparent diffusion coefficient (ADC) histogram analysis has been widely used in determining tumor prognosis. Purpose To investigate the dynamic changes of ADC histogram parameters during concurrent chemo-radiotherapy (CCRT) in patients with advanced cervical cancers. Material and Methods This prospective study enrolled 32 patients with advanced cervical cancers undergoing CCRT who received diffusion-weighted (DW) magnetic resonance imaging (MRI) before CCRT, at the end of the second and fourth week during CCRT and one month after CCRT completion. The ADC histogram for the entire tumor volume was generated, and a series of histogram parameters was obtained. Dynamic changes of those parameters in cervical cancers were investigated as early biomarkers for treatment response. Results All histogram parameters except AUC low showed significant changes during CCRT (all P < 0.05). There were three variable trends involving different parameters. The mode, 5th, 10th, and 25th percentiles showed similar early increase rates (33.33%, 33.99%, 34.12%, and 30.49%, respectively) at the end of the second week of CCRT. The pre-CCRT 5th and 25th percentiles of the complete response (CR) group were significantly lower than those of the partial response (PR) group. Conclusion A series of ADC histogram parameters of cervical cancers changed significantly at the early stage of CCRT, indicating their potential in monitoring early tumor response to therapy.

  11. Changes in Water Mobility Measured by Diffusion MRI Predict Response of Metastatic Breast Cancer to Chemotherapy

    PubMed Central

    Theilmann, Rebecca J; Borders, Rebecca; Trouard, Theodore P; Xia, Guowei; Outwater, Eric; Ranger-Moore, James; Gillies, Robert J; Stopeck, Alison

    2004-01-01

    Abstract A goal of oncology is the individualization of patient care to optimize therapeutic responses and minimize toxicities. Achieving this will require noninvasive, quantifiable, and early markers of tumor response. Preclinical data from xenografted tumors using a variety of antitumor therapies have shown that magnetic resonance imaging (MRI)-measured mobility of tissue water (apparent diffusion coefficient of water, or ADCw) is a biomarker presaging cell death in the tumor. This communication tests the hypothesis that changes in water mobility will quantitatively presage tumor responses in patients with metastatic liver lesions from breast cancer. A total of 13 patients with metastatic breast cancer and 60measurable liver lesionsweremonitored by diffusion MRI after initiation of new courses of chemotherapy. MR images were obtained prior to, and at 4, 11, and 39 days following the initiation of therapy for determination of volumes and ADCw values. The data indicate that diffusion MRI can predict response by 4 or 11 days after commencement of therapy, depending on the analytic method. The highest concordance was observed in tumor lesions that were less than 8 cm3 in volume at presentation. These results suggest that diffusion MRI can be useful to predict the response of liver metastases to effective chemotherapy. PMID:15720810

  12. Response to ovarian stimulation is not impacted by a breast cancer diagnosis.

    PubMed

    Quinn, Molly M; Cakmak, Hakan; Letourneau, Joseph M; Cedars, Marcelle I; Rosen, Mitchell P

    2017-03-01

    Does a breast cancer diagnosis impact ovarian function in the setting of fertility preservation? Ovarian reserve and ovarian stimulation outcomes are similar in patients with a new diagnosis of breast cancer and patients undergoing elective fertility preservation. Prior studies, with small study populations, lack of controlling for individual differences in ovarian reserve and infertile controls, have reported conflicting outcomes for cancer patients undergoing ovarian stimulation for fertility preservation. This retrospective cohort analysis included 589 patients undergoing ovarian stimulation for fertility preservation between 2009 and 2015. Women with a recent breast cancer diagnosis (n = 191) and women desiring elective fertility preservation (n = 398) underwent ovarian stimulation with an antagonist protocol at an academic medical center. The aromatase inhibitor letrozole was administered to breast cancer patients with estrogen-sensitive disease. Baseline antral follicle count (AFC) was not different between the breast cancer patients and controls (15.4 ± 10.4 [mean ± SD] vs 15.4 ± 10.0, P = NS), even after categorization by age. Total (19.4 ± 0.9 [mean ± SEM] vs 17.0 ± 0.5, P = NS) and mature (MII) oocytes retrieved (13.7 ± 0.7 vs 13.2 ± 0.4, P = NS), adjusted for age, BMI and total gonadotropin dose, were also similar between the two groups. Letrozole use was associated with a decreased maturity rate (MII/total oocytes retrieved) compared to elective cryopreservation (0.71 ± 0.01 vs 0.77 ± 0.01, P < 0.001), although the mature oocyte yield [MII/AFC] was comparable (1.01 ± 0.06 vs 0.93 ± 0.03, P = NS). The single center design may impact generalizability. Additionally, the lack of subsequent embryo and pregnancy data is an inherent weakness. In females, a breast cancer diagnosis does not impact gonadal function as measured by AFC or ovarian stimulation outcomes. Breast cancer patients should be counseled that their response to ovarian stimulation

  13. Validation of the Intestinal Part of the Prostate Cancer Questionnaire 'QUFW94': Psychometric Properties, Responsiveness, and Content Validity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Reidunsdatter, Randi J.; Lund, Jo-Asmund; Department of Oncology, St. Olavs University Hospital, Trondheim

    Purpose: Several treatment options are available for patients with prostate cancer. Applicable and valid self-assessment instruments for assessing health-related quality of life (HRQOL) are of paramount importance. The aim of this study was to explore the validity and responsiveness of the intestinal part of the prostate cancer-specific questionnaire QUFW94. Methods and Materials: The content of the intestinal part of QUFW94 was examined by evaluation of experienced clinicians and reviewing the literature. The psychometric properties and responsiveness were assessed by analyzing HRQOL data from the randomized study Scandinavian Prostate Cancer Group 7 (SPCG)/Swedish Association for Urological Oncology 3 (SFUO). Subscales weremore » constructed by means of exploratory factor analyses. Internal consistency was assessed by Cronbach's alpha. Responsiveness was investigated by comparing baseline scores with the 4-year posttreatment follow-up. Results: The content validity was found acceptable, but some amendments were proposed. The factor analyses revealed two symptom scales. The first scale comprised five items regarding general stool problems, frequency, incontinence, need to plan toilet visits, and daily activity. Cronbach's alpha at 0.83 indicated acceptable homogeneity. The second scale was less consistent with a Cronbach's alpha at 0.55. The overall responsiveness was found to be very satisfactory. Conclusion: Two scales were identified in the bowel dimension of the QUFW94; the first one had good internal consistency. The responsiveness was excellent, and some modifications are suggested to strengthen the content validity.« less

  14. Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response.

    PubMed

    McKallip, Robert J; Nagarkatti, Mitzi; Nagarkatti, Prakash S

    2005-03-15

    In the current study, we tested the central hypothesis that exposure to Delta-9-tetrahydrocannabinol (Delta9-THC), the major psychoactive component in marijuana, can lead to enhanced growth of tumors that express low to undetectable levels of cannabinoid receptors by specifically suppressing the antitumor immune response. We demonstrated that the human breast cancer cell lines MCF-7 and MDA-MB-231 and the mouse mammary carcinoma 4T1 express low to undetectable levels of cannabinoid receptors, CB1 and CB2, and that these cells are resistant to Delta9-THC-induced cytotoxicity. Furthermore, exposure of mice to Delta9-THC led to significantly elevated 4T1 tumor growth and metastasis due to inhibition of the specific antitumor immune response in vivo. The suppression of the antitumor immune response was mediated primarily through CB2 as opposed to CB1. Furthermore, exposure to Delta9-THC led to increased production of IL-4 and IL-10, suggesting that Delta9-THC exposure may specifically suppress the cell-mediated Th1 response by enhancing Th2-associated cytokines. This possibility was further supported by microarray data demonstrating the up-regulation of a number of Th2-related genes and the down-regulation of a number of Th1-related genes following exposure to Delta9-THC. Finally, injection of anti-IL-4 and anti-IL-10 mAbs led to a partial reversal of the Delta9-THC-induced suppression of the immune response to 4T1. Such findings suggest that marijuana exposure either recreationally or medicinally may increase the susceptibility to and/or incidence of breast cancer as well as other cancers that do not express cannabinoid receptors and are resistant to Delta9-THC-induced apoptosis.

  15. Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia.

    PubMed

    Bohnert, Kyle R; Gallot, Yann S; Sato, Shuichi; Xiong, Guangyan; Hindi, Sajedah M; Kumar, Ashok

    2016-09-01

    Cachexia is a devastating syndrome that causes morbidity and mortality in a large number of patients with cancer. However, the mechanisms of cancer cachexia remain poorly understood. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes stress. The ER responds to this stress through activating certain pathways commonly known as the unfolding protein response (UPR). The main function of UPR is to restore homeostasis, but excessive or prolonged activation of UPR can lead to pathologic conditions. In this study, we examined the role of ER stress and UPR in regulation of skeletal muscle mass in naïve conditions and during cancer cachexia. Our results demonstrate that multiple markers of ER stress are highly activated in skeletal muscle of Lewis lung carcinoma (LLC) and Apc(Min/+) mouse models of cancer cachexia. Treatment of mice with 4-phenylbutyrate (4-PBA), a chemical chaperon and a potent inhibitor of ER stress, significantly reduced skeletal muscle strength and mass in both control and LLC-bearing mice. Blocking the UPR also increased the proportion of fast-type fibers in soleus muscle of both control and LLC-bearing mice. Inhibition of UPR reduced the activity of Akt/mTOR pathway and increased the expression of the components of the ubiquitin-proteasome system and autophagy in LLC-bearing mice. Moreover, we found that the inhibition of UPR causes severe atrophy in cultured myotubes. Our study provides initial evidence that ER stress and UPR pathways are essential for maintaining skeletal muscle mass and strength and for protection against cancer cachexia.-Bohnert, K. R., Gallot, Y. S., Sato, S., Xiong, G., Hindi, S. M., Kumar, A. Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia. © FASEB.

  16. Prediction of Response to Preoperative Chemoradiotherapy in Rectal Cancer by Multiplex Kinase Activity Profiling

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Folkvord, Sigurd; Flatmark, Kjersti; Department of Cancer and Surgery, Norwegian Radium Hospital, Oslo University Hospital

    2010-10-01

    Purpose: Tumor response of rectal cancer to preoperative chemoradiotherapy (CRT) varies considerably. In experimental tumor models and clinical radiotherapy, activity of particular subsets of kinase signaling pathways seems to predict radiation response. This study aimed to determine whether tumor kinase activity profiles might predict tumor response to preoperative CRT in locally advanced rectal cancer (LARC). Methods and Materials: Sixty-seven LARC patients were treated with a CRT regimen consisting of radiotherapy, fluorouracil, and, where possible, oxaliplatin. Pretreatment tumor biopsy specimens were analyzed using microarrays with kinase substrates, and the resulting substrate phosphorylation patterns were correlated with tumor response to preoperative treatmentmore » as assessed by histomorphologic tumor regression grade (TRG). A predictive model for TRG scores from phosphosubstrate signatures was obtained by partial-least-squares discriminant analysis. Prediction performance was evaluated by leave-one-out cross-validation and use of an independent test set. Results: In the patient population, 73% and 15% were scored as good responders (TRG 1-2) or intermediate responders (TRG 3), whereas 12% were assessed as poor responders (TRG 4-5). In a subset of 7 poor responders and 12 good responders, treatment outcome was correctly predicted for 95%. Application of the prediction model on the remaining patient samples resulted in correct prediction for 85%. Phosphosubstrate signatures generated by poor-responding tumors indicated high kinase activity, which was inhibited by the kinase inhibitor sunitinib, and several discriminating phosphosubstrates represented proteins derived from signaling pathways implicated in radioresistance. Conclusions: Multiplex kinase activity profiling may identify functional biomarkers predictive of tumor response to preoperative CRT in LARC.« less

  17. Hypoxia-Responsive Polymersomes for Drug Delivery to Hypoxic Pancreatic Cancer Cells.

    PubMed

    Kulkarni, Prajakta; Haldar, Manas K; You, Seungyong; Choi, Yongki; Mallik, Sanku

    2016-08-08

    Hypoxia in tumors contributes to overall tumor progression by assisting in epithelial-to-mesenchymal transition, angiogenesis, and metastasis of cancer. In this study, we have synthesized a hypoxia-responsive, diblock copolymer poly(lactic acid)-azobenzene-poly(ethylene glycol), which self-assembles to form polymersomes in an aqueous medium. The polymersomes did not release any encapsulated contents for 50 min under normoxic conditions. However, under hypoxia, 90% of the encapsulated dye was released in 50 min. The polymersomes encapsulated the combination of anticancer drugs gemcitabine and erlotinib with entrapment efficiency of 40% and 28%, respectively. We used three-dimensional spheroid cultures of pancreatic cancer cells BxPC-3 to demonstrate hypoxia-mediated release of the drugs from the polymersomes. The vesicles were nontoxic. However, a significant decrease in cell viability was observed in hypoxic spheroidal cultures of BxPC-3 cells in the presence of drug encapsulated polymersomes. These polymersomes have potential for future applications in imaging and treatment of hypoxic tumors.

  18. A facile approach to enhance antigen response for personalized cancer vaccination

    NASA Astrophysics Data System (ADS)

    Li, Aileen Weiwei; Sobral, Miguel C.; Badrinath, Soumya; Choi, Youngjin; Graveline, Amanda; Stafford, Alexander G.; Weaver, James C.; Dellacherie, Maxence O.; Shih, Ting-Yu; Ali, Omar A.; Kim, Jaeyun; Wucherpfennig, Kai W.; Mooney, David J.

    2018-06-01

    Existing strategies to enhance peptide immunogenicity for cancer vaccination generally require direct peptide alteration, which, beyond practical issues, may impact peptide presentation and result in vaccine variability. Here, we report a simple adsorption approach using polyethyleneimine (PEI) in a mesoporous silica microrod (MSR) vaccine to enhance antigen immunogenicity. The MSR-PEI vaccine significantly enhanced host dendritic cell activation and T-cell response over the existing MSR vaccine and bolus vaccine formulations. Impressively, a single injection of the MSR-PEI vaccine using an E7 peptide completely eradicated large, established TC-1 tumours in about 80% of mice and generated immunological memory. When immunized with a pool of B16F10 or CT26 neoantigens, the MSR-PEI vaccine eradicated established lung metastases, controlled tumour growth and synergized with anti-CTLA4 therapy. Our findings from three independent tumour models suggest that the MSR-PEI vaccine approach may serve as a facile and powerful multi-antigen platform to enable robust personalized cancer vaccination.

  19. Appraisal of breast cancer symptoms by Iranian women: entangled cognitive, emotional and socio-cultural responses.

    PubMed

    Khakbazan, Zohreh; Roudsari, Robab Latifnejad; Taghipour, Ali; Mohammadi, Eesa; Pour, Ramesh Omrani

    2014-01-01

    Breast cancer is the most common cancer in Iranian women and usually features delayed presentation and late diagnosis. Interpretation of symptoms, as the most important step, has a significant impact on patient delay in seeking treatment. There is a dearth of studies on symptom appraisal and the process leading to seeking help in breast cancer patients. This study explored the perceptions and experiences of Iranian women with self-detected possible breast cancer symptoms. A qualitative method was conducted involving in-depth semi-structured interviews with 27 Iranian women with self-discovered breast cancer symptoms. Participants were purposefully selected from women who attended Cancer Institute of Tehran University of Medical Sciences during June 2012 to August 2013. The audiotaped interviews were transcribed and analyzed using conventional content analysis with MAXQDA soft ware version 10. The trustworthiness of the study was verified by prolonged engagement, member validation of codes, and thick description. The main concepts emerging from data analysis were categorized in four categories: symptom recognition, labeling of symptoms, interactive understanding, and confronting the fear of cancer. Symptom recognition through breast self-examination, symptom monitoring and employing prior knowledge distinguished normal from abnormal symptoms and accompanied with perception of being at risk of breast cancer led to symptom labeling. Social interaction by selective disclosure and receiving reassurance from a consultant led to confirmation or redefinition of the situation. Perceived seriousness of the situation and social meanings of breast cancer as a stigmatized and incurable illness associated with loss of femininity were reasons for patient worries and fear. This study emphasized that entangled cognitive, emotional and socio-cultural responses affecting understanding of symptom seriousness require further investigation. It is suggested that programs aimed at

  20. An 80-gene set to predict response to preoperative chemoradiotherapy for rectal cancer by principle component analysis.

    PubMed

    Empuku, Shinichiro; Nakajima, Kentaro; Akagi, Tomonori; Kaneko, Kunihiko; Hijiya, Naoki; Etoh, Tsuyoshi; Shiraishi, Norio; Moriyama, Masatsugu; Inomata, Masafumi

    2016-05-01

    Preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer not only improves the postoperative local control rate, but also induces downstaging. However, it has not been established how to individually select patients who receive effective preoperative CRT. The aim of this study was to identify a predictor of response to preoperative CRT for locally advanced rectal cancer. This study is additional to our multicenter phase II study evaluating the safety and efficacy of preoperative CRT using oral fluorouracil (UMIN ID: 03396). From April, 2009 to August, 2011, 26 biopsy specimens obtained prior to CRT were analyzed by cyclopedic microarray analysis. Response to CRT was evaluated according to a histological grading system using surgically resected specimens. To decide on the number of genes for dividing into responder and non-responder groups, we statistically analyzed the data using a dimension reduction method, a principle component analysis. Of the 26 cases, 11 were responders and 15 non-responders. No significant difference was found in clinical background data between the two groups. We determined that the optimal number of genes for the prediction of response was 80 of 40,000 and the functions of these genes were analyzed. When comparing non-responders with responders, genes expressed at a high level functioned in alternative splicing, whereas those expressed at a low level functioned in the septin complex. Thus, an 80-gene expression set that predicts response to preoperative CRT for locally advanced rectal cancer was identified using a novel statistical method.