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1

Radiosensitization effect of zidovudine on human malignant glioma cells  

SciTech Connect

Telomeres are shortened with each cell division and play an important role in maintaining chromosomal integrity and function. Telomerase, responsible for telomere synthesis, is activated in 90% of human tumor cells but seldom in normal somatic cells. Zidovudine (AZT) is a reverse transcriptase inhibitor. In this study, we have investigated the effects of {gamma}-radiation in combination with AZT on telomerase activity (TA), telomere length, DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs), and the changes in radiosensitivity of human malignant glioma cell line U251. The results showed that the TA was suppressed by AZT but enhanced by irradiation, resulting in a deceleration of restored rate of shortened telomere, decreased repair rate of DNA strand breaks, and increased radiosensitivity of U251 cells. Our results suggested that telomerase activity and telomere length may serve as markers for estimating the efficacy of cancer radiotherapy and reverse transcriptase inhibitors, such as AZT, may be used clinically as a new radiosensitizer in cancer radiotherapy.

Zhou Fuxiang [Department of Chemo-Radiotherapy Oncology, Zhongnan Hospital, Wuhan University, Cancer Center of Wuhan University, Wuhan, Hubei 430071 (China); Liao Zhengkai [Department of Chemo-Radiotherapy Oncology, Zhongnan Hospital, Wuhan University, Cancer Center of Wuhan University, Wuhan, Hubei 430071 (China); Dai Jing [Department of Chemo-Radiotherapy Oncology, Zhongnan Hospital, Wuhan University, Cancer Center of Wuhan University, Wuhan, Hubei 430071 (China); Xiong Jie [Department of Chemo-Radiotherapy Oncology, Zhongnan Hospital, Wuhan University, Cancer Center of Wuhan University, Wuhan, Hubei 430071 (China); Xie CongHua [Department of Chemo-Radiotherapy Oncology, Zhongnan Hospital, Wuhan University, Cancer Center of Wuhan University, Wuhan, Hubei 430071 (China); Luo Zhiguo [Department of Chemo-Radiotherapy Oncology, Zhongnan Hospital, Wuhan University, Cancer Center of Wuhan University, Wuhan, Hubei 430071 (China); Liu Shiquan [Department of Chemo-Radiotherapy Oncology, Zhongnan Hospital, Wuhan University, Cancer Center of Wuhan University, Wuhan, Hubei 430071 (China); Zhou Yunfeng [Department of Chemo-Radiotherapy Oncology, Zhongnan Hospital, Wuhan University, Cancer Center of Wuhan University, Wuhan, Hubei 430071 (China)]. E-mail: yfzhouwhu@163.com

2007-03-09

2

Radiosensitization by fullerene-C60 dissolved in squalene on human malignant melanoma through lipid peroxidation and enhanced mitochondrial membrane potential  

NASA Astrophysics Data System (ADS)

We examined fullerene-C60 dissolved in squalene (C60/Sqe) for the ability to potentiate the radiosensitization under X-ray irradiation on human malignant melanoma HMV-II cells, which were treated with C60/Sqe and thereafter irradiated with X-ray. The cell proliferation for C60/Sqe was inhibited more markedly than for Sqe alone. Meanwhile, cell proliferation was almost unaltered for C60/squalane (Sqa) or Sqa, a hydrogenated form of Sqe, as compared to no-additive control. Thus radiosensitization of C60/Sqe is attributed to peroxidation of unsaturated bonds of squalene by X-ray-excited C60 in contrast to squalane. The fluorescence images of HMV-II cells stained with Rhodamine123, an indicator for mitochondrial membrane potential, were monitored for 6 h after X-ray irradiation. C60/Sqe obviously exhibited more augmented fluorescence intensity on perinuclear region of HMV-II cells than Sqe alone. TBARS assay showed that the lipid peroxidation level as malondialdehyde-equivalent increased by combination of C60/Sqe and X-ray dose-dependently on X-ray doses. C60/Sqe exhibited lipid peroxidation more markedly by 1.2-fold than Sqe alone. Thus the level of lipid peroxidation of squalene was sufficiently higher in C60/Sqe than in Sqe in the absence of C60 under X-ray irradiation, suggesting the combination of C60/Sqe and X-ray irradiation induced radiosensitization on HMV-II cells by peroxidation of absorbed Sqe in mitochondrial membrane via oxidative stress mediated by fullerene-C60.

Kato, Shinya; Kimura, Masatsugu; Miwa, Nobuhiko

2014-04-01

3

Radiosensitization of malignant glioma cells through overexpression of dominant-negative epidermal growth factor receptor.  

PubMed

The epidermal growth factor receptor (EGFR) plays an important role in neoplastic growth control of malignant gliomas. We have demonstrated that radiation activates EGFR Tyr-phosphorylation (EGFR Tyr-P) and the proliferation of surviving human carcinoma cells, a likely mechanism of accelerated cellular repopulation, a major cytoprotective response after radiation. We now investigate the importance of radiation-induced activation of EGFR on the radiosensitivity of the human malignant glioma cells U-87 MG and U-373 MG. The function of EGFR was inhibited through a genetic approach of transducing cells with an Adenovirus (Ad) vector containing dominant-negative (DN) EGFR-CD533 (Ad-EGFR-CD533) at efficiencies of 85-90%. The resulting cells are referred to as U-87-EGFR-CD533 and U-373-EGFR-CD533. After irradiation at 2 Gy, both of the cell lines exhibited a mean 3-fold increase in EGFR Tyr-P. The expression of EGFR-CD533 completely inhibited the radiation-induced activation of EGFR. In clonogenic survival assays after a single radiation exposure, the radiation dose for a survival of 37% (D37) for U-87-EGFR-CD533 cells was 1.4- to 1.5-fold lower, relative to cells transduced with AdLacZ or untransduced U-87 MG cells. This effect was amplified with repeated radiation exposures (3 x 2 Gy) yielding a D37 ratio of 1.8-2.0. In clonogenic survival studies with U-373 MG cells, the radiosensitizing effect of EGFR-CD533 was similar. Furthermore, in vivo studies with U-87 MG xenografts confirmed the effect of EGFR-CD533 on tumor radiosensitization (dose enhancement ratio, 1.8). We conclude that inhibition of EGFR function via Ad-mediated gene transfer of EGFR-CD533 results in significant radiosensitization. As underlying mechanism, we suggest the disruption of a major cytoprotective response involving EGFR and its downstream effectors, such as mitogen-activated protein kinase. The experiments demonstrate for the first time that radiosensitization of malignant glioma cells through disruption of EGFR function may be achieved by genetic therapy approaches. PMID:11297265

Lammering, G; Valerie, K; Lin, P S; Mikkelsen, R B; Contessa, J N; Feden, J P; Farnsworth, J; Dent, P; Schmidt-Ullrich, R K

2001-03-01

4

Intra-arterial bromodeoxyuridine radiosensitization of malignant gliomas  

SciTech Connect

In the 1950's it was first observed that mammalian cells exposed to the halogenated deoxyuridines were more sensitive to ultraviolet light and radiation than untreated cells. This prompted early clinical trials with bromodeoxyuridine (BUdR) which showed mixed results. More recently, several Phase I studies, while establishing the feasibility of continuous intravenous (IV) infusion of BUdR, have reported significant dose limiting skin and bone marrow toxicities and have questioned the optimal method of BUdR delivery. To exploit the high mitotic activity of malignant gliomas relative to surrounding normal brain tissue, we have developed a permanently implantable infusion pump system for safe, continuous intraarterial (IA) internal carotid BUdR delivery. Since July 1985, 23 patients with malignant brain tumors (18 grade 4, 5 grade 3) have been treated in a Phase I clinical trial using IA BUdR (400-600 mg/m2/day X 8 1/2 weeks) and focal external beam radiotherapy (59.4 Gy at 1.8 Gy/day in 6 1/2 weeks). Following initial biopsy/surgery the infusion pump system was implanted; BUdR infusion began 2 weeks prior to and continued throughout the 6 1/2 week course of radiotherapy. There have been no vascular complications. Side-effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Myelosuppression requiring dose reduction occurred in one patient. An overall Kaplan-Meier estimated median survival of 20 months has been achieved. As in larger controlled series, histologic grade and age are prognostically significant. We have shown in a Phase I study that IA BUdR radiosensitization is safe, tolerable, may lead to improved survival, and appears to be an efficacious primary treatment of malignant gliomas.

Hegarty, T.J.; Thornton, A.F.; Diaz, R.F.; Chandler, W.F.; Ensminger, W.D.; Junck, L.; Page, M.A.; Gebarski, S.S.; Hood, T.W.; Stetson, P.L. (Univ. of Michigan Medical Center, Ann Arbor (USA))

1990-08-01

5

SU11657 Enhances Radiosensitivity of Human Meningioma Cells  

SciTech Connect

Purpose: To analyze the effect of the multireceptor tyrosine kinase inhibitor SU11657 (primarily vascular endothelial growth factor, platelet-derived growth factor) in combination with irradiation in freshly isolated primary human meningioma cells. Methods and Materials: Tumor specimens were obtained from meningioma patients undergoing surgery at the Department of Neurosurgery, University of Heidelberg, Germany. For the present study only cells up to passage 6 were used. Benign and atypical meningioma cells and human umbilical vein endothelial cells (HUVEC) were treated with SU11657 alone and in combination with 6-MV photons (0-10 Gy). Clonogenic survival and cell proliferation were determined alone and in coculture assays to determine direct and paracrine effects. Results: Radiation and SU11657 alone reduced cell proliferation in atypical and benign meningioma cells as well as in HUVEC in a dose-dependent manner. SU11657 alone also reduced clonogenic survival of benign and atypical meningioma cells. SU11657 increased radiosensitivity of human meningioma cells in clonogenic survival and cell number/proliferation assays. The anticlonogenic and antiproliferative effects alone and the radiosensitization effects of SU11657 were more pronounced in atypical meningioma cells compared with benign meningioma cells. Conclusion: Small-molecule tyrosine kinase inhibitors like SU11657 are capable of amplifying the growth inhibitory effects of irradiation in meningioma cells. These data provide a rationale for further clinical evaluation of this combination concept, especially in atypical and malignant meningioma patients.

Milker-Zabel, Stefanie [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany)], E-mail: stefanie_milker-zabel@med.uni-heidelberg.de; Bois, Angelika Zabel-du [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany); Ranai, Gholamreza [Department of Neurosurgery, University of Heidelberg, Heidelberg (Germany); Trinh, Thuy [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany); Department of Radiation Oncology, German Cancer Research Center, Heidelberg (Germany); Unterberg, Andreas [Department of Neurosurgery, University of Heidelberg, Heidelberg (Germany); Debus, Juergen [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany); Lipson, Kenneth E. [3M Pharmaceuticals, St. Paul, MN (United States); Abdollahi, Amir; Huber, Peter E. [Department of Radiation Oncology, University of Heidelberg, Heidelberg (Germany); Department of Radiation Oncology, German Cancer Research Center, Heidelberg (Germany)

2008-03-15

6

Radiosensitization of human bronchogenic carcinoma cells by interferon beta  

SciTech Connect

The effects of interferons on the radiosensitivity of in vitro human bronchogenic carcinoma cells was investigated. Human fibroblast-derived interferon (IFN-beta) was found to sensitize cells to gamma irradiation while either HuIFN-alpha or mouse IFN-alpha/beta did not. The observed radiosensitization was supra-additive and resulted in a decrease in the shoulder width of the radiation dose-cell survival curve but did not affect the slope. The degree of radiosensitization of the various IFNs tested paralleled the antiproliferative effects of these IFNs on this cell line.

Gould, M.N.; Kakria, R.C.; Olson, S.; Borden, E.C.

1984-01-01

7

Hyaluronan in human malignancies  

SciTech Connect

Hyaluronan, a major macropolysaccharide in the extracellular matrix of connective tissues, is intimately involved in the biology of cancer. Hyaluronan accumulates into the stroma of various human tumors and modulates intracellular signaling pathways, cell proliferation, motility and invasive properties of malignant cells. Experimental and clinicopathological evidence highlights the importance of hyaluronan in tumor growth and metastasis. A high stromal hyaluronan content is associated with poorly differentiated tumors and aggressive clinical behavior in human adenocarcinomas. Instead, the squamous cell carcinomas and malignant melanomas tend to have a reduced hyaluronan content. In addition to the stroma-cancer cell interaction, hyaluronan can influence stromal cell recruitment, tumor angiogenesis and epithelial-mesenchymal transition. Hyaluronan receptors, hyaluronan synthases and hyaluronan degrading enzymes, hyaluronidases, are involved in the modulation of cancer progression, depending on the tumor type. Furthermore, intracellular signaling and angiogenesis are affected by the degradation products of hyaluronan. Hyaluronan has also therapeutic implications since it is involved in multidrug resistance.

Sironen, R.K. [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland) [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland); Department of Pathology, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland); Tammi, M.; Tammi, R. [Institute of Biomedicine, Anatomy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland)] [Institute of Biomedicine, Anatomy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland); Auvinen, P.K. [Department of Oncology, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland)] [Department of Oncology, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland); Anttila, M. [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland) [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland); Department of Gynecology and Obstetrics, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland); Kosma, V-M., E-mail: Veli-Matti.Kosma@uef.fi [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland); Department of Pathology, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland)

2011-02-15

8

Siah1 proteins enhance radiosensitivity of human breast cancer cells  

Microsoft Academic Search

BACKGROUND: Siah proteins play an important role in cancer progression. We evaluated the effect of Siah1, its splice variants Siah1L and the Siah1 mutant with the RING finger deleted (Siah1?R) on radiosensitization of human breast cancer cells. METHODS: The status of Siah1 and Siah1L was analysed in five breast cancer cell lines. To establish stable cells, SKBR3 cells were transfected

Hai-Tao He; Emmanouil Fokas; An You; Rita Engenhart-Cabillic; Han-Xiang An

2010-01-01

9

Radiosensitization effects of berberine on human breast cancer cells.  

PubMed

Berberine, an isoquinoline derivative alkaloid, has recently been shown to have antitumor activity. The present study aimed to investigate the effects of the concomitant administration of berberine and radiation on breast cancer. The effects of berberine on the radiosensitivity of MCF-7 and MDA-MB-468 cells were evaluated by using cell clonogenic assays. Cells pre-treated with berberine or dimethyl sulfoxide (DMSO) for 24 h were irradiated using a Faxitron Cabinet X-ray System to deliver the indicated doses (0, 1, 2, 3 and 4 Gy). Changes in cell cycle distribution were determined by flow cytometry. ?-H2AX foci were detected by immunofluorescence staining. The levels of Ku70, Ku86 and RAD51 proteins were evaluated by western blot analysis. We observed that berberine increased the MCF-7 and MDA-MB-468 cell radiosensitivity with cell clonogenic assays. the radiation-induced G2/M cell cycle delay was reduced in the MCF-7 cells pre-teated with berberine. Berberine pre-treatment prolonged the persistence of DNA double-strand breaks in the MCF-7 cell line. In comparison with the control cells, the protein levels of RAD51 were decreased in the MCF-7 and MDA-MB-468 cells treated with berberine, and in the cells pre-treated with 15 µM berberine for 24 h, the level of RAD51 protein decreased significantly at the indicated time-points (0, 2, 6 and 24 h) following X-ray exposure. In conclusion, berberine sensitizes human breast cancer cells to ionizing radiation by inducing cell cycle arrest and the downregulation of the homologous recombination repair protein, RAD51. Berberine may be a promising radiosensitizer for the treatment of breast cancer. PMID:22895634

Wang, Jing; Liu, Qiao; Yang, Qifeng

2012-11-01

10

Studies of the in vivo radiosensitivity of human skin fibroblasts  

PubMed Central

Background and Purpose To examine the radiosensitivity of skin cells obtained directly from the irradiated skin of patients undergoing fractionated radiation treatment prior to surgery for treatment of soft tissue sarcoma (STS) and to determine if there was a relationship with the development of wound healing complications associated with the surgery post-radiotherapy. Methods Micronucleus (MN) formation was measured in cells (primarily dermal fibroblasts) obtained from human skin at their first division after being removed from STS patients during post radiotherapy surgery (2-9 weeks after the end of the radiotherapy). At the time of radiotherapy (planned tumor dose - 50 Gy in 25 daily fractions) measurements were made of surface skin dose at predetermined marked sites. Skin from these sites was obtained at surgery and cell suspensions were prepared directly for the cytokinesis-blocked MN assay. Cultured strains of the fibroblasts were also established from skin nominally outside the edge of the radiation beam and DNA damage (MN formation) was examined following irradiation in vitro for comparison with the results from the in situ irradiations. Results Extensive DNA damage (MN) was detectable in fibroblasts from human skin at extended periods after irradiation (2-9 weeks after the end of the 5-week fractionated radiotherapy). Analysis of skin receiving a range of doses demonstrated that the level of damage observed was dose dependent. There was no clear correlation between the level of damage observed after irradiation in situ and irradiation of cell strains in culture. Similarly, there was no correlation between the extent of MN formation following in situ irradiation and the propensity for the patient to develop wound healing complications post surgery. Conclusions Despite the presence of DNA damage in dermal fibroblasts weeks after the end of the radiation treatment, there was no relationship between this damage and wound healing complications following surgery post irradiation. These results suggest that factors other than the radiosensitivity of the skin fibroblasts likely also play a role in wound healing in deep wound sites associated with surgery for STS following radiation therapy. PMID:17590467

Hill, R. P.; Kaspler, P.; Griffin, A.M.; O'Sullivan, B.; Catton, C.; Alasti, H.; Abbas, A.; Heydarian, M.; Ferguson, P.; Wunder, J.S.; Bell, R.S.

2007-01-01

11

Fulvestrant radiosensitizes human estrogen receptor-positive breast cancer cells  

SciTech Connect

Highlights: ? Fulvestrant radiosensitizes MCF-7 cells. ? Fulvestrant increases G1 arrest and decreases S phase in MCF-7 cells. ? Fulvestrant down-regulates DNA-PKcs and RAD51 in MCF-7 cells. -- Abstract: The optimal sequencing for hormonal therapy and radiation are yet to be determined. We utilized fulvestrant, which is showing promise as an alternative to other agents in the clinical setting of hormonal therapy, to assess the cellular effects of concomitant anti-estrogen therapy (fulvestrant) with radiation (F + RT). This study was conducted to assess the effects of fulvestrant alone vs. F + RT on hormone-receptor positive breast cancer to determine if any positive or negative combined effects exist. The effects of F + RT on human breast cancer cells were assessed using MCF-7 clonogenic and tetrazolium salt colorimetric (MTT) assays. The assays were irradiated with a dose of 0, 2, 4, 6 Gy ± fulvestrant. The effects of F + RT vs. single adjuvant treatment alone on cell-cycle distribution were assessed using flow cytometry; relative expression of repair proteins (Ku70, Ku80, DNA-PKcs, Rad51) was assessed using Western Blot analysis. Cell growth for radiation alone vs. F + RT was 0.885 ± 0.013 vs. 0.622 ± 0.029 @2 Gy, 0.599 ± 0.045 vs. 0.475 ± 0.054 @4 Gy, and 0.472 ± 0.021 vs. 0.380 ± 0.018 @6 Gy RT (p = 0.003). While irradiation alone induced G2/M cell cycle arrest, the combination of F + RT induced cell redistribution in the G1 phase and produced a significant decrease in the proportion of cells in G2 phase arrest and in the S phase in breast cancer cells (p < 0.01). Furthermore, levels of repair proteins DNA-PKcs and Rad51 were significantly decreased in the cells treated with F + RT compared with irradiation alone. F + RT leads to a decrease in the surviving fraction, increased cell cycle arrest, down regulating of nonhomologous repair protein DNA-PKcs and homologous recombination repair protein RAD51. Thus, our findings suggest that F + RT increases breast cancer cell radiosensitivity compared with radiation alone. These findings have salient implications for designing clinical trials using fulvestrant and radiation therapy.

Wang, Jing, E-mail: wangstella5@163.com [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China) [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China); Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Shandong Province (China); Yang, Qifeng, E-mail: qifengy@gmail.com [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China)] [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China); Haffty, Bruce G., E-mail: hafftybg@umdnj.edu [Department of Radiation Oncology, UMDNJ-Robert Wood Johnson School of Medicine, Cancer Institute of New Jersey, NB (United States); Li, Xiaoyan, E-mail: xiaoyanli1219@gmail.com [Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Shandong Province (China)] [Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Shandong Province (China); Moran, Meena S., E-mail: meena.moran@yale.edu [Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT (United States)

2013-02-08

12

Evaluation of nitroimidazole hypoxic cell radiosensitizers in a human tumor cell line high in intracellular glutathione  

SciTech Connect

Five nitroimidazole hypoxic cell radiosensitizers were evaluated in a human lung adenocarcinoma cell line (A549) whose GSH level was 8-fold higher than Chinese hamster V79 cells. One millimolar concentrations of Misonidazole (MISO), SR-2508, RSU-1164, RSU-1172, and Ro-03-8799 sensitized hypoxic A549 cells to radiation, with Ro-03-8799 giving the highest sensitizer enhancement ration (SER) (2.3). However, MISO, SR-2508 and Ro-03-8799 were less effective in this cell line than in V79 cells, presumably due to higher GSH content of the A549 cells. Increased hypoxic radiosensitization was seen with 0.1 mM Ro-03-8799 after GSH depletion by BSO as compared to 0.1 mM Ro-03-8799 alone (SER-1.8 vs 1.3). The combination of GSH depletion and 0.1 mM Ro-03-8799 was considerably more toxic than 0.1 mM or 1.0 mM Ro-03-8799 alone. This sensitivity was much greater than has been observed for SR-2508. These data show that Ro-03-8799 was the most efficient hypoxic cell radiosensitizer in a human tumor cell line considerably higher in GSH than the rodent cell lines often used in hypoxic radiosensitization studies. Thus, Ro-03-8799 may be a more effective hypoxic cell sensitizer in human tumors that are high in GSH.

DeGraff, W.G.; Russo, A.; Gamson, J.; Mitchell, J.B.

1989-04-01

13

Antiviral agent Cidofovir decreases Epstein–Barr virus (EBV) oncoproteins and enhances the radiosensitivity in EBV-related malignancies  

Microsoft Academic Search

The Epstein–Barr virus (EBV) is involved in the carcinogenesis of several human cancers such as nasopharyngeal carcinoma (NPC) and Burkitt lymphoma (BL). Given the consistent role of EBV in transformation and maintenance of malignant phenotype, antiviral strategies provide an attractive approach to target EBV-expressing cells. In that aim, we have tested the Cidofovir, which is an acyclic nucleoside phosphonate analog

Bassam Abdulkarim; Siham Sabri; Diana Zelenika; Eric Deutsch; Valerie Frascogna; Jerzy Klijanienko; William Vainchenker; Irène Joab; Jean Bourhis

2003-01-01

14

Overview of Radiosensitivity of Human Tumor Cells to Low-Dose-Rate Irradiation  

SciTech Connect

Purpose: We compared clonogenic survival in 27 human tumor cell lines that vary in genotype after low-dose-rate (LDR) or high-dose rate (HDR) irradiation. We measured susceptibility to LDR-induced redistribution in the cell cycle in eight of these cell lines. Methods and Materials: We measured clonogenic survival after up to 96 hours of LDR (0.25 Gy/h) irradiation. We compared these with clonogenic survival after HDR irradiation (50 Gy/h). Using flow cytometry, we measured LDR-induced redistribution as a function of time during LDR irradiation in eight of these cell lines. Results: Coefficients that describe clonogenic survival after both LDR and HDR irradiation segregate into four radiosensitivity groups that associate with cell genotype: mutant (mut)ATM, wild-type TP53, mutTP53, and an unidentified gene in radioresistant glioma cells. The LDR and HDR radiosensitivity correlates at lower doses ({approx}2 Gy HDR, {approx}6 Gy LDR), but not at higher doses (HDR > 4 Gy; LDR > 6 Gy). The rate of LDR-induced loss of clonogenic survival changes at approximately 24 hours; wild-type TP53 cells become more resistant and mutTP53 cells become more sensitive. Redistribution induced by LDR irradiation also changes at approximately 24 hours. Conclusions: Radiosensitivity of human tumor cells to both LDR and HDR irradiation is genotype dependent. Analysis of coefficients that describe cellular radiosensitivity segregates 27 cell lines into four statistically distinct groups, each associating with specific genotypes. Changes in cellular radiosensitivity and redistribution in the cell cycle are strongly time dependent. Our data establish a genotype-dependent time-dependent model that predicts clonogenic survival, explains the inverse dose-rate effect, and suggests possible clinical applications.

Williams, Jerry R. [Molecular Radiation Biology Program, Department of Radiation Medicine, Loma Linda Medical Center, Loma Linda, CA (United States); Laboratory of Radiobiology, Johns Hopkins School of Medicine, Baltimore, MD (United States)], E-mail: jrwilliams_france@yahoo.com; Zhang Yonggang; Zhou Haoming [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD (United States); Gridley, Daila S. [Molecular Radiation Biology Program, Department of Radiation Medicine, Loma Linda Medical Center, Loma Linda, CA (United States); Koch, Cameron J. [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA (United States); Slater, James M. [Molecular Radiation Biology Program, Department of Radiation Medicine, Loma Linda Medical Center, Loma Linda, CA (United States); Little, John B. [Center for Radiation Sciences and Environmental Health, Harvard School of Public Health, Boston, MA (United States)

2008-11-01

15

MicroRNA-218 Enhances the Radiosensitivity of Human Cervical Cancer via Promoting Radiation Induced Apoptosis  

PubMed Central

We previously reported frequent loss of microRNA-218 (miR-218) in cervical cancer, which was associated with tumor progression and poor prognosis. As microRNAs were found invovled in the regulation of radiosensitivity in various human cancers, we therefore aim to investigate the effects of miR-218 on radiosensitivity of cervical cancer in the present study. The clonogenic survival assay demonstrated that loss of miR-218 could predict radioresistance in the primary cervical cancer cells (R2=0.6516, P<0.001). In vitro, abundant miR-218 increased the radiosensitivity in cervical cancer cells (P<0.001 for HeLa, P=0.009 for SiHa, P=0.016 for C33A and P=0.01 for CaSki). Upregulation of miR-218 significantly enhanced the radiation-induced apoptosis, which was further enhanced by the combination of miR-218 overexpression and radiation In xenograft growth assay, combination of miR-218 overexpression and radiation notably induced cellular apoptosis and suppressed tumor growth. In conclusion, we demonstrated that miR-218 resensitized cervical cancer cells to radiation via promoting cellular apoptosis. Moreover, we proved that miR-218 as a potent predictor of radiosensitivity in cervical cancer, especially for those patients with loss of miR-218. PMID:24843318

Yuan, Wang; Xiaoyun, Han; Haifeng, Qiu; Jing, Li; Weixu, Hu; Ruofan, Dong; Jinjin, Yu; Zongji, Shen

2014-01-01

16

Therapeutic and radiosensitizing effects of armillaridin on human esophageal cancer cells.  

PubMed

Background. Armillaridin (AM) is isolated from Armillaria mellea. We examined the anticancer activity and radiosensitizing effect on human esophageal cancer cells. Methods. Human squamous cell carcinoma (CE81T/VGH and TE-2) and adenocarcinoma (BE-3 and SKGT-4) cell lines were cultured. The MTT assay was used for cell viability. The cell cycle was analyzed using propidium iodide staining. Mitochondrial transmembrane potential was measured by DiOC6(3) staining. The colony formation assay was performed for estimation of the radiation surviving fraction. Human CE81T/VGH xenografts were established for evaluation of therapeutic activity in vivo. Results. AM inhibited the viability of four human esophageal cancer cell lines with an estimated concentration of 50% inhibition (IC50) which was 3.4-6.9??M. AM induced a hypoploid cell population and morphological alterations typical of apoptosis in cells. This apoptosis induction was accompanied by a reduction of mitochondrial transmembrane potential. AM accumulated cell cycle at G2/M phase and enhanced the radiosensitivity in CE81T/VGH cells. In vivo, AM inhibited the growth of CE81T/VGH xenografts without significant impact on body weight and white blood cell counts. Conclusion. Armillaridin could inhibit growth and enhance radiosensitivity of human esophageal cancer cells. There might be potential to integrate AM with radiotherapy for esophageal cancer treatment. PMID:23864890

Chi, Chih-Wen; Chen, Chien-Chih; Chen, Yu-Jen

2013-01-01

17

Therapeutic and Radiosensitizing Effects of Armillaridin on Human Esophageal Cancer Cells  

PubMed Central

Background. Armillaridin (AM) is isolated from Armillaria mellea. We examined the anticancer activity and radiosensitizing effect on human esophageal cancer cells. Methods. Human squamous cell carcinoma (CE81T/VGH and TE-2) and adenocarcinoma (BE-3 and SKGT-4) cell lines were cultured. The MTT assay was used for cell viability. The cell cycle was analyzed using propidium iodide staining. Mitochondrial transmembrane potential was measured by DiOC6(3) staining. The colony formation assay was performed for estimation of the radiation surviving fraction. Human CE81T/VGH xenografts were established for evaluation of therapeutic activity in vivo. Results. AM inhibited the viability of four human esophageal cancer cell lines with an estimated concentration of 50% inhibition (IC50) which was 3.4–6.9??M. AM induced a hypoploid cell population and morphological alterations typical of apoptosis in cells. This apoptosis induction was accompanied by a reduction of mitochondrial transmembrane potential. AM accumulated cell cycle at G2/M phase and enhanced the radiosensitivity in CE81T/VGH cells. In vivo, AM inhibited the growth of CE81T/VGH xenografts without significant impact on body weight and white blood cell counts. Conclusion. Armillaridin could inhibit growth and enhance radiosensitivity of human esophageal cancer cells. There might be potential to integrate AM with radiotherapy for esophageal cancer treatment. PMID:23864890

Chi, Chih-Wen; Chen, Chien-Chih; Chen, Yu-Jen

2013-01-01

18

Lin28-let7 Modulates Radiosensitivity of Human Cancer Cells With Activation of K-Ras  

SciTech Connect

Purpose: To evaluate the potential of targeting Lin28-let7 microRNA regulatory network for overcoming the radioresistance of cancer cells having activated K-Ras signaling. Methods and Materials: A549 lung carcinoma cells and ASPC1 pancreatic cancer cells possessing K-RAS mutation were transfected with pre-let7a microRNA or Lin28 siRNA, respectively. Clonogenic assay, quantitative reverse transcription polymerase chain reaction, and Western analysis were performed. The effects of Lin28 on SQ20B cells having wild-type K-RAS, and a normal fibroblast were also assessed. Results: The overexpression of let-7a decreased expression of K-Ras and radiosensitized A549 cells. Inhibition of Lin28, a repressor of let-7, attenuated K-Ras expression and radiosensitized A549 and ASPC1 cells. Neither SQ20B cells expressing wild-type K-RAS nor HDF, the normal human fibroblasts, were radiosensitized by this approach. Conclusions: The Lin28-let7 regulatory network may be a potentially useful therapeutic target for overcoming the radioresistance of human cancers having activated K-Ras signaling.

Oh, Jee-Sun.; Kim, Jae-Jin; Byun, Ju-Yeon [Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnamsi (Korea, Republic of); Kim, In-Ah, E-mail: inah228@snu.ac.k [Department of Radiation Oncology, Cancer Research Institute, Seoul National University, Seoul (Korea, Republic of)

2010-01-15

19

Effect of downregulation of survivin expression on radiosensitivity of human epidermoid carcinoma cells  

SciTech Connect

Purpose: The expression of survivin, a member of the inhibitor-of-apoptosis protein family, is elevated in many types of human cancer. High survivin expression has been associated with poor patient prognosis and tumor resistance to chemotherapy and radiotherapy. The purpose of this study was to compare the radiosensitizing effects of five agents that target survivin on their relative ability to downregulate survivin expression. Methods and Materials: The human epidermoid carcinoma cell line A431 was treated with adenoviral-mediated wild-type p53, antisense to survivin, the mitogen-activated protein kinase inhibitor PD98059, the cyclin-dependent kinase inhibitor Purvalanol A, or the histone deacetylase inhibitor trichostatin A. The radiosensitizing effects of these treatments were determined by clonogenic survival curve analysis and their abilities to suppress survivin expression by Western blot analysis. Results: All the strategies were shown to radiosensitize A431 cells. This effect correlated with their abilities to downregulate survivin. Conclusion: Expression of survivin appears to confer a radioresistant phenotype that can be overcome using several clinically achievable strategies that target survivin either specifically or nonspecifically.

Sah, Nand K. [Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX (United States); Munshi, Anupama [Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX (United States); Hobbs, Marvette B.A. [Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX (United States); Carter, Bing Z. [Department of Bone Marrow Transplantation, University of Texas M.D. Anderson Cancer Center, Houston, TX (United States); Andreeff, Michael [Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX (United States); Department of Bone Marrow Transplantation, University of Texas M.D. Anderson Cancer Center, Houston, TX (United States); Meyn, Raymond E. [Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX (United States)]. E-mail: rmeyn@mdanderson.org

2006-11-01

20

MicroRNAs in Human Malignant Gliomas  

PubMed Central

MicroRNA (miRNA) is a new class of small noncoding RNA molecules that regulate a wide spectrum of gene expression in a posttranscriptional manner. MiRNAs play crucial roles in tumorigenesis, angiogenesis, invasion, and apoptosis for various types of tumor. Recent studies have identified dysregulation of specific miRNAs in malignant gliomas. Global expression profiling of miRNAs has revealed several miRNAs clinically implicated in human glioblastomas. Some miRNAs are clearly associated with clinical outcome and chemo- and radio-therapy resistance in these tumors. Furthermore, miRNAs also regulate specific signaling pathways, including the critical core pathways in glioblastoma. As a result, miRNAs have the potential to affect the responses to molecular-targeted therapies. More recent studies have revealed that miRNAs might be associated with cancer stem cell properties, affecting tumor maintenance and progression. Recent investigation have revealed that miRNAs are not only biological markers with diagnostic implications, but also one of the most promising treatment targets in human glioblastoma. Herein, we summarized the novel insights of miRNAs into human malignant gliomas. PMID:22848219

Mizoguchi, Masahiro; Guan, Yanlei; Yoshimoto, Koji; Hata, Nobuhiro; Amano, Toshiyuki; Nakamizo, Akira; Sasaki, Tomio

2012-01-01

21

Silencing of MicroRNA-21 Confers Radio-Sensitivity through Inhibition of the PI3K/AKT Pathway and Enhancing Autophagy in Malignant Glioma Cell Lines  

PubMed Central

Radiation is a core part of therapy for malignant glioma and is often provided following debulking surgery. However, resistance to radiation occurs in most patients, and the underlying molecular mechanisms of radio-resistance are not fully understood. Here, we demonstrated that microRNA 21 (miR-21), a well-known onco-microRNA in malignant glioma, is one of the major players in radio-resistance. Radio-resistance in different malignant glioma cell lines measured by cytotoxic cell survival assay was closely associated with miR-21 expression level. Blocking miR-21 with anti-miR-21 resulted in radio-sensitization of U373 and U87 cells, whereas overexpression of miR-21 lead to a decrease in radio-sensitivity of LN18 and LN428 cells. Anti-miR-21 sustained ?-H2AX DNA foci formation, which is an indicator of double-strand DNA damage, up to 24 hours and suppressed phospho-Akt (ser473) expression after exposure to ?-irradiation. In a cell cycle analysis, a significant increase in the G2/M phase transition by anti-miR-21 was observed at 48 hours after irradiation. Interestingly, our results showed that anti-miR-21 increased factors associated with autophagosome formation and autophagy activity, which was measured by acid vesicular organelles, LC3 protein expression, and the percentage of GFP-LC3 positive cells. Furthermore, augmented autophagy by anti-miR-21 resulted in an increase in the apoptotic population after irradiation. Our results show that miR-21 is a pivotal molecule for circumventing radiation-induced cell death in malignant glioma cells through the regulation of autophagy and provide a novel phenomenon for the acquisition of radio-resistance. PMID:23077620

Jo, Guk Heui; Kim, Youn-Jae; Kwak, Hee-Jin; Kim, Jong Heon; Yin, Jinlong; Yoo, Heon; Lee, Seung Hoon; Park, Jong Bae

2012-01-01

22

Guggulsterone-Mediated Enhancement of Radiosensitivity in Human Tumor Cell Lines  

PubMed Central

Purpose: To observe the effect of guggulsterone (GS) on the radiation response in human cancer cell lines. Materials and methods: The radiation response of cancer cells treated with GS was observed by cell survival studies, cell growth assay, NF-?B activity assay, western blotting of some key growth promoting receptors, the DNA repair protein ?H2AX, and flow cytometry for DNA analyses. Results: GS inhibited radiation induced NF-?B activation and enhanced radiosensitivity in the pancreatic cell line, PC-Sw. It reduced both cell cycle movement and cell growth. GS reduced ER? protein in MCF7 cells and IGF1-R? protein in colon cancer cells and pancreatic cancer cells and inhibited DNA double strand break (DSB) repair following radiation. Conclusion: GS induced radiation sensitization may be due to several different mechanisms including the inhibition of NF-?B activation and reductions in IGF1-R?. In addition, GS induced ?H2AX formation, primarily in the S-phase, indicates that DNA DSB's in the S-phase may be another reason for GS induced radiosensitivity. ER? down-regulation in response to GS suggests that it can be of potential use in the treatment of estrogen positive tumors that are resistant to tamoxifen. PMID:22649756

Choudhuri, Rajani; DeGraff, William; Gamson, Janet; Mitchell, James B.; Cook, John A.

2011-01-01

23

Replication-Dependent Radiosensitization of Human Glioma Cells by Inhibition of Poly(ADP-Ribose) Polymerase: Mechanisms and Therapeutic Potential  

SciTech Connect

Purpose: Current treatments for glioblastoma multiforme are inadequate and limited by the radiation sensitivity of normal brain. Because glioblastoma multiforme are rapidly proliferating tumors within nondividing normal tissue, the therapeutic ratio might be enhanced by combining radiotherapy with a replication-specific radiosensitizer. KU-0059436 (AZD2281) is a potent and nontoxic inhibitor of poly(ADP-ribose) polymerase-1 (PARP-1) undergoing a Phase II clinical trial as a single agent. Methods and Materials: Based on previous observations that the radiosensitizing effects of PARP inhibition are more pronounced in dividing cells, we investigated the mechanisms underlying radiosensitization of human glioma cells by KU-0059436, evaluating the replication dependence of this effect and its therapeutic potential. Results: KU-0059436 increased the radiosensitivity of four human glioma cell lines (T98G, U373-MG, UVW, and U87-MG). Radiosensitization was enhanced in populations synchronized in S phase and abrogated by concomitant exposure to aphidicolin. Sensitization was further enhanced when the inhibitor was combined with a fractionated radiation schedule. KU-0059436 delayed repair of radiation-induced DNA breaks and was associated with a replication-dependent increase in {gamma}H2AX and Rad51 foci. Conclusion: The results of our study have shown that KU-0059436 increases radiosensitivity in a replication-dependent manner that is enhanced by fractionation. A mechanism is proposed whereby PARP inhibition increases the incidence of collapsed replication forks after ionizing radiation, generating persistent DNA double-strand breaks. These observations indicate that KU-0059436 is likely to enhance the therapeutic ratio achieved by radiotherapy in the treatment of glioblastoma multiforme. A Phase I clinical trial is in development.

Dungey, Fiona A.; Loeser, Dana A. [Genome Damage and Stability Centre, University of Sussex, Brighton (United Kingdom); Chalmers, Anthony J. [Genome Damage and Stability Centre, University of Sussex, Brighton (United Kingdom); Brighton and Sussex Medical School, University of Sussex, Brighton (United Kingdom)], E-mail: a.j.chalmers@sussex.ac.uk

2008-11-15

24

Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells  

PubMed Central

The aim of this study was to assess niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase (PARP) inhibitor, for its ability to radiosensitize human tumor cells. Human tumor cells derived from lung, breast and prostate cancers were tested for radiosensitization by niraparib using clonogenic survival assays. Both p53 wild-type and p53-defective lines were included. The ability of niraparib to alter the repair of radiation-induced DNA double strand breaks (DSBs) was determined using detection of ?-H2AX foci and RAD51 foci. Clonogenic survival analyses indicated that micromolar concentrations of niraparib radiosensitized tumor cell lines derived from lung, breast, and prostate cancers independently of their p53 status but not cell lines derived from normal tissues. Niraparib also sensitized tumor cells to H2O2 and converted H2O2-induced single strand breaks (SSBs) into DSBs during DNA replication. These results indicate that human tumor cells are significantly radiosensitized by the potent and selective PARP-1 inhibitor, niraparib, in the in vitro setting. The mechanism of this effect appears to involve a conversion of sublethal SSBs into lethal DSBs during DNA replication due to the inhibition of base excision repair by the drug. Taken together, our findings strongly support the clinical evaluation of niraparib in combination with radiation. PMID:24970803

Bridges, Kathleen A.; Toniatti, Carlo; Buser, Carolyn A.; Liu, Huifeng; Buchholz, Thomas A.; Meyn, Raymond E.

2014-01-01

25

Embryonic stem cell (ESC)-mediated transgene delivery induces growth suppression, apoptosis, radiosensitization, and overcomes temozolomide resistance in malignant gliomas  

PubMed Central

High-grade gliomas are among the most lethal of all cancers. Despite considerable advances in multi-modality treatment, including surgery, radiotherapy, and chemotherapy, the overall prognosis for patients with this disease remains dismal. Currently available treatments necessitate the development of more effective tumor-selective therapies. The use of gene therapy for malignant gliomas is promising as it allows in situ delivery and selectively targets brain tumor cells while sparing the adjacent normal brain tissue. Viral vectors to deliver pro-apoptotic genes to malignant glioma cells have been investigated. Although tangible results on patients’ survival remains to be further documented, significant advances in therapeutic gene transfer strategies have been made. Recently, cell-based gene delivery has been sought as an alternative method. In this paper, we report the pro-apoptotic effects of embryonic stem cell (ESC)-mediated mda-7/IL-24 delivery to malignant glioma cell lines. Our data show that these are similar to those observed using a viral vector. Additionally, acknowledging the heterogeneity of malignant glioma cells and their signaling pathways, we assessed the effects of conventional treatment for high grade gliomas, IR and TMZ, when combined with ESC-mediated transgene delivery. This combination resulted in synergistic effects on tumor cell death. The mechanisms involved in this beneficial effect included activation of both apoptosis and autophagy. Our in vitro data supports the concept that ESC-mediated gene delivery might offer therapeutic advantages over standard approaches to malignant gliomas. Our results corroborate the theory that combined treatments exploiting different signaling pathways are needed to succeed in the treatment of malignant gliomas. PMID:20523363

Germano, Isabelle M.; Emdad, Luni; Qadeer, Zulekha A.; Uzzaman, Mahmud

2010-01-01

26

Radiosensitization of Oropharyngeal Squamous Cell Carcinoma Cells by Human Papillomavirus 16 Oncoprotein E6*I  

SciTech Connect

Purpose: Patients with oropharyngeal squamous cell carcinoma (OSCC) whose disease is associated with high-risk human papillomavirus (HPV) infection have a significantly better outcome than those with HPV-negative disease, but the reasons for the better outcome are not known. We postulated that they might relate to an ability of HPV proteins to confer a better response to radiotherapy, a commonly used treatment for OSCC. Methods and Materials: We stably expressed the specific splicing-derived isoforms, E6*I and E6*II, or the entire E6 open reading frame (E6total), which gives rise to both full length and E6*I isoforms, in OSCC cell lines. Radiation resistance was measured in clonogenicity assays, p53 activity was measured using transfected reporter genes, and flow cytometry was used to analyze cell cycle and apoptosis. Results: E6*I and E6total sensitized the OSCC cells to irradiation, E6*I giving the greatest degree of radiosensitization (approximately eightfold lower surviving cell fraction at 10 Gy), whereas E6*II had no effect. In contrast to radiosensitivity, E6*I was a weaker inhibitor than E6total of tumor suppressor p53 transactivator activity in the same cells. Flow cytometric analyses showed that irradiated E6*I expressing cells had a much higher G2M:G1 ratio than control cells, indicating that, after G2, cells were diverted from the cell cycle to programmed cell death. Conclusion: This study supports a role for E6*I in the enhanced responsiveness of HPV-positive oropharyngeal carcinomas to p53-independent radiation-induced death.

Pang, Ervinna [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Discipline of Infectious Diseases and Immunology, University of Sydney, NSW (Australia); Delic, Naomi C. [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Discipline of Dermatology, University of Sydney, NSW (Australia); Hong, Angela; Zhang Mei [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Department of Radiation Oncology, Royal Prince Alfred Hospital, NSW (Australia); Rose, Barbara R. [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Discipline of Infectious Diseases and Immunology, University of Sydney, NSW (Australia); Lyons, J. Guy, E-mail: guy.lyons@sydney.edu.a [Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital, NSW (Australia); Discipline of Dermatology, University of Sydney, NSW (Australia)

2011-03-01

27

Radiosensitization of Human Leukemic HL-60 Cells by ATR Kinase Inhibitor (VE-821): Phosphoproteomic Analysis  

PubMed Central

DNA damaging agents such as ionizing radiation or chemotherapy are frequently used in oncology. DNA damage response (DDR)—triggered by radiation-induced double strand breaks—is orchestrated mainly by three Phosphatidylinositol 3-kinase-related kinases (PIKKs): Ataxia teleangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK) and ATM and Rad3-related kinase (ATR). Their activation promotes cell-cycle arrest and facilitates DNA damage repair, resulting in radioresistance. Recently developed specific ATR inhibitor, VE-821 (3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide), has been reported to have a significant radio- and chemo-sensitizing effect delimited to cancer cells (largely p53-deficient) without affecting normal cells. In this study, we employed SILAC-based quantitative phosphoproteomics to describe the mechanism of the radiosensitizing effect of VE-821 in human promyelocytic leukemic cells HL-60 (p53-negative). Hydrophilic interaction liquid chromatography (HILIC)-prefractionation with TiO2-enrichment and nano-liquid chromatography—tandem mass spectrometry (LC-MS/MS) analysis revealed 9834 phosphorylation sites. Proteins with differentially up-/down-regulated phosphorylation were mostly localized in the nucleus and were involved in cellular processes such as DDR, all phases of the cell cycle, and cell division. Moreover, sequence motif analysis revealed significant changes in the activities of kinases involved in these processes. Taken together, our data indicates that ATR kinase has multiple roles in response to DNA damage throughout the cell cycle and that its inhibitor VE-821 is a potent radiosensitizing agent for p53-negative HL-60 cells. PMID:25003641

Salovska, Barbora; Fabrik, Ivo; Durisova, Kamila; Link, Marek; Vavrova, Jirina; Rezacova, Martina; Tichy, Ales

2014-01-01

28

Hypoxia-targeted triple suicide gene therapy radiosensitizes human colorectal cancer cells  

PubMed Central

The hypoxic microenvironment, an important feature of human solid tumors but absent in normal tissue, may provide an opportunity for cancer-specific gene therapy. The purpose of the present study was to investigate whether hypoxia-driven triple suicide gene TK/CD/UPRT expression enhances cytotoxicity to ganciclovir (GCV) and 5-fluorocytosine (5-FC), and sensitizes human colorectal cancer to radiation in vitro and in vivo. Stable transfectant of human colorectal HCT8 cells was established which expressed hypoxia-inducible vectors (HRE-TK/eGFP and HRE-CD/UPRT/mDsRed). Hypoxia-induced expression/function of TK, CD and UPRT was verified by western blot analysis, flow cytometry, fluorescent microscopy and cytotoxicity assay of GCV and 5-FC. Significant radiosensitization effects were detected after 5-FC and GCV treatments under hypoxic conditions. In the tumor xenografts, the distribution of TK/eGFP and CD/UPRT/mDsRed expression visualized with fluorescence microscopy was co-localized with the hypoxia marker pimonidazole positive staining cells. Furthermore, administration of 5-FC and GCV in mice in combination with local irradiation resulted in tumor regression, as compared with prodrug or radiation treatments alone. Our data suggest that the hypoxia-inducible TK/GCV+CDUPRT/5-FC triple suicide gene therapy may have the ability to specifically target hypoxic cancer cells and significantly improve the tumor control in combination with radiotherapy. PMID:24912473

HSIAO, HUNG TSUNG; XING, LIGANG; DENG, XUELONG; SUN, XIAORONG; LING, C. CLIFTON; LI, GLORIA C.

2014-01-01

29

Regulation of radiosensitivity by HDAC inhibitor trichostatin A in the human cervical carcinoma cell line Hela.  

PubMed

Histone deacetylase (HDAC) inhibitors play an important role in inducing growth arrest, differentiation, and/or apoptosis in cancer cells. Given their ability to disrupt critical biological processes in cancer cells, these agents are emerging as potential therapeutics for cancer. Recently, it has been identified that HDAC inhibitors can also efficiently enhance the radiation sensitivity of cells, both in vitro and in vivo. In this study, we investigated whether the potent HDAC inhibitor, Trichostatin A, modulates the radiation sensitivity of the human cervical carcinoma cell line Hela under hypoxic conditions. We concluded that TSA could significantly inhibit the proliferation of Hela cells in a dose-and time-dependent manner under normoxic and hypoxic conditions. Hypoxia resulted in the cervical carcinoma Hela cells resistant to TSA. The findings from clonogenic survival assays indicate that incubation with TSA for 24 hours prior to irradiation enhances the radiation sensitivity of Hela cells under hypoxic conditions. More generally, we found Hela cells under hypoxic conditions treated with TSA could significantly down-regulate the expressions of HIF-1alpha and VEGF proteins. Taken together, our results demonstrated that TSA acts as a powerful radiosensitizer in Hela cells under hypoxic conditions probably by down-regulated expression of HIF-1alpha and VEGF proteins. PMID:22873101

Yu, J; Mi, J; Wang, Y; Wang, A; Tian, X

2012-01-01

30

Ionizing Radiation Activates AMP-Activated Kinase (AMPK): A Target for Radiosensitization of Human Cancer Cells  

SciTech Connect

Purpose: Adenosine monophosphate (AMP)-activated kinase (AMPK) is a molecular energy sensor regulated by the tumor suppressor LKB1. Starvation and growth factors activate AMPK through the DNA damage sensor ataxia-telangiectasia mutated (ATM). We explored the regulation of AMPK by ionizing radiation (IR) and its role as a target for radiosensitization of human cancer cells. Methods and Materials: Lung, prostate, and breast cancer cells were treated with IR (2-8 Gy) after incubation with either ATM or AMPK inhibitors or the AMPK activator metformin. Then, cells were subjected to either lysis and immunoblotting, immunofluorescence microscopy, clonogenic survival assays, or cell cycle analysis. Results: IR induced a robust phosphorylation and activation of AMPK in all tumor cells, independent of LKB1. IR activated AMPK first in the nucleus, and this extended later into cytoplasm. The ATM inhibitor KU-55933 blocked IR activation of AMPK. AMPK inhibition with Compound C or anti-AMPK {alpha} subunit small interfering RNA (siRNA) blocked IR induction of the cell cycle regulators p53 and p21{sup waf/cip} as well as the IR-induced G2/M arrest. Compound C caused resistance to IR, increasing the surviving fraction after 2 Gy, but the anti-diabetic drug metformin enhanced IR activation of AMPK and lowered the surviving fraction after 2 Gy further. Conclusions: We provide evidence that IR activates AMPK in human cancer cells in an LKB1-independent manner, leading to induction of p21{sup waf/cip} and regulation of the cell cycle and survival. AMPK appears to (1) participate in an ATM-AMPK-p21{sup waf/cip} pathway, (2) be involved in regulation of the IR-induced G2/M checkpoint, and (3) may be targeted by metformin to enhance IR responses.

Sanli, Toran; Rashid, Ayesha; Liu Caiqiong [Department of Oncology, Juravinski Cancer Center and McMaster University, Hamilton, Ontario (Canada)

2010-09-01

31

Targeting FAK Radiosensitizes 3-Dimensional Grown Human HNSCC Cells Through Reduced Akt1 and MEK1/2 Signaling  

SciTech Connect

Purpose: Focal adhesion kinase (FAK), a main regulator of integrin signaling and cell migration, is frequently overexpressed and hyperphosphorylated in human head-and-neck squamous cell carcinoma (HNSCC). We have previously shown that pharmacologic FAK inhibition leads to radiosensitization of 3-dimensionally grown HNSCC cell lines. To further evaluate the role of FAK in radioresistance and as a potential cancer target, we examined FAK and FAK downstream signaling in HNSCC cell lines grown in more physiologic extracellular matrix-based 3-dimensional cell cultures. Methods and Materials: Seven HNSCC cell lines were grown in 3-dimensional extracellular matrix and the clonogenic radiation survival, expression, and phosphorylation of FAK, paxillin, Akt1, extracellular signal-regulated kinase (ERK)1/2, and MEK1/2 were analyzed after siRNA-mediated knockdown of FAK, Akt1, MEK1, FAK+Akt1, or FAK+MEK1 compared with controls or stable overexpression of FAK. The role of MEK1/2 for clonogenic survival and signaling was investigated using the MEK inhibitor U0126 with or without irradiation. Results: FAK knockdown moderately or significantly enhanced the cellular radiosensitivity of 3-dimensionally grown HNSCC cells. The FAK downstream targets paxillin, Akt1, and ERK1/2 were substantially dephosphorylated under FAK depletion. FAK overexpression, in contrast, increased radiation survival and paxillin, Akt1, and ERK1/2 phosphorylation. The degree of radiosensitization upon Akt1, ERK1/2, or MEK1 depletion or U0126 was superimposable to FAK knockdown. Combination knockdown conditions (ie, Akt1/FAK, MEK1/FAK, or U0126/FAK) failed to provide additional radiosensitization. Conclusions: Our data provide further evidence for FAK as important determinant of radiation survival, which acts in the same signaling axis as Akt1 and ERK1/2. These data strongly support our hypothesis that FAK is a relevant molecular target for HNSCC radiotherapy.

Hehlgans, Stephanie [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany) [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany); Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt am Main (Germany); Institute of Radiopharmacy, Helmholtz Center Dresden-Rossendorf, Dresden (Germany); Eke, Iris [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany)] [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany); Cordes, Nils, E-mail: Nils.Cordes@OncoRay.de [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany) [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany); Institute of Radiopharmacy, Helmholtz Center Dresden-Rossendorf, Dresden (Germany); Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany)

2012-08-01

32

Radiosensitivity of human ovarian carcinoma and melanoma cells to ?-rays and protons  

PubMed Central

Introduction Proton radiation offers physical advantages over conventional radiation. Radiosensitivity of human 59M ovarian cancer and HTB140 melanoma cells was investigated after exposure to ?-rays and protons. Material and methods Irradiations were performed in the middle of a 62 MeV therapeutic proton spread out Bragg peak with doses ranging from 2 to 16 Gy. The mean energy of protons was 34.88 ±2.15 MeV, corresponding to the linear energy transfer of 4.7 ±0.2 keV/µm. Irradiations with ?-rays were performed using the same doses. Viability, proliferation and survival were assessed 7 days after both types of irradiation while analyses of cell cycle and apoptosis were performed 48 h after irradiation. Results Results showed that ?-rays and protons reduced the number of viable cells for both cell lines, with stronger inactivation achieved after irradiation with protons. Surviving fractions for 59M were 0.91 ±0.01 for ?-rays and 0.81 ±0.01 for protons, while those for HTB140 cells were 0.93 ±0.01 for ?-rays and 0.86 ±0.01 for protons. Relative biological effectiveness of protons, being 2.47 ±0.22 for 59M and 2.08 ±0.36 for HTB140, indicated that protons provoked better cell elimination than ?-rays. After proton irradiation proliferation capacity of the two cell lines was slightly higher as compared to ?-rays. Proliferation was higher for 59M than for HTB140 cells after both types of irradiation. Induction of apoptosis and G2 arrest detected after proton irradiation were more prominent in 59M cells. Conclusions The obtained results suggest that protons exert better antitumour effects on ovarian carcinoma and melanoma cells than ?-rays. The dissimilar response of these cells to radiation is related to their different features. PMID:25097591

Keta, Otilija; Todorovic, Danijela; Popovic, Natasa; Koricanac, Lela; Cuttone, Giacomo; Petrovic, Ivan

2014-01-01

33

Simultaneous Inhibition of EGFR and PI3K Enhances Radiosensitivity in Human Breast Cancer  

SciTech Connect

Purpose: Mutations in the epidermal growth factor receptor (EGFR)/phosphoinositide 3-kinase (PI3K)/Akt signaling transduction pathway are common in cancer. This pathway is imperative to the radiosensitivity of cancer cells. We aimed to investigate the radiosensitizing effects of the simultaneous inhibition of EGFR and PI3K in breast cancer cells. Methods and Materials: MCF-7 cell lines with low expression of EGFR and wild-type PTEN and MDA-MB-468 cell lines with high expression of EGFR and mutant PTEN were used. The radiosensitizing effects by the inhibition of EGFR with AG1478 and/or PI3K with Ly294002 were determined by colony formation assay, Western blot was used to investigate the effects on downstream signaling. Flow cytometry was used for apoptosis and cell cycle analysis. Mice-bearing xenografts of MDA-MB-468 breast cancer cells were also used to observe the radiosensitizing effect. Results: Simultaneous inhibition of EGFR and PI3K greatly enhanced radiosensitizing effect in MDA-MB-468 in terms of apoptosis and mitotic death, either inhibition of EGFR or PI3K alone could enhance radiosensitivity with a dose-modifying factor (DMF{sub SF2}) of 1.311 and 1.437, radiosensitizing effect was further enhanced by simultaneous inhibition of EGFR and PI3K with a DMF{sub SF2} at 2.698. DNA flow cytometric analysis indicated that dual inhibition combined with irradiation significantly induced G0/G1 phase arrest in MDA-MB-468 cells. The expression of phosphor-Akt and phosphor-Erk1/2 (induced by irradiation and PI3K inhibitor) were fully attenuated by simultaneous treatment with both inhibitors in combination with irradiation. In addition, dual inhibition combined with irradiation induced dramatic tumor growth delay in MDA-MB-468 xenografts. Conclusions: Our study indicated that simultaneous inhibition of EGFR and PI3K could further sensitize the cancer cells to irradiation compared to the single inhibitor with irradiation in vitro and in vivo. The approach may have important therapeutic implication in the treatment of a subset of breast cancer patients with high expression of EGFR and deficient function of PTEN.

Li Ping; Zhang Qing [Department of Radiation Oncology, 6th People's Hospital of Jiao Tong University, Shanghai 200233 (China); Torossian, Artour [Vanderbilt University, School of Medicine, Nashville, TN (United States); Li Zhaobin; Xu Wencai [Department of Radiation Oncology, 6th People's Hospital of Jiao Tong University, Shanghai 200233 (China); Lu Bo [Department of Radiation Oncology, Thomas Jefferson University and Hospitals, Inc. Philadelphia, PA (United States); Fu Shen, E-mail: fushen1117@gmail.com [Department of Radiation Oncology, 6th People's Hospital of Jiao Tong University, Shanghai 200233 (China)

2012-07-01

34

Celecoxib Enhances the Radiosensitizing Effect of 7-Hydroxystaurosporine (UCN-01) in Human Lung Cancer Cell Lines  

SciTech Connect

Purpose: 7-Hydroxystaurosporine (UCN-01), a Chk1-specific inhibitor, showed promising in vitro and in vivo chemo- or radiosensitizing activity. However, there have been concerns about its limited therapeutic efficacy and risk of side effects. A method of enhancing the treatment efficacy of UCN-01 while not increasing its side effects on normal tissue may therefore be required to apply this drug in clinical settings. Celecoxib is a cyclooxygenase-2 (COX-2)-specific inhibitor that downregulates ataxia telangiectasia and rad3-related (ATR) protein, an upstream kinase of Chk1. In this study, we investigated whether the addition of celecoxib can potentiate the radiosensitizing effect of UCN-01. Methods and Materials: The cooperative radiosensitizing effects and the underlying molecular mechanisms of UCN-01 plus celecoxib were determined by clonogenic assay, tumor growth delay assay, flow cytometry, and Western blotting. Synergism of the three agents combined (UCN-01 plus celecoxib plus radiation) were evaluated using median drug effect analysis and drug-independent action model analysis. Results: The combination of UCN-01 and celecoxib could induce synergistic cytotoxicity and radiosensitizing effects in in vitro and in vivo systems. The combination of both drugs also cooperatively inhibited IR-induced G{sub 2}/M arrest, and increased the G{sub 2} to mitotic transition. Conclusions: Combined treatment with UCN-01 and celecoxib can exert synergistically enhanced radiosensitizing effects via cooperative inhibition of the ionizing radiation-activated G{sub 2} checkpoint. We propose that this combination strategy may be useful in clinical applications of UCN-01 for radiotherapy of cancer patients.

Kim, Young-Mee; Jeong, In-Hye [Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Pyo, Hongryull, E-mail: Quasar93@yahoo.co.kr [Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

2012-07-01

35

Hemoglobin enhances tissue factor expression on human malignant cells.  

PubMed

Tissue Factor (TF) is a transmembrane glycoprotein that complexes with factor VII/activated factor VII to initiate blood coagulation. TF may be expressed on the surface of various cells including monocytes and endothelial cells. Over-expression of TF in human tumor cell lines promotes metastasis. We recently showed that hemoglobin (Hb) forms a specific complex with TF purified from human malignant melanoma cells and enhances its procoagulant activity (PCA). To further study this interaction, we examined the effect of Hb on the expression of TF on human malignant (TF+) cells and KG1 myeloid leukemia (TF-) cells. Human melanoma A375 and J82 bladder carcinoma cells, which express TF at moderate and relatively high levels, respectively, were incubated with varying concentrations (0-1.5 mg/ml) of Hb. After washing, cells were analyzed for Hb binding and TF expression using flow cytometry and confocal microscopy. Hb bound to the cells in a concentration-dependent manner, and increased both TF expression and PCA. The human A375 malignant melanoma cells incubated with Hb (1 mg/ml) expressed up to six times more TF antigen than cells without Hb. This increase in TF expression and PCA of intact cells incubated with Hb was significantly inhibited by cycloheximide at a concentration of 10 microg/ml (P < 0.01). An increase in total cellular TF antigen content was demonstrated by specific immunoassay. In contrast, Hb (5 mg/ml) did not induce TF expression and PCA on KG1 cells as determined by flow cytometry and TF (FXAA) activity. We conclude that Hb specifically binds to TF-bearing malignant cells and increases their PCA. This effect seems to be at least partly due to de novo synthesis of TF and increased surface expression. However, the exact mechanism by which Hb binds and upregulates TF expression remains to be determined. PMID:11414630

Siddiqui, F A; Amirkhosravi, A; Amaya, M; Meyer, T; Biggerstaff, J; Desai, H; Francis, J L

2001-04-01

36

Role of human papillomavirus and its detection in potentially malignant and malignant head and neck lesions: updated review  

Microsoft Academic Search

Head and neck malignancies are characterized by a multiphasic and multifactorial etiopathogenesis. Tobacco and alcohol consumption are the most common risk factors for head and neck malignancy. Other factors, including DNA viruses, especially human papilloma virus (HPV), may also play a role in the initiation or development of these lesions. The pathways of HPV transmission in the head and neck

Ajay Kumar Chaudhary; Mamta Singh; Shanthy Sundaram; Ravi Mehrotra

2009-01-01

37

Effect of Recombinant Human Endostatin on Radiosensitivity in Patients With Non-Small-Cell Lung Cancer  

SciTech Connect

Purpose: To observe the effects of recombinant human endostatin (RHES) on the radiosensitivity of non-small cell lung cancer (NSCLC). Methods and Materials: First, 10 hypoxia-positive cases of pathology-diagnosed NSCLC selected from 15 patients were used to determine the normalization window, a period during which RHES improves NSCLC hypoxia. Second, 50 hypoxia-positive cases of pathology-diagnosed NSCLC (Stages I-III) were randomly divided into a RHES plus radiotherapy group (25 cases) and a radiotherapy-alone group (25 cases). Intensity = modulated radiotherapy with a total dose of 60 Gy in 30 fractions for 6 weeks was adopted in the two groups. The target area included primary foci and metastatic lymph nodes. In the RHES plus radiotherapy group, RHES (15 mg/day) was intravenously given during the normalization window. Results: After RHES administration, the tumor-to=normal tissue radioactivity ratio and capillary permeability surface were first decreased and then increased, with their lowest points on the fifth day compared with the first day (all p < 0.01). Blood flow was first increased and then decreased, with the highest point on the fifth day, compared with the first and tenth day (all p < 0.01). In the RHES plus radiotherapy group and the radiotherapy-alone group, the total effective rates (complete response plus partial response) were 80% and 44% (p = 0.009), respectively. The median survival times were 21.1 {+-} 0.97 months and 16.5 {+-} 0.95 months (p = 0.004), respectively. The 1-year and 2-year local control rates were 78.9 {+-} 8.4% and 68.1 {+-} 7.8% (p = 0.027) and 63.6 {+-} 7.2% and 43.4 {+-} 5.7% (p = 0.022), respectively. The 1-year and 2-year overall survival rates were 83.3 {+-} 7.2% and 76.6 {+-} 9.3% (p = 0.247) and 46.3 {+-} 2.4% and 37.6 {+-} 9.1% (p = 0.218), respectively. Conclusion: The RHES normalization window is within about 1 week after administration. RHES combined with radiotherapy within the normalization window has better short-term therapeutic effects and local control rates and no severe adverse reactions in the treatment of NSCLC, but it failed to significantly improve the 1-year and 3-year overall survival rates.

Jiang Xiaodong; Dai Peng; Wu Jin; Song Daan [Department of Oncology, Lianyungang First People's Hospital, Lianyungang (China); Yu Jinming, E-mail: jxdysy@sohu.com [Department of Radiation Oncology, Shandong Cancer Hospital, Jinan (China)

2012-07-15

38

Poor Prognosis Associated With Human Papillomavirus ?7 Genotypes in Cervical Carcinoma Cannot Be Explained by Intrinsic Radiosensitivity  

SciTech Connect

Purpose: To investigate the relationship between human papillomavirus (HPV) genotype and outcome after radiation therapy and intrinsic radiosensitivity. Methods and Materials: HPV genotyping was performed on cervix biopsies by polymerase chain reaction using SPF-10 broad-spectrum primers, followed by deoxyribonucleic acid enzyme immunoassay and genotyping by reverse hybridization line probe assay (LiPA{sub 25}) (version 1) (n=202). PapilloCheck and quantitative reverse transcription-polymerase chain reaction were used to genotype cervix cancer cell lines (n=16). Local progression-free survival after radiation therapy alone was assessed using log-rank and Cox proportionate hazard analyses. Intrinsic radiosensitivity was measured as surviving fraction at 2 Gy (SF2) using clonogenic assays. Results: Of the 202 tumors, 107 (53.0%) were positive for HPV16, 29 (14.4%) for HPV18, 9 (4.5%) for HPV45, 23 (11.4%) for other HPV genotypes, and 22 (10.9%) were negative; 11 (5.5%) contained multiple genotypes, and 1 tumor was HPV X (0.5%). In 148 patients with outcome data, those with HPV?9-positive tumors had better local progression-free survival compared with ?7 patients in univariate (P<.004) and multivariate (hazard ratio 1.54, 95% confidence interval 1.11-1.76, P=.021) analyses. There was no difference in the median SF2 of ?9 and ?7 cervical tumors (n=63). In the cell lines, 9 were ?7 and 4 ?9 positive and 3 negative. There was no difference in SF2 between ?9 and ?7 cell lines (n=14). Conclusion: The reduced radioresponsiveness of ?7 cervical tumors is not related to intrinsic radiosensitivity.

Hall, John S.; Iype, Rohan; Armenoult, Lucile S.C. [Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester (United Kingdom)] [Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester (United Kingdom); Taylor, Janet [Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester (United Kingdom) [Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester (United Kingdom); Applied Computational Biology and Bioinformatics Group, Paterson Institute for Cancer Research, Manchester (United Kingdom); Miller, Crispin J. [Applied Computational Biology and Bioinformatics Group, Paterson Institute for Cancer Research, Manchester (United Kingdom)] [Applied Computational Biology and Bioinformatics Group, Paterson Institute for Cancer Research, Manchester (United Kingdom); Davidson, Susan [Christie National Health Service Foundation Trust, Manchester (United Kingdom)] [Christie National Health Service Foundation Trust, Manchester (United Kingdom); Sanjose, Silvia de; Bosch, Xavier [Cancer Epidemiology Research Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat (Spain)] [Cancer Epidemiology Research Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat (Spain); Stern, Peter L. [Immunology Group, Paterson Institute for Cancer Research, Manchester (United Kingdom)] [Immunology Group, Paterson Institute for Cancer Research, Manchester (United Kingdom); West, Catharine M.L., E-mail: Catharine.West@manchester.ac.uk [Translational Radiobiology Group, Institute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester (United Kingdom)

2013-04-01

39

Phenotypes and Karyotypes of Human Malignant Mesothelioma Cell Lines  

PubMed Central

Background Malignant mesothelioma is an aggressive tumour of serosal surfaces most commonly pleura. Characterised cell lines represent a valuable tool to study the biology of mesothelioma. The aim of this study was to develop and biologically characterise six malignant mesothelioma cell lines to evaluate their potential as models of human malignant mesothelioma. Methods Five lines were initiated from pleural biopsies, and one from pleural effusion of patients with histologically proven malignant mesothelioma. Mesothelial origin was assessed by standard morphology, Transmission Electron Microscopy (TEM) and immunocytochemistry. Growth characteristics were assayed using population doubling times. Spectral karyotyping was performed to assess chromosomal abnormalities. Authentication of donor specific derivation was undertaken by DNA fingerprinting using a panel of SNPs. Results Most of cell lines exhibited spindle cell shape, with some retaining stellate shapes. At passage 2 to 6 all lines stained positively for calretinin and cytokeratin 19, and demonstrated capacity for anchorage-independent growth. At passage 4 to 16, doubling times ranged from 30–72 hours, and on spectral karyotyping all lines exhibited numerical chromosomal abnormalities ranging from 41 to 113. Monosomy of chromosomes 8, 14, 22 or 17 was observed in three lines. One line displayed four different karyotypes at passage 8, but only one karyotype at passage 42, and another displayed polyploidy at passage 40 which was not present at early passages. At passages 5–17, TEM showed characteristic features of mesothelioma ultrastructure in all lines including microvilli and tight intercellular junctions. Conclusion These six cell lines exhibit varying cell morphology, a range of doubling times, and show diverse passage-dependent structural chromosomal changes observed in malignant tumours. However they retain characteristic immunocytochemical protein expression profiles of mesothelioma during maintenance in artificial culture systems. These characteristics support their potential as in vitro model systems for studying cellular, molecular and genetic aspects of mesothelioma. PMID:23516439

Relan, Vandana; Morrison, Leanne; Parsonson, Kylie; Clarke, Belinda E.; Duhig, Edwina E.; Windsor, Morgan N.; Matar, Kevin S.; Naidoo, Rishendran; Passmore, Linda; McCaul, Elizabeth; Courtney, Deborah; Yang, Ian A.; Fong, Kwun M.; Bowman, Rayleen V.

2013-01-01

40

Ectopically hTERT expressing adult human mesenchymal stem cells are less radiosensitive than their telomerase negative counterpart  

SciTech Connect

During the past several years increasing evidence indicating that the proliferation capacity of mammalian cells is highly radiosensitive, regardless of the species and the tissue of origin of the cells, has accumulated. It has also been shown that normal bone marrow cells of mice have a similar radiosensitivity to other mammalian cells so far tested. In this study, we investigated the genetic effects of ionizing radiation (2.5-15 Gy) on normal human mesenchymal stem cells and their telomerised counterpart hMSC-telo1. We evaluated overall genomic integrity, DNA damage/repair by applying a fluorescence-detected alkaline DNA unwinding assay together with Western blot analyses for phosphorylated H2AX and Q-FISH was applied for investigation of telomeric damage. Our results indicate that hMSC and TERT-immortalized hMSCs can cope with relatively high doses of {gamma}-rays and that overall DNA repair is similar in the two cell lines. The telomeres were extensively destroyed after irradiation in both cell types suggesting that telomere caps are especially sensitive to radiation. The TERT-immortalized hMSCs showed higher stability at telomeric regions than primary hMSCs indicating that cells with long telomeres and high telomerase activity have the advantage of re-establishing the telomeric caps.

Serakinci, Nedime [Department of Human Genetics, University of Aarhus, Aarhus (Denmark) and Institute of Medical Biology, Department of Anatomy and Neurobiology, Southern Denmark University, Odense (Denmark)]. E-mail: nserakinci@health.sdu.dk; Christensen, Rikke [Department of Human Genetics, University of Aarhus, Aarhus (Denmark); Graakjaer, Jesper [Department of Clinical Genetics, Vejle County Hospital, Vejle (Denmark); Cairney, Claire J. [Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK, Beatson Laboratories, Garscube Estate, Glasgow (United Kingdom); Keith, W. Nicol [Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK, Beatson Laboratories, Garscube Estate, Glasgow (United Kingdom); Alsner, Jan [Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus (Denmark); Saretzki, Gabriele [Henry Wellcome Laboratory for Biogerontology, Newcastle General Hospital, University of Newcastle upon Tyne, Newcastle (United Kingdom); Kolvraa, Steen [Department of Clinical Genetics, Vejle County Hospital, Vejle (Denmark)

2007-03-10

41

Development of novel radiosensitizers for cancer therapy  

E-print Network

The novel radiosensitizers for cancer therapy, which have some atoms with large X-ray absorption cross sections, were synthesized. The chemical and radiation (X-rays, W target, 100kVp) toxicities and the radiosensitivities to LS-180 human colon adenocarcinoma cells were also evaluated. 2,3,4,5,6-pentabromobenzylalcohol (PBBA) derivatives were not radiosensitive even around the maximum concentration. On the other hand, the hydrophilic sodium 2,4,6-triiodobenzoate (STIB) indicated meaningful radiosensitivity to the cells. Moreover, the membrane-specific radiosensitizers, cetyl fluorescein isthiocyanate (cetyl FITC), cetyl eosin isothiocyanate (cetyl br-FITC), cetyl erythrosin isothiocyanate (cetyl I-FITC), which aim for the membrane damage by X-ray photoabsorption on the target atoms, were localized in the plasma membrane. As the results of the colony formation assay, it was found that both cetyl FITC are similarly radiosensitive. In this report, we demonstrate the synthetic methods of the radiosensitizers, the...

Akamatsu, K

2002-01-01

42

Inhibition of human positive cofactor 4 radiosensitizes human esophageal squmaous cell carcinoma cells by suppressing XLF-mediated nonhomologous end joining.  

PubMed

Radiotherapy has the widest application to esophageal squamous cell carcinoma (ESCC) patients. Factors associated with DNA damage repair have been shown to function in cell radiosensitivity. Human positive cofactor 4 (PC4) has a role in nonhomologous end joining (NHEJ) and is involved in DNA damage repair. However, the clinical significance and biological role of PC4 in cancer progression and cancer cellular responses to chemoradiotherapy (CRT) remain largely unknown. The aim of the present study was to investigate the potential roles of PC4 in the radiosensitivity of ESCC. In this study, we showed that knockdown of PC4 substantially increased ESCC cell sensitivity to ionizing radiation (IR) both in vitro and in vivo and enhanced radiation-induced apoptosis and mitotic catastrophe (MC). Importantly, we demonstrated that silencing of PC4 suppressed NHEJ by downregulating the expression of XLF in ESCC cells, whereas reconstituting the expression of XLF protein in the PC4-knockdown ESCC cells restored NHEJ activity and radioresistance. Moreover, high expression of PC4 positively correlated with ESCC resistance to CRT and was an independent predictor for short disease-specific survival of ESCC patients in both of our cohorts. These findings suggest that PC4 protects ESCC cells from IR-induced death by enhancing the NHEJ-promoting activity of XLF and could be used as a novel radiosensitivity predictor and a promising therapeutic target for ESCCs. PMID:25321468

Qian, D; Zhang, B; Zeng, X-L; Le Blanc, J M; Guo, Y-H; Xue, C; Jiang, C; Wang, H-H; Zhao, T-S; Meng, M-B; Zhao, L-J; Hao, J-H; Wang, P; Xie, D; Lu, B; Yuan, Z-Y

2014-01-01

43

Inhibition of UBE2D3 Expression Attenuates Radiosensitivity of MCF-7 Human Breast Cancer Cells by Increasing hTERT Expression and Activity  

PubMed Central

The known functions of telomerase in tumor cells include replenishing telomeric DNA and maintaining cell immortality. We have previously shown the existence of a negative correlation between human telomerase reverse transcriptase (hTERT) and radiosensitivity in tumor cells. Here we set out to elucidate the molecular mechanisms underlying regulation by telomerase of radiosensitivity in MCF-7 cells. Toward this aim, yeast two-hybrid (Y2H) screening of a human laryngeal squamous cell carcinoma radioresistant (Hep2R) cDNA library was first performed to search for potential hTERT interacting proteins. We identified ubiquitin-conjugating enzyme E2D3 (UBE2D3) as a principle hTERT-interacting protein and validated this association biochemically. ShRNA-mediated inhibition of UBE2D3 expression attenuated MCF-7 radiosensitivity, and induced the accumulation of hTERT and cyclin D1 in these cells. Moreover, down-regulation of UBE2D3 increased hTERT activity and cell proliferation, accelerating G1 to S phase transition in MCF-7 cells. Collectively these findings suggest that UBE2D3 participates in the process of hTERT-mediated radiosensitivity in human breast cancer MCF-7 cells by regulating hTERT and cyclin D1. PMID:23741361

Hu, Liu; Li, Fen; Ren, Li; Yu, Haijun; Liu, Yu; Xia, Ling; Lei, Han; Liao, Zhengkai; Zhou, Fuxiang; Xie, Conghua; Zhou, Yunfeng

2013-01-01

44

Pharmacokinetics of the hypoxic radiosensitizers misonidazole and demethylmisonidazole after intraperitoneal administration in humans  

SciTech Connect

The hypoxic radiosensitizers misonidazole or demethylmisonidazole were administered i.p. in a 2-liter volume to 6 patients affected by advanced ovarian carcinoma, and the pharmacokinetic course of the two drugs was studied. The clearance of misonidazole and demethylmisonidazole from the peritoneal fluid was 19.1 and 12.4 ml/min, respectively. At 3 hr after drug administration, both radiosensitizers had peritoneal fluid concentrations more than 8 times larger than in the plasma. The concentration x time exposure in the peritoneal fluid was 3.2 times larger than in plasma for misonidazole and 7.6 times for demethylmisonidazole. The advantage of i.p. delivery compared with systemic delivery decreases with distance from the peritoneal surface, but the advantage may be maintained for up to 1 mm or 100 cell layers. These differences between the two routes of administration provide a rational basis for the expectation that a substantial increase of the therapeutic benefits of misonidazole and demethylmisonidazole in potentiating radiation therapy or chemotherapy can be expected in treating tumors confined to the i.p. space.

Gianni, L.; Jenkins, J.F.; Greene, R.F.; Lichter, A.S.; Myers, C.E.; Collins, J.M.

1983-02-01

45

5-Iodo-2-Pyrimidinone-2'-Deoxyribose-Mediated Cytotoxicity and Radiosensitization in U87 Human Glioblastoma Xenografts  

SciTech Connect

Purpose: 5-Iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is a novel orally administered (p.o.) prodrug of 5-iododeoxyuridine. Because p.o. IPdR is being considered for clinical testing as a radiosensitizer in patients with high-grade gliomas, we performed this in vivo study of IPdR-mediated cytotoxicity and radiosensitization in a human glioblastoma xenograft model, U87. Methods and Materials: Groups of 8 or 9 athymic male nude mice (6-8 weeks old) were implanted with s.c. U87 xenograft tumors (4 x 10{sup 6} cells) and then randomized to 10 treatment groups receiving increasing doses of p.o. IPdR (0, 100, 250, 500, and 1000 mg/kg/d) administered once daily (q.d.) x 14 days with or without radiotherapy (RT) (0 or 2 Gy/d x 4 days) on days 11-14 of IPdR treatment. Systemic toxicity was determined by body weight measurements during and after IPdR treatment. Tumor response was assessed by changes in tumor volumes. Results: IPdR alone at doses of {>=}500 mg/kg/d resulted in moderate inhibition of tumor growth. The combination of IPdR plus RT resulted in a significant IPdR dose-dependent tumor growth delay, with the maximum radiosensitization using {>=}500 mg/kg/d. IPdR doses of 500 and 1000 mg/kg/d resulted in transient 5-15% body weight loss during treatment. Conclusions: In U87 human glioblastoma s.c. xenografts, p.o. IPdR given q.d. x 14 days and RT given 2 Gy/d x 4 days (days 11-14 of IPdR treatment) results in a significant tumor growth delay in an IPdR dose-dependent pattern. The use of p.o. IPdR plus RT holds promise for Phase I/II testing in patients with high-grade gliomas.

Kinsella, Timothy J. [Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (United States)], E-mail: timothy.kinsella@UHhospitals.org; Kinsella, Michael T.; Seo, Yuji [Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH (United States); Berk, Gregory [Hana Biosciences, South San Francisco, CA (United States)

2007-11-15

46

Reduced Fhit protein expression in human malignant mesothelioma.  

PubMed

Human malignant mesothelioma (MM) is an aggressive neoplasm related to occupational exposure to asbestos and characterised by a long latency time. Multiple chromosomal deletions and DNA losses have been revealed in MM by studies performed with karyotypic, comparative genomic hybridisation and loss of heterozygosity (LOH) analyses. Among frequently deleted chromosomal sites, LOH at chromosome 3p has been detected in MM, suggesting the presence of one or several tumour suppressor genes that have an important role in development of the disease. The FHIT (fragile histidine triad) tumour suppressor gene, located at 3p14.2, has been proposed to be a target to major human lung carcinogens, such as tobacco smoke and asbestos. Although many studies have indicated decreased Fhit protein expression in a variety of malignancies, there is no report of FHIT gene aberrations or Fhit protein abnormalities in MM. We examined expression of the Fhit protein and LOH at the FHIT gene in malignant mesothelioma. Altogether, 13 paraffin embedded MM tumours were analysed for Fhit protein expression, and 21 fresh tumours and 10 cell cultures for LOH at the FHIT gene with two intragenic microsatellite markers. All tumours showed less intense immunostaining than normal bronchial epithelium or mesothelium. Fhit expression was absent or reduced in 54% (7 of 13) of the tumours, with the weakest staining observed in poorly differentiated areas. Allele loss was seen in 3 of 10 (30%) of the MM cell lines, but only in 1 of the 21 fresh tumours studied, suggesting concealment of LOH by normal cells present in MM tumours. In conclusion, our present data indicate a frequent decrease of Fhit protein expression, thus supporting the significance of FHIT inactivation in development of MM. PMID:14569398

Pylkkänen, Lea; Wolff, Henrik; Stjernvall, Tuula; Knuuttila, Aija; Anttila, Sisko; Husgafvel-Pursiainen, Kirsti

2004-01-01

47

Radiosensitization of Human Vascular Endothelial Cells Through Hsp90 Inhibition With 17-N-Allilamino-17-Demethoxygeldanamycin  

SciTech Connect

Purpose: In addition to invasive tumor cells, endothelial cells (ECs) of the tumor vasculature are an important target for anticancer radiotherapy. The purpose of the present work is to investigate how 17-N-allilamino-17-demethoxygeldanamycin (17AAG), known as an anticancer drug inhibiting heat shock protein 90 (Hsp90), modifies radiation responses of human vascular ECs. Methods and Materials: The ECs cultured from human umbilical veins were exposed to {gamma}-irradiation, whereas some EC samples were pretreated with growth factors and/or 17AAG. Postirradiation cell death/survival and morphogenesis were assessed by means of terminal deoxynucleotidyl transferase biotin-deoxyuridine triphosphate nick end labeling or annexin V staining and clonogenic and tube-formation assays. The 17AAG-affected expression and phosphorylation of radioresistance-related proteins were probed by means of immunoblotting. Dominant negative or constitutively activated Akt was transiently expressed in ECs to manipulate Akt activity. Results: It was found that nanomolar concentrations of 17AAG sensitize ECs to relatively low doses (2-6 Gy) of {gamma}-irradiation and abolish the radioprotective effects of vascular endothelial growth factor and basic fibroblast growth factor. The drug-induced radiosensitization of ECs seems to be caused by prevention of Hsp90-dependent phosphorylation (activation) of Akt that results in blocking the radioprotective phosphatidylinositol 3-kinase/Akt pathway. Conclusions: Clinically achievable concentrations of 17AAG can decrease the radioresistance intrinsic to vascular ECs and minimize the radioprotection conferred upon them by tumor-derived growth factors. These findings characterize 17AAG as a promising radiosensitizer for the tumor vasculature.

Kabakov, Alexander E. [Department of Radiation Biochemistry, Medical Radiology Research Center, Obninsk (Russian Federation)], E-mail: aekabakov@hotmail.com; Makarova, Yulia M.; Malyutina, Yana V. [Department of Radiation Biochemistry, Medical Radiology Research Center, Obninsk (Russian Federation)

2008-07-01

48

Inhibitory effect of cinnamoyl compounds against human malignant cell line.  

PubMed

In the present study, anti-proliferative effects of dietary polyphenolic compounds have been observed and demonstrated the strong anticancer efficacy of curcumin (CMN), an active constituent of dietary spice (turmeric) using human leukemia cancer cell line. CMN inhibited the proliferation of K562 leukemic cells by induction of apoptosis. The current study demonstrated synergy with combination of drug therapy, and suggested that combination of ferulic acid and cisplatin synergistically inhibited cellular proliferation. Cytotoxic synergy was observed independent of the sequence of addition of two drugs to cultured cells. The synergized growth inhibitory effect with cisplatin was probably associated with G2-M arrest in cell cycle progression. These findings suggested that among the cinnamoyl compounds, CMN was most potent and FER appeared to be a better modulating agent on human malignant cell line. PMID:16538860

Indap, M A; Radhika, S; Motiwale, Leena; Rao, K V K

2006-03-01

49

Correlation between the radiosensitivity in vitro of clones and variants derived from a human melanoma cell line and their spontaneous metastatic potential in vivo.  

PubMed

With an experimental model of spontaneous lung metastases of human melanoma in immunosuppressed newborn rats, a large panel of clones and variants with different metastatic potential were derived from a single human melanoma parental cell line (M4Be). Seven clones and variants from M4Be were selected, respectively, for their low (parental, clone 1), intermediate (clones 2 and 3, subvariant 1-) and high (variant 1, subvariant 1+, clone 4) metastatic potential. This paper investigates the relationship between the in vivo metastatic potential of the eight cell lines and their sensitivity to ionizing radiation in vitro (range 0.05-7 Gy). The radiosensitivity was estimated from the mean inactivation dose, a parameter equal to the area under the survival curve plotted in linear coordinates. Examination of the eight survival curves, obtained with cells cultured for no more than five passages after defrost, shows that clone 1, subvariant 1- and the M4be parental line are the most radioresistant cells, clone 4 and subvariant 1+ are the most radiosensitive cells, while clones 2 and 3 and variant 1 showed an intermediate response to radiation. The metastatic potential in vivo of the parental line and the seven sublines is significantly correlated to their radiosensitivity in vitro: the higher the metastatic potential, the higher the radiosensitivity. PMID:7874696

Thomas, C P; Buronfosse, A; Portoukalian, J; Fertil, B

1995-01-27

50

Bcl-B Expression in Human Epithelial and Nonepithelial Malignancies  

PubMed Central

Purpose Apoptosis plays an important role in neoplastic processes. Bcl-B is an antiapoptotic Bcl-2 family member, which is known to change its phenotype upon binding to Nur77/TR3. The expression pattern of this protein in human malignancies has not been reported. Experimental Design We investigated Bcl-B expression in normal human tissues and several types of human epithelial and nonepithelial malignancy by immunohistochemistry, correlating results with tumor stage, histologic grade, and patient survival. Results Bcl-B protein was strongly expressed in all normal plasma cells but found in only18%of multiple myelomas (n = 133). Bcl-B immunostaining was also present in normal germinal center centroblasts and centrocytes and in approximately half of diffuse large B-cell lymphoma (n =48) specimens, whereas follicular lymphomas (n = 57) did not contain Bcl-B. In breast (n = 119), prostate (n = 66), gastric (n = 180), and colorectal (n = 106) adenocarcinomas, as well as in non – small cell lung cancers (n = 82), tumor-specific overexpression of Bcl-B was observed. Bcl-B expression was associated with variables of poor prognosis, such as high tumor grade in breast cancer (P = 0.009), microsatellite stability (P = 0.0002), and left-sided anatomic location (P = 0.02) of colorectal cancers, as well as with greater incidence of death from prostate cancer (P = 0.005) and shorter survival of patients with small cell lung cancer (P = 0.009). Conversely, although overexpressed in many gastric cancers, Bcl-B tended to correlate with better outcome (P = 0.01) and more differentiated tumor histology (P < 0.0001). Conclusions Tumor-specific alterations in Bcl-B expressionmay define subsets of nonepithelial and epithelial neoplasms with distinct clinical behaviors. PMID:18483366

Krajewska, Maryla; Kitada, Shinichi; Winter, Jane N.; Variakojis, Daina; Lichtenstein, Alan; Zhai, Dayong; Cuddy, Michael; Huang, Xianshu; Luciano, Frederic; Baker, Cheryl H.; Kim, Hoguen; Shin, Eunah; Kennedy, Susan; Olson, Allen H.; Badzio, Andrzej; Jassem, Jacek; Meinhold-Heerlein, Ivo; Duffy, Michael J.; Schimmer, Aaron D.; Tsao, Ming; Brown, Ewan; Sawyers, Anne; Andreeff, Michael; Mercola, Dan; Krajewski, Stan; Reed, John C.

2014-01-01

51

Radiosensitivity of human clonogenic myeloma cells and normal bone marrow precursors: Effect of different dose rates and fractionation  

SciTech Connect

Evaluation of radiation dose rate and fractionation effects on clonogenic myeloma cells was carried out. The radiosensitivity of clonogenic myeloma cells was evaluated for seven human myeloma cell lines. The lines were maintained in liquid suspension culture. Following radiation, cells were plated in semisolid medium using methylcellulose as viscous support. Radiation doses up to 12 Gy were delivered at dose rates of 0.05 and 0.5 Gy/min by a [sup 60]Co source. Each total dose was administered either as a single dose or in multiple fractions of 2 Gy. The data were analyzed according to the linear quadratic and multi target model of irradiation. Clonogenic progenitors of the seven myeloma cell lines differed in their radiosensitivity as measured by multiple parameters. The differences were mainly observed at low dose. The most effective cytoreduction was seen when radiation was administered in a single fraction at high dose rate. The cytoreductive effect on clonogenic myeloma cells was compared for clinically practiced total body irradiation (TBI) schedules delivered either in a single or in multiple fractions without causing significant pulmonary toxicity. The administration of 12 Gy delivered in six fractions of 2 Gy resulted in a superior reduction of clonogenic cells compared to a single fraction of 5 Gy. The preparation of bone marrow transplant recipients with multiple myeloma using fractionated radiation with a total dose of 12 Gy appears to afford better ablation than a single dose of 5 Gy while maintaining a low incidence of pulmonary toxicity. 20 refs., 4 figs., 4 tabs.

Glueck, S.; Van Dyk, J.; Messner, H.A. (Univ. of Toronto, Ontario (Canada))

1994-03-01

52

Human RGM249-Derived Small RNAs Potentially Regulate Tumor Malignancy  

PubMed Central

The human noncoding RNA gene RGM249 has been shown to regulate the degree of cancer cell differentiation. In this study, we investigated the effects of 3 microRNA-like molecules digested from RGM249 on the loss of malignant properties in cancer cells in immunodeficient KSN/Slc mice. We utilized small interfering RNAs (siRNAs) alone or in combination with a cationized drug delivery system (DDS) consisting of atelocollagen or gelatin hydrogel microspheres. The results demonstrated growth inhibition and apoptosis and the inhibition of both neovascularization and metastasis, indicating that the DDSs effectively infiltrated the majority of tumor cells in vivo. Systemic administration of the 3 siRNAs inhibited the metastatic ability of malignant cells. Cotransfection of these siRNAs exerted a regulatory effect upon the genes involved in differentiation, pluripotency, and proliferation in cancer cells. These results suggest that RGM249-derived oligonucleotides may be involved in the regulation of metastasis, proliferation, and differentiation in vivo, and that the tested siRNAs may therefore represent a new anticancer therapeutic approach. PMID:23988019

Shimizu, Mika; Shinoda, Waka; Tsuno, Satoshi; Sato, Reina; Wang, Xinhui; Jo, Jun-ichiro; Tabata, Yasuhiko; Hasegawa, Junichi

2013-01-01

53

Management of human papillomavirus-related gynecological malignancies.  

PubMed

Human papillomavirus (HPV) infections affect women in every age group and in various benign, premalignant as well as malignant gynecological conditions. As a benign condition, condylomata acuminata of the whole female genital tract can be observed, transmitted by low risk HPV types 6 and 11, whilst dysplastic changes of the vulva appear as vulvar intraepithelial neoplasia, of the vagina as vaginal intraepithelial neoplasia and of the cervix as cervical intraepithelial neoplasia, and are caused by high risk HPV types most notably 16 and 18. These dysplastic changes give rise to precursor lesions of vulvar and cervical cancer, both driven via immune regression and potentially hormonal changes by promoting the malignant transformation profile of HPV subtypes. Attributes which can support this process are smoking, immunodeficiency, vitamin deficiency, stress, vaginal infections and hormonal influence. The causal relationship between persistent infection with high-risk HPV genotypes and vulvar and cervical cancer has been clearly demonstrated and is stronger than the relationship observed between smoking and lung cancer. New global cancer prevention can be envisaged by implementing vaccination against HPV in young women, with 2 vaccines currently approved by the Food and Drug Administration: the quadrivalent Gardasil (HPV-6, -11, -16, -18) and the bivalent Cervarix (HPV-16, -18). PMID:24643189

Heinzelmann-Schwarz, Viola A; Kind, André B; Jacob, Francis

2014-01-01

54

Late G1 accumulation after 2 Gy of gamma-irradiation is related to endogenous Raf-1 protein expression and intrinsic radiosensitivity in human cells.  

PubMed Central

We have previously reported a correlation between high endogenous expression of the protein product of the RAF-1 proto-oncogene, intrinsic cellular radiosensitivity and rapid exit from a G2/M delay induced by 2 Gy of gamma-irradiation. Raf1 is a positive serine/threonine kinase signal transduction factor that relays signals from the cell membrane to the MAP kinase system further downstream and is believed to be involved in an ionizing radiation signal transduction pathway modulating the G1/S checkpoint. We therefore extended our flow cytometric studies to investigate relationships between radiosensitivity, endogenous expression of the Raf1 protein and perturbation of cell cycle checkpoints, leading to alterations in the G1, S and G2/M populations after 2 Gy of gamma-irradiation. Differences in intrinsic radiosensitivity after modulation of the G1/S checkpoint have generally been understood to involve p53 function up to the present time. A role for dominant oncogenes in control of G1/S transit in radiation-treated cells has not been identified previously. Here, we show in 12 human in vitro cancer cell lines that late G1 accumulation after 2 Gy of radiation is related to both Raf1 expression (r = 0.91, P = 0.0001) and the radiosensitivity parameter SF2 (r = -0.71, P = 0.009). PMID:9579826

Warenius, H. M.; Jones, M.; Jones, M. D.; Browning, P. G.; Seabra, L. A.; Thompson, C. C.

1998-01-01

55

Radiosensitizing effect of gold nanoparticles in carbon ion irradiation of human cervical cancer cells  

SciTech Connect

Noble metal nanoparticles have received considerable attention in biotechnology for their role in bio sensing due to surface plasmon resonance, medical diagnostics due to better imaging contrast and therapy. The radiosensitization effect of gold nanoparticles (AuNP) has been gaining popularity in radiation therapy of cancer cells. The better depth dose profile of energetic ion beam proves its superiority over gamma radiation for fighting against cancer. In the present work, the glucose capped gold nanoparticles (Glu-AuNP) were synthesised and internalized in the HeLa cells. Transmission electron microscopic analysis of ultrathin sections of Glu-AuNP treated HeLa cells confirmed the internalization of Glu-AuNPs. Control HeLa cells and Glu-AuNp treated HeLa cells were irradiated at different doses of 62 MeV 12C ion beam (LET - 290keV/{mu}m) at BIO beam line of using 15UD Pelletron accelerator at Inter University Accelerator Centre, New Delhi, India. The survival fraction was assessed by colony forming assay which revealed that the dose of carbon ion for 90% cell killing in Glu-AuNP treated HeLa cells and control HeLa cells are 2.3 and 3.2 Gy respectively. This observation shows {approx} 28% reduction of {sup 12}C{sup 6+} ion dose for Glu-AuNP treated HeLa cells as compared to control HeLa cells.

Kaur, Harminder; Avasthi, D. K.; Pujari, Geetanjali; Sarma, Asitikantha [Inter University Accelerator Centre, Aruna Asaf Ali Marg, Post box-10502, New Delhi-110067 (India)

2013-07-18

56

Chromosomal radiosensitivity in patients with common variable immunodeficiency  

Microsoft Academic Search

Common variable immunodeficiency (CVID) is a heterogeneous group of primary immunodeficiency disorders. In addition to recurrent infections and autoimmunity, cancers are more prevalent in these patients than the normal population. Increased radiosensitivity may be a reason for the increased malignancies. To analyze chromosomal radiosensitivity of CVID patients, lymphocytes were cultured from 20 CVID patients. After irradiation (50, 100cGy), metaphases were

Asghar Aghamohammadi; Mostafa Moin; Ali Kouhi; Mohammad-Ali Mohagheghi; Alireza Shirazi; Nima Rezaei; Sanaz Tavassoli; Mahbod Esfahani; Taher Cheraghi; Jila Dastan; Jeanet Nersesian; Saeed Reza Ghaffari

2008-01-01

57

Asbestos Fiber Analysis in the Lung and Mesothelial Tissues from 168 Cases of Human Malignant Mesothelioma  

Microsoft Academic Search

To identify and characterize asbestos fibers associated with the induction of human malignant mesothelioma, we have investigated type(s), number and size of asbestos fibers detected in the lung and mesothelial tissues taken from 168 cases of human malignant mesothelioma (including 164 males and 4 females; 156 pleural and 12 peritoneal; definite or probable; autopsy or biopsy samples). Their occupational history

Yasunosuke Suzuki; Steven R. Yuen; Richard Ashley

58

Mechanism of binding of the radiosensitizers metronidazole and misonidazole (RO-07-0582) to bovine and human serum albumin: a proton NMR study  

SciTech Connect

High-resolution proton NMR spectra of the radiosensitizer metronidazole and its derivative misonidazole (RO-07-0582) were measured in D/sub 2/O at resonance frequency 60 MHz and interpreted in the aliphatic and aromatic regions. The linewidths of the NMR peaks attributed to individual fragments of nitroimidazole molecules were then analyzed in the presence of bovine and human serum albumin. With increasing concentration of serum albumin, a selectively larger broadening of the lines attributable to the protons of the aliphatic moieties than of those of the imidazole rings was observed for both compounds. This broadening for misonidazole strongly depends on the ionic strength of the solution. The results indicate a specific immobilization of the molecules of both radiosensitizers during their interaction with serum albumin and the involvement of the aliphatic chains of misonidazole and metronidazole as the primary binding sites.

Sulkowska, A.; Lubas, B.; Wilczok, T.

1981-01-01

59

Pathological changes in human malignant carcinoma treated with high-intensity focused ultrasound  

Microsoft Academic Search

The purpose of this study was to investigate the pathologic changes of extracorporeal ablation of human malignant tumors with high-intensity focused ultrasound (HIFU). HIFU treatment was performed in the 164 patients with liver cancer, breast cancer, malignant bone tumor, soft tissue sarcoma and other malignant tumors at focal peak intensities from 5000 W cm?2 to 20,000 W cm?2, with operating

Feng Wu; Wen-Zhi Chen; Jin Bai; Jian-Zhong Zou; Zhi-Long Wang; Hui Zhu; Zhi-Biao Wang

2001-01-01

60

Syntenic relationships between genomic profiles of fiber-induced murine and human malignant mesothelioma  

E-print Network

: malignant mesothelioma; N2+/- : heterozygous N2+/- mice; RCF: refractory ceramic fibers; SNP: singlePage 1 Syntenic relationships between genomic profiles of fiber-induced murine and human malignant words: array CGH ­ Mesothelioma ­ Mineral fibers ­ Mouse models Abbreviations: aCGH: array

61

Depletion of Securin Induces Senescence After Irradiation and Enhances Radiosensitivity in Human Cancer Cells Regardless of Functional p53 Expression  

SciTech Connect

Purpose: Radiotherapy is one of the best choices for cancer treatment. However, various tumor cells exhibit resistance to irradiation-induced apoptosis. The development of new strategies to trigger cancer cell death besides apoptosis is necessary. This study investigated the role of securin in radiation-induced apoptosis and senescence in human cancer cells. Methods and Materials: Cell survival was determined using clonogenic assays. Western blot analysis was used to analyze levels of securin, caspase-3, PARP, p53, p21, Rb, gamma-H2AX, and phospho-Chk2. Senescent cells were analyzed using a beta-galactosidase staining assay. A securin-expressed vector (pcDNA-securin) was stably transfected into securin-null HCT116 cells. Securin gene knockdown was performed by small interfering RNA and small hairpin RNA in HCT116 and MDA-MB-231 cells, respectively. Results: Radiation was found to induce apoptosis in securin wild type HCT116 cells but induced senescence in securin-null cells. Restoration of securin reduced senescence and increased cell survival in securin-null HCT116 cells after irradiation. Radiation-induced gamma-H2AX and Chk2 phosphorylation were induced transiently in securin-wild-type cells but exhibited sustained activation in securin-null cells. Securin gene knockdown switches irradiation-induced apoptosis to senescence in both HCT116 p53-null and MDA-MB-231 cells. Conclusions: Our results demonstrated that the level of securin expression plays a determining role in the radiosensitivity and fate of cells. Depletion of securin impairs DNA repair after irradiation, increasing DNA damage and promoting senescence in the residual surviving cells regardless of functional p53 expression. The knockdown of securin may contribute to a novel radiotherapy protocol for the treatment of human cancer cells that are resistant to irradiation.

Chen Wenshu; Yu Yichu [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China); Lee Yijang [Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan (China); Chen, J.-H. [Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan (China); Hsu, H.-Y. [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China); Chiu, S.-J., E-mail: chiusj@mail.tcu.edu.t [Department of Life Science, Tzu Chi University, Hualien, Taiwan (China); Institute of Radiation Sciences, Tzu Chi Technology College, Hualien, Taiwan (China)

2010-06-01

62

Enhancement of radiosensitivity in human glioblastoma cells by the DNA N-mustard alkylating agent BO1051 through augmented and sustained DNA damage response  

Microsoft Academic Search

BACKGROUND: 1-{4-[Bis(2-chloroethyl)amino]phenyl}-3-[2-methyl-5-(4-methylacridin-9-ylamino)phenyl]urea (BO-1051) is an N-mustard DNA alkylating agent reported to exhibit antitumor activity. Here we further investigate the effects of this compound on radiation responses of human gliomas, which are notorious for the high resistance to radiotherapy. METHODS: The clonogenic assay was used to determine the IC50 and radiosensitivity of human glioma cell lines (U87MG, U251MG and GBM-3) following

Pei-Ming Chu; Shih-Hwa Chiou; Tsann-Long Su; Yi-Jang Lee; Li-Hsin Chen; Yi-Wei Chen; Sang-Hue Yen; Ming-Teh Chen; Ming-Hsiung Chen; Yang-Hsin Shih; Pang-Hsien Tu; Hsin-I Ma

2011-01-01

63

Metabolomics of Human Cerebrospinal Fluid Identifies Signatures of Malignant Glioma*  

PubMed Central

Cerebrospinal fluid is routinely collected for the diagnosis and monitoring of patients with neurological malignancies. However, little is known as to how its constituents may change in a patient when presented with a malignant glioma. Here, we used a targeted mass-spectrometry based metabolomics platform using selected reaction monitoring with positive/negative switching and profiled the relative levels of over 124 polar metabolites present in patient cerebrospinal fluid. We analyzed the metabolic profiles from 10 patients presenting malignant gliomas and seven control patients that did not present malignancy to test whether a small sample size could provide statistically significant signatures. We carried out multiple unbiased forms of classification using a series of unsupervised techniques and identified metabolic signatures that distinguish malignant glioma patients from the control patients. One subtype identified contained metabolites enriched in citric acid cycle components. Newly diagnosed patients segregated into a different subtype and exhibited low levels of metabolites involved in tryptophan metabolism, which may indicate the absence of an inflammatory signature. Together our results provide the first global assessment of the polar metabolic composition in cerebrospinal fluid that accompanies malignancy, and demonstrate that data obtained from high throughput mass spectrometry technology may have suitable predictive capabilities for the identification of biomarkers and classification of neurological diseases. PMID:22240505

Locasale, Jason W.; Melman, Tamar; Song, Susan; Yang, Xuemei; Swanson, Kenneth D.; Cantley, Lewis C.; Wong, Eric T.; Asara, John M.

2012-01-01

64

September 28, 2005: Mechanisms Leading to the Formation of Human Malignancies  

Cancer.gov

Mechanisms Leading to the Formation of Human Malignancies Star Speakers Robert Weinberg, PhD Member, Whitehead Institute for Biomedical Research Daniel K. Ludwig and American Cancer Society Research Professor of Molecular Biology Dept. of Biology, Massachusetts

65

Role of human papillomavirus and its detection in potentially malignant and malignant head and neck lesions: updated review  

PubMed Central

Head and neck malignancies are characterized by a multiphasic and multifactorial etiopathogenesis. Tobacco and alcohol consumption are the most common risk factors for head and neck malignancy. Other factors, including DNA viruses, especially human papilloma virus (HPV), may also play a role in the initiation or development of these lesions. The pathways of HPV transmission in the head and neck mucosal lesions include oral-genital contact, more than one sexual partner and perinatal transmission of HPV to the neonatal child. The increase in prevalence of HPV infection in these lesions may be due to wider acceptance of oral sex among teenagers and adults as this is perceived to be a form of safe sex. The prevalence of HPV in benign lesions as well as malignancies has been assessed by many techniques. Among these, the polymerase chain reaction is the most sensitive method. Review of literature reveals that HPV may be a risk factor for malignancies, but not in all cases. For confirmation of the role of HPV in head and neck squamous cell carcinoma, large population studies are necessary in an assortment of clinical settings. Prophylactic vaccination against high-risk HPV types eventually may prevent a significant number of cervical carcinomas. Of the two vaccines currently available, Gardasil® (Merck & Co., Inc.) protects against HPV types 6, 11, 16 and 18, while the other vaccine, Cervarix® (GlaxoSmithKline, Rixensart, Belgium) protects against HPV types 16 and 18 only. However, the HPV vaccine has, to the best of our knowledge, not been tried in head and neck carcinoma. The role of HPV in etiopathogenesis, prevalence in benign and malignant lesions of this area and vaccination strategies are briefly reviewed here. PMID:19555477

Chaudhary, Ajay Kumar; Singh, Mamta; Sundaram, Shanthy; Mehrotra, Ravi

2009-01-01

66

Synthetic, implantable polymers for local delivery of IUdR to experimental human malignant glioma  

Microsoft Academic Search

Purpose: Recently, polymeric controlled delivery of chemotherapy has been shown to improve survival of patients with malignant glioma. We evaluated whether we could similarly deliver halogenated pyrimidines to experimental intracranial human malignant glioma. To address this issue we studied the in vitro release from polymers and the in vivo drug delivery of IUdR to experimental human U251 glioblastoma xenografts.Methods and

Jeffery A Williams; Xuan Yuan; Larry E Dillehay; Venkatram R Shastri; Henry Brem; Jerry R Williams

1998-01-01

67

GNG2 inhibits invasion of human malignant melanoma cells with decreased FAK activity  

PubMed Central

It is well known that heterotrimeric G protein is composed of a G?-subunit and a G??-dimer and promotes cancer characteristics. Our recent study showed reduced G protein ?2 subunit (Gng2/GNG2) expression levels in malignant melanoma cells compared with those in benign melanocytic cells in both mice and humans. Our recent study also showed that reduced GNG2 alone augmented proliferation of malignant melanoma cells. To our knowledge, however, there is no evidence showing an effect of Gng2/GNG2 alone on metastasis of any cancers including malignant melanoma. In his study, we first prepared GNG2-overexpressed SK-Mel28 human malignant melanoma cells, in which GNG2 protein expression level was undetectably low. Migration and invasion activities of the GNG2-overexpressed malignant melanoma cells were suppressed up to 1/10th, with decreased activity of focal adhesion kinase (FAK). We then found that the expression level of GNG2 in A375M, a highly metastatic cell line, was significantly lower than that in A375P, the parental cell line of A375M. We finally showed that knockdown of GNG2 alone in A375P cells enhanced migration and invasion with increased FAK activity. Taken together, our results suggest that overexpression of GNG2 alone inhibits metastasis in human malignant melanoma cells with decreased FAK activity. Thus, GNG2 might be a candidate of molecular targets of prevention and therapy for metastasis of malignant melanoma. PMID:24660107

Yajima, Ichiro; Kumasaka, Mayuko Y; Yamanoshita, Osamu; Zou, Cunchao; Li, Xiang; Ohgami, Nobutaka; Kato, Masashi

2014-01-01

68

[Human caspase-14 expression in malignant melanoma and its significance].  

PubMed

Objective To detect the caspase-14 expression in malignant melanoma cells and tumor tissues and its effect on tumor resistance to drug. Methods The mRNA and protein level of caspase-14 in 4 melanoma cell lines (A375, A875, M14, and SK-Mel-1) and the melanocytes, was detected by reverse transcription PCR (RT-PCR) and Western blotting. Caspase-14 expression in 34 malignant melanoma tumor tissues and 10 dermal nevus tissues was determined by in situ hybridization and immunohistochemistry. Results Caspase-14 expression was seen in melanoma cells and melanocytes. It was higher in melanoma-associated antigen 1 recognized by T cells (MART-1) positive cells than in MART-1 negative cells. The cells expressing the lower caspase-14 were more sensitive to the treatment with either chemotherapy drugs camptothecin and cisplatin or radiotherapy than the ones expressing the higher caspase-14 (P<0.01). Caspase-14 expression was observed in 70% dermal nevus, as well as 97% in malignant melanoma tissues, and the difference between them was statistically significant (P<0.05). Conclusion Caspase-14 is expressed in tissues and cells of malignant melanoma. Our data indicated that the expression level of caspase-14 affected the drug sensitivity of melanoma. PMID:25374083

Wang, Xinyuan; Zhang, Ji; Cheng, Yao; DU, Jipei; Chen, Degao; Yang, Zhimei; Wang, Yufang; Huang, Ning

2014-11-01

69

Serum Levels of Circulating Intercellular Adhesion Molecule 1 in Human Malignant Melanoma1  

Microsoft Academic Search

Current reports have suggested a role for intracellular adhesion mol ecule 1 (ICAM-1) in the progression of human malignant melanoma and other cancers. Stage I, II, and III patients with histologically diagnosed malignant melanoma had significantly increased serum levels of circulat ing ICAM-1 (cICAM-1) and a striking increase in the incidence of positive sera. In Stage II and III patients,

Ronald Harning; Elizabeth Mainolfi; Jean-Claude Bystryn; Milagros Henn; Vincent J. Merluzzi; Robert Rothlein

70

The potential value of the neutral comet assay and ?H2AX foci assay in assessing the radiosensitivity of carbon beam in human tumor cell lines  

PubMed Central

Background Carbon ions (12C6+) are high linear energy transfer (LET) radiation characterized by higher relative biological effectiveness than low LET radiation. The assessment of tumour radiosensitivity would be particularly useful in optimizing the radiation dose during radiotherapy. The aim of the current study was to evaluate the potential value of the neutral comet assay and ?H2AX foci assay in assessing 12C6+ radiosensitivity of tumour cells. Materials and methods The doses of 12C6+ and X-rays used in the present study were 2 and 4 Gy. The survival fraction, DNA double-strand breaks (DSB) and repair kinetics of DSB were assayed with clonogenic survival, neutral comet assay and ?H2AX foci assay in human cervical carcinoma HeLa cells, hepatoma HepG2 cells, and mucoepidermoid carcinoma MEC-1 cells at the time points of 0.5, 4, 16 and 24 h after 12C6+ and X-rays irradiation. Results The survival fraction for 12C6+ irradiation was much more inhibited than for X-rays (p < 0.05) in all three tumour cell lines tested. Substantial amounts of residual damage, assessed by the neutral comet assay, were present after irradiation (p < 0.05). The highest residual damage was observed at 0.5 or 4 h, both for 12C6+ and X-ray irradiation. However, the residual damage in HeLa and MEC-1 cells was higher for 12C6+ than X-rays (p < 0.05). The strongest induction of ?H2AX foci was observed after 30 min, for all three tumour cell lines (p < 0.01). The franction of ?H2AX foci persisted for at least 24 h after 12C6+ irradiation; in HeLa cells and MEC-1 was higher than after X-ray irradiation (p < 0.05). The correlation coefficients between the clonogenic survival, neutral comet assay and ?H2AX foci assay were not statistically significant, except for some tumour cells at individual irradiation doses and types. Conclusions Our study demonstrated that the neutral comet assay and ?-H2AX foci assay could be used to assess the radiosensitivity of 12C6+ in human tumour cells. PMID:24133390

Zhao, Jin; Guo, Zhong; Zhang, Hong; Wang, Zhenhua; Song, Lei; Ma, Jianxiu; Pei, Shuyan; Wang, Chenjing

2013-01-01

71

Analysis of polypeptide expression in benign and malignant human breast lesions: down-regulation of cytokeratins  

Microsoft Academic Search

Malignant progression of tumour cells is caused by the accumulation of genetic defects, which when combined will generate a large phenotypic diversity. Simultaneous quantitation of a large number of gene products in tumour cells is desirable, but difficult to achieve. We have here quantitated the levels of a number of abundant polypeptides in human breast carcinoma cells using two-dimensional gel

B Franzén; S Linder; AA Alaiya; E Eriksson; K Uruy; T Hirano; K Okuzawa; G Auer

1996-01-01

72

Radiosensitization of hematoporphyrin derivative: clinical trial on 69 patients  

NASA Astrophysics Data System (ADS)

Sixty-nine patients with various malignant tumors were treated with different regimens of radiotherapy or chemotherapy combined with HpD. The immediate response showed that the over-all response rate was 94.2% and complete response rate was 60.9%. The present study suggests that HpD be used as a radiosensitizer with mild side effects but no drug resistance on repeated administrations. Special effects of HpD on radio-resistant tumors, such as malignant melanoma, were observed. It may render radiation effective in advanced or recurrent lesions. Mechanism of radiosensitization of HpD is discussed. Tentative ideas for further investigations are put forward.

Huang, Shao-Yong; Yu, Tian-Hu

1993-03-01

73

What is the malignant nature of human ductal carcinoma in situ?  

PubMed Central

Invasive, genetically abnormal carcinoma progenitor cells have been propagated from human and mouse breast ductal carcinoma in situ (DCIS) lesions, providing new insights into breast cancer progression. The survival of DCIS cells in the hypoxic, nutrient-deprived intraductal niche could promote genetic instability and the derepression of the invasive phenotype. Understanding potential survival mechanisms, such as autophagy, that might be functioning in DCIS lesions provides strategies for arresting invasion at the pre-malignant stage. A new, open trial of neoadjuvant therapy for patients with DCIS constitutes a model for testing investigational agents that target malignant progenitor cells in the intraductal niche. PMID:21150936

Espina, Virginia; Liotta, Lance A.

2013-01-01

74

Diverse mechanisms of AKT pathway activation in human malignancy  

PubMed Central

AKT/PKB (Protein Kinase B) are central proteins mediating signals from receptor tyrosine kinases and phosphatidylinositol 3-kinase. AKT kinases are involved in a number of important cellular processes including cell proliferation and survival, cell size in response to nutrient availability, tumor invasion/metastasis, and angiogenesis. Various components of the AKT signaling pathway are encoded by tumor suppressor genes and oncogenes whose loss or activation, respectively, plays an important role in tumorigenesis. The growing body of evidence connecting deregulated AKT signaling with sporadic human cancers and inherited cancer predisposition syndromes is discussed. We also highlight new findings regarding the involvement of activating mutations of AKT1, AKT2, and AKT3 in somatic overgrowth disorders: Proteus syndrome, hypoglycemia with hypertrophy, and hemimegalencephaly, respectively. In addition, we review recent literature documenting the various ways the AKT signaling pathway is activated in human cancers and consequences for molecularly targeted therapies. PMID:23297823

Cheung, Mitchell; Testa, Joseph R.

2013-01-01

75

Copper and Zinc-containing Superoxide Dismutase and Manganese containing Superoxide Dismutase in Human Tissues and Human Malignant Tumors1  

Microsoft Academic Search

Superoxide dismutases might conceivably protect against both ionizing radiation and free radical-producing antibiotic antitumor drugs. Copper- and zinc-containing Superoxide dis- mutase (CuZn Superoxide dismutase) and manganese-contain ing Superoxide dismutase (Mn Superoxide dismutase) were specifically assayed in human malignant tumors and for com parison in human tissues. The tumors possessed less CuZn Superoxide dismutase than did the more metabolically active tissues,

N. Gunnar Westman; Stefan L. Marklund

76

Calreticulin, a Molecular Chaperone in the Endoplasmic Reticulum, Modulates Radiosensitivity of Human Glioblastoma U251MG Cells  

Microsoft Academic Search

Radiotherapy is the primary and most important adjuvant therapy for malignant gliomas. Although the mechanism of radiation resistance in gliomas has been studied for decades, it is still not clear how the resistance is related with functions of molecular chaperones in the endoplasmic reticulum. Calreticulin (CRT) is a Ca2+-binding molecular chaperone in the endoplasmic reticulum. Recently, it was reported that

Tomohiro Okunaga; Yoshishige Urat; Shinji Goto; Takayuki Matsuo; Shingo Mizota; Keisuke Tsutsumi; Izumi Nagata; Takahito Kondo; Yoshito Ihara

2006-01-01

77

Genetic Analysis of the Human Oncoprotein MDM2 in Benign and Malignant Tumors of the Salivary Gland  

Microsoft Academic Search

Introduction: Genetic alterations of oncogene MDM2 promote malignant transformation of several human tumors. In tumors of the salivary gland, however, the genetic status of MDM2 has not been evaluated so far. Methods and Results: Benign and malignant tumors of the salivary gland (6 pleomorphic adenomas, 3 Warthin’s tumors, 1 adenocarcinoma, 1 basal cell adenocarcinoma, 1 mucoepidermoid carcinoma, 3 acinic cell

Thilo Schlott; Holger Nagel; Rainer Laskawi; Helmut Eiffert; Manfred Droese

2001-01-01

78

Large-Scale Molecular Comparison of Human Schwann Cells to Malignant Peripheral Nerve Sheath Tumor Cell Lines and Tissues  

Microsoft Academic Search

Malignant peripheral nerve sheath tumors (MPNST) are highly invasive soft tissue sarcomas that arise within the peripheral nerve and frequently metastasize. To identify molecular events contributing to malignant transformation in peripheral nerve, we compared eight cell lines derived from MPNSTs and seven normal human Schwann cell samples. We found that MPNST lines are heterogeneous in their in vitro growth rates

Shyra J. Miller; Fatima Rangwala; Jon Williams; Peter Ackerman; Sue Kong; Anil G. Jegga; Sergio Kaiser; Bruce J. Aronow; Silke Frahm; Lan Kluwe; Victor Mautner; Meena Upadhyaya; David Muir; Margaret Wallace; Jussara Hagen; Mark A. Watson; Arie Perry; David H. Gutmann; Nancy Ratner

2006-01-01

79

Evidence for posttranscriptional regulation of the keratins expressed during hyperproliferation and malignant transformation in human epidermis  

Microsoft Academic Search

Keratin K6 is a protein that is expressed in human skin under conditions of hyperproliferation (e.g., wound-healing, psoriasis, and cell culture) and malignant transformation (e.g., squamous cell carci- nomas). When induced, the appearance of K6 is rapid: if skin tissue is placed in radiolabeled culture medium, this protein can be detected within an hour. The regulation of K6 seems to

Angela L. Tyner; Elaine Fuchs

1986-01-01

80

In Vivo Imaging of Human Malignant Mesothelioma Grown Orthotopically in the Peritoneal Cavity of Nude Mice  

Microsoft Academic Search

Malignant mesothelioma (MM) causes significant morbidity and mortality in patients. With increasing efforts devoted to developing therapeutics targeting mesothelioma, a xenograft mouse model with in vivo tumor imaging is especially desired for evaluating anti-tumor therapies. In the present study, we fluorescently labeled the NCI-H226 human mesothelioma cell line by a lentiviral vector harboring a luciferase-GFP (Luc\\/GFP) fusion gene driven by

Mingqian Feng; Jingli Zhang; Miriam Anver; Raffit Hassan; Mitchell Ho

2011-01-01

81

Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies  

Microsoft Academic Search

Mutations of receptor tyrosine kinases are implicated in the constitutive activation and development of human malignancy.An inter- nal tandem duplication (ITD) of the jux- tamembrane (JM) domain-coding sequence of the FLT3 gene (FLT3\\/ITD) is found in 20% of patients with acute myeloid leukemia (AML) and is strongly associated with leuko- cytosis and a poor prognosis. On the other hand, mutations

Yukiya Yamamoto; Hitoshi Kiyoi; Yasuyuki Nakano; Ritsuro Suzuki; Yoshihisa Kodera; Shuichi Miyawaki; Norio Asou; Kazutaka Kuriyama; Fumiharu Yagasaki; Chihiro Shimazaki; Hideki Akiyama; Kenji Saito; Miki Nishimura; Toshiko Motoji; Katsuji Shinagawa; Akihiro Takeshita; Hidehiko Saito; Ryuzo Ueda; Ryuzo Ohno; Tomoki Naoe

2010-01-01

82

Endoglin (CD105): A Strong Candidate for Immunologic Targeting of Tumor Neovasculature in Human Malignancies  

Microsoft Academic Search

Tumor-associated angiogenesis is a well-acknowledged therapeutic target for human malignancies, and different markers of tumor\\u000a neovasculature are actively investigated as potential candidates for antiangiogenetic therapy in cancer. Among these is endoglin\\u000a (CD105), a homodimeric transmembrane glycoprotein overexpressed on proliferating endothelial cells, which has been identified\\u000a as a functional component of the transforming growth factor-? (TGF-?) receptor system about a decade

Ester Fonsatti; Michele Maio

83

Cadmium Malignantly Transforms Normal Human Breast Epithelial Cells into a Basal-like Phenotype  

PubMed Central

Background Breast cancer has recently been linked to cadmium exposure. Although not uniformly supported, it is hypothesized that cadmium acts as a metalloestrogenic carcinogen via the estrogen receptor (ER). Thus, we studied the effects of chronic exposure to cadmium on the normal human breast epithelial cell line MCF-10A, which is ER-negative but can convert to ER-positive during malignant transformation. Methods Cells were continuously exposed to low-level cadmium (2.5 ?M) and checked in vitro and by xenograft study for signs of malignant transformation. Transformant cells were molecularly characterized by protein and transcript analysis of key genes in breast cancer. Results Over 40 weeks of cadmium exposure, cells showed increasing secretion of matrix metalloproteinase-9, loss of contact inhibition, increased colony formation, and increasing invasion, all typical for cancer cells. Inoculation of cadmium-treated cells into mice produced invasive, metastatic anaplastic carcinoma with myoepithelial components. These cadmium-transformed breast epithelial (CTBE) cells displayed characteristics of basal-like breast carcinoma, including ER-? negativity and HER2 (human epidermal growth factor receptor 2) negativity, reduced expression of BRCA1 (breast cancer susceptibility gene 1), and increased CK5 (cytokeratin 5) and p63 expression. CK5 and p63, both breast stem cell markers, were prominently overexpressed in CTBE cell mounds, indicative of persistent proliferation. CTBE cells showed global DNA hypomethylation and c-myc and k-ras overexpression, typical in aggressive breast cancers. CTBE cell xenograft tumors were also ER-? negative. Conclusions Cadmium malignantly transforms normal human breast epithelial cells—through a mechanism not requiring ER-?—into a basal-like cancer phenotype. Direct cadmium induction of a malignant phenotype in human breast epithelial cells strongly fortifies a potential role in breast cancer. PMID:20049202

Benbrahim-Tallaa, Lamia; Tokar, Erik J.; Diwan, Bhalchandra A.; Dill, Anna L.; Coppin, Jean-Francois; Waalkes, Michael P.

2009-01-01

84

The mechanisms responsible for the radiosensitizing effects of sorafenib on colon cancer cells.  

PubMed

Colorectal cancer is one of the most common malignancies in the world, and is generally treated more effectively by chemoradiotherapy rather than radiotherapy or chemotherapy alone. Targeted radiosensitizers are often used in order to enhance the radiosensitivity of tumor cells. The aim of the present study was to identify the mechanism of radiosensitization by sorafenib in colorectal cancer. Three human colorectal adenocarcinoma cell lines (HCT116, HT29 and SW480) were treated with sorafenib alone or radiation followed by sorafenib. In vitro tests were performed using colony forming assays, FACS analysis, immunohistochemistry, tumor cell motility assays, invasion assays and endothelial tube formation assays. Sorafenib enhanced the anti-proliferative effects of radiation, reducing colony formation, increasing G2/M arrest and enhancing radiation-induced apoptosis by reactive oxygen species. Sorafenib also inhibited the repair of radiation-induced DNA damage by blocking the activation of DNA-dependent protein kinase. Combination treatment significantly inhibited tumor cell migration, tumor cell invasion and vascular endothelial growth factor-mediated angiogenesis in vitro. Taken together, our results provide a scientific rationale for the use of sorafenib with radiotherapy in colon cancer and suggest a clinical utility for this approach. PMID:25242034

Kim, Eun Ho; Kim, Mi-Sook; Jung, Won-Gyun

2014-12-01

85

The softening of human bladder cancer cells happens at an early stage of the malignancy process  

PubMed Central

Summary Various studies have demonstrated that alterations in the deformability of cancerous cells are strongly linked to the actin cytoskeleton. By using atomic force microscopy (AFM), it is possible to determine such changes in a quantitative way in order to distinguish cancerous from non-malignant cells. In the work presented here, the elastic properties of human bladder cells were determined by means of AFM. The measurements show that non-malignant bladder HCV29 cells are stiffer (higher Young’s modulus) than cancerous cells (HTB-9, HT1376, and T24 cell lines). However, independently of the histological grade of the studied bladder cancer cells, all cancerous cells possess a similar level of the deformability of about a few kilopascals, significantly lower than non-malignant cells. This underlines the diagnostic character of stiffness that can be used as a biomarker of bladder cancer. Similar stiffness levels, observed for cancerous cells, cannot be fully explained by the organization of the actin cytoskeleton since it is different in all malignant cells. Our results underline that it is neither the spatial organization of the actin filaments nor the presence of stress fibers, but the overall density and their 3D-organization in a probing volume play the dominant role in controlling the elastic response of the cancerous cell to an external force. PMID:24778971

Ramos, Jorge R; Pabijan, Joanna

2014-01-01

86

An effective strategy for increasing the radiosensitivity of Human lung Cancer cells by blocking Nrf2-dependent antioxidant responses.  

PubMed

Radiotherapy and chemotherapeutic agents can effectively induce apoptosis through generation of reactive oxygen species (ROS). Cancer cells frequently express high levels of ROS-scavenging enzymes, which confer resistance to ROS-mediated cell death. Keap1 (Kelch-like ECH-associated protein 1) sequesters and promotes the degradation of the antioxidant response element-binding transcription factor Nrf2 (nuclear factor erythroid-2-related factor 2). In non-small-cell lung cancer (NSCLC) cell lines and NSCLC patients, Keap1 is often present as a biallelic mutant that results in constitutive activation of Nrf2 function, which contributes to cytoprotection against oxidative stress and xenobiotics. To identify small molecules that inhibit antioxidant responses and increase apoptotic death after radiotherapy, we screened a chemical library containing 8000 synthetic compounds using a cell-based luciferase assay system. 4-(2-Cyclohexylethoxy)aniline (IM3829) inhibited the increase in Nrf2-binding activity and expression of the Nrf2 target genes induced by treatment with tertiary butylhydroquinone or radiation. Combined treatment with IM3829 and radiation significantly inhibited clonogenic survival of H1299, A549, and H460 lung cancer cells. IM3829 significantly increased ROS accumulation in irradiated cells compared with cells exposed to radiation alone and led to apoptotic cell death, as confirmed by caspase-3 and PARP cleavage. In mice bearing H1299 or A549 lung cancer xenografts, IM3829 together with radiation inhibited tumor growth more effectively than radiation alone. Our findings suggest that IM3829 could be a promising radiosensitizer in lung cancer patients, particularly those with high expression of Nrf2. PMID:22684019

Lee, Saelooom; Lim, Min-Jin; Kim, Mi-Hyoung; Yu, Chi-Ho; Yun, Yeon-Sook; Ahn, Jiyeon; Song, Jie-Young

2012-08-15

87

Localization of human malignant tumors with radioiodinated recombinant tissue plasminogen activator  

SciTech Connect

Human recombinant tissue plasminogen activator (tPA), labeled with /sup 131/I(1.1 to 6.2 mCi) by the iodogen method, was administered intravenously to 15 patients with various soft-tissue malignant tumors after blocking of thyroidal radioiodine uptake. Gamma camera imaging was performed 4 and 24 hr after injection; three patients were also imaged 5 days following injection. We observed accumulation of radioactivity in primary and secondary lesions in 11 patients. In this preliminary study we did not detect any definite association between the magnitude of uptake and type of tumor. Tumors were usually visualized already after 4 hr but the uptake was more intense at 24 hr. The target-to-nontarget ratios at 24 hr, determined by computer analysis of stored images, varied from less than 1.2 to 2.1. This is the first demonstration of accumulation of radiolabeled tPA in malignant tissue. We do not know the mechanism of the uptake but because tPA is known to be avidly bound to fibrin, a component of the stroma of many malignant tumors, it is possible that (/sup 131/I)tPA is bound to fibrin rather than taken up by the malignant cell; various possible cell uptake mechanisms are discussed. Due to the relatively early maximal uptake of this radiopharmaceutical it will be possible to substitute 123I for 131I, a possibility suggesting a potential clinical use of radioiodinated tPA for the detection of malignant tumors of various origin.

Karonen, S.L.; Aronen, H.; Liewendahl, K.; Nikkinen, P.; Maentylae, M.Li.; Lindgren, J.

1988-07-01

88

Dielectric spectroscopy of normal and malignant human lung cells at ultra-high frequencies  

NASA Astrophysics Data System (ADS)

Microwave techniques for biomedical applications aimed at cancer treatment or diagnosis, either by imaging or spectroscopy, are promising. Their use relies on knowledge of the dielectric properties of tissues, especially on a detectable difference between malignant and normal tissues. As most studies investigated the dielectric properties of ex vivo tissues, there is a need for better biophysical understanding of human tissues in their living state. As an essential component of tissues, cells represent valuable objects of analysis. The approach developed in this study is an investigation at cell level. Its aim was to compare human lung normal and malignant cells by dielectric spectroscopy in the beginning of the microwave range, where such information is of substantial biomedical importance. These cells were embedded in small and low-conductivity agarose hydrogels and laid on an open-ended coaxial probe connected to a vector network analyser operated from 200 MHz to 2 GHz. The comparison between normal and malignant cells was drawn using the variation of measured dielectric properties and fitting the measurements using the Maxwell-Wagner equation. Both methods revealed slight differences between the two cell lines, which were statistically significant regarding conductivities of composite gels and cells.

Egot-Lemaire, S.; Pijanka, J.; Sulé-Suso, J.; Semenov, S.

2009-04-01

89

Role of phosphodiesterase 2 in growth and invasion of human malignant melanoma cells.  

PubMed

Cyclic nucleotide phosphodiesterases (PDEs) regulate the intracellular concentrations and effects of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP). The role of PDEs in malignant tumor cells is still uncertain. The role of PDEs, especially PDE2, in human malignant melanoma PMP cell line was examined in this study. In PMP cells, 8-bromo-cAMP, a cAMP analog, inhibited cell growth and invasion. However, 8-bromo-cGMP, a cGMP analog, had little or no effect. PDE2 and PDE4, but not PDE3, were expressed in PMP cells. Growth and invasion of PMP cells were inhibited by erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), a specific PDE2 inhibitor, but not by rolipram, a specific PDE4 inhibitor. Moreover, cell growth and invasion were inhibited by transfection of small interfering RNAs (siRNAs) specific for PDE2A and a catalytically-dead mutant of PDE2A. After treating cells with EHNA or rolipram, intracellular cAMP concentrations were increased. Growth and invasion were stimulated by PKA14-22, a PKA inhibitor, and inhibited by N(6)-benzoyl-c AMP, a PKA specific cAMP analog, whereas 8-(4-chlorophenylthio)-2'-O-methyl-cAMP, an Epac specific cAMP analog, did not. Invasion, but not growth, was stimulated by A-kinase anchor protein (AKAP) St-Ht31 inhibitory peptide. Based on these results, PDE2 appears to play an important role in growth and invasion of the human malignant melanoma PMP cell line. Selectively suppressing PDE2 might possibly inhibit growth and invasion of other malignant tumor cell lines. PMID:24705027

Hiramoto, Kenichi; Murata, Taku; Shimizu, Kasumi; Morita, Hiroshi; Inui, Madoka; Manganiello, Vincent C; Tagawa, Toshiro; Arai, Naoya

2014-09-01

90

NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro  

PubMed Central

Aim: NVP-BEZ235 is a novel dual PI3K/mTOR inhibitor and shows dramatic effects on gliomas. The aim of this study was to investigate the effects of NVP-BEZ235 on the radiosensitivity and autophagy of glioma stem cells (GSCs) in vitro. Methods: Human GSCs (SU-2) were tested. The cell viability and survival from ionizing radiation (IR) were evaluated using MTT and clonogenic survival assay, respectively. Immunofluorescence assays were used to identify the formation of autophagosomes. The apoptotic cells were quantified with annexin V-FITC/PI staining and flow cytometry, and observed using Hoechst 33258 staining and fluorescence microscope. Western blot analysis was used to analyze the expression levels of proteins. Cell cycle status was determined by measuring DNA content after staining with PI. DNA repair in the cells was assessed using a comet assay. Results: Treatment of SU-2 cells with NVP-BEZ235 (10–320 nmol/L) alone suppressed the cell growth in a concentration-dependent manner. A low concentration of NVP-BEZ235 (10 nmol/L) significantly increased the radiation sensitivity of SU-2 cells, which could be blocked by co-treatment with 3-MA (50 ?mol/L). In NVP-BEZ235-treated SU-2 cells, more punctate patterns of microtubule-associated protein LC3 immunoreactivity was observed, and the level of membrane-bound LC3-II was significantly increased. A combination of IR with NVP-BEZ235 significantly increased the apoptosis of SU-2 cells, as shown in the increased levels of BID, Bax, and active caspase-3, and decreased level of Bcl-2. Furthermore, the combination of IR with NVP-BEZ235 led to G1 cell cycle arrest. Moreover, NVP-BEZ235 significantly attenuated the repair of IR-induced DNA damage as reflected by the tail length of the comet. Conclusion: NVP-BEZ235 increases the radiosensitivity of GSCs in vitro by activating autophagy that is associated with synergistic increase of apoptosis and cell-cycle arrest and decrease of DNA repair capacity. PMID:23603977

Wang, Wen-juan; Long, Lin-mei; Yang, Neng; Zhang, Qing-qing; Ji, Wen-jun; Zhao, Jiang-hu; Qin, Zheng-hong; Wang, Zhong; Chen, Gang; Liang, Zhong-qin

2013-01-01

91

L1 adhesion molecule (CD 171) in development and progression of human malignant melanoma.  

PubMed

The L1 adhesion molecule (CD171) plays an important role in axon guidance and cell migration in the nervous system. In the human, L1 is expressed on tumors derived from neurocrest and on certain carcinomas. We have analyzed immunohistochemically L1 expression on paraffin embedded specimens of acquired melanocytic nevi, primary cutaneous melanomas, and cutaneous and lymph node metastases of malignant melanomas. We found an increase in L1 immunoreactivity in malignant melanomas and metastases of malignant melanomas as compared to acquired melanocytic nevi that was statistically significant (P<0.05). Additionally, a correlation of L1 immunoreactivity with histological data of prognostic value such as Clark level and the expression of alphav-integrins was found. We detected soluble L1 in the conditioned medium of cultivated melanoma cells but only in 1/40 serum samples from a panel of melanoma patients representing various stages of disease. Our findings suggest that the presence of L1 might contribute to tumor progression by promoting cell adhesion and migration. PMID:12490317

Fogel, Mina; Mechtersheimer, Sabine; Huszar, Monica; Smirnov, Asya; Abu-Dahi, Adel; Tilgen, Wolfgang; Reichrath, Jörg; Georg, Thomas; Altevogt, Peter; Gutwein, Paul

2003-01-28

92

A complete compilation of matrix metalloproteinase expression in human malignant gliomas  

PubMed Central

Glioblastomas are characterized by an aggressive local growth pattern, a marked degree of invasiveness and poor prognosis. Tumor invasiveness is facilitated by the increased activity of proteolytic enzymes which are involved in destruction of the extracellular matrix of the surrounding healthy brain tissue. Elevated levels of matrix metalloproteinases (MMPs) were found in glioblastoma (GBM) cell-lines, as well as in GBM biopsies as compared with low-grade astrocytoma (LGA) and normal brain samples, indicating a role in malignant progression. A careful review of the available literature revealed that both the expression and role of several of the 23 human MMP proteins is controversely discussed and for some there are no data available at all. We therefore screened a panel of 15 LGA and 15 GBM biopsy samples for those MMPs for which there is either no, very limited or even contradictory data available. Hence, this is the first complete compilation of the expression pattern of all 23 human MMPs in astrocytic tumors. This study will support a better understanding of the specific expression patterns and interaction of proteolytic enzymes in malignant human glioma and may provide additional starting points for targeted patient therapy. PMID:22582165

Hagemann, Carsten; Anacker, Jelena; Ernestus, Ralf-Ingo; Vince, Giles H

2012-01-01

93

Preclinical in vivo evaluation of rapamycin in human malignant peripheral nerve sheath explant xenograft.  

PubMed

Neurofibromatosis type 1 (NF1) patients are prone to the development of malignant tumors, the most common being Malignant Peripheral Nerve Sheath Tumor (MPNST). NF1-MPNST patients have an overall poor survival due to systemic metastasis. Currently, the management of MPNSTs includes surgery and radiation; however, conventional chemotherapy is not very effective, underscoring the need for effective biologically-targeted therapies. Recently, the NF1 gene product, neurofibromin, was shown to negatively regulate the phosphoinositide-3-kinase (PI3K)/Protein Kinase-B (Akt)/mammalian Target Of Rapamycin (mTOR) pathway, with loss of neurofibromin expression in established human MPNST cell lines associated with high levels of mTOR activity. We developed and characterized a human NF1-MPNST explant grown subcutaneously in NOD-SCID mice, to evaluate the effect of the mTOR inhibitor rapamycin. We demonstrate that rapamycin significantly inhibited human NF1-MPNST mTOR pathway activation and explant growth in vivo at doses as low as 1.0 mg/kg/day, without systemic toxicities. While rapamycin was effective at reducing NF1-MPNST proliferation and angiogenesis, with decreased CyclinD1 and VEGF respectively, there was no increase in tumor apoptosis. Rapamycin effectively decreased activation of S6 downstream of mTOR, but there was accompanied increased Akt activation. This study demonstrates the therapeutic potential and limitations of rapamycin in NF1-associated, and likely sporadic, MPNSTs. PMID:19634141

Bhola, Priya; Banerjee, Sutapa; Mukherjee, Joydeep; Balasubramanium, Anand; Arun, Vedant; Karim, Zia; Burrell, Kelly; Croul, Sidney; Gutmann, David H; Guha, Abhijit

2010-01-15

94

Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations  

PubMed Central

We used CDK4/hTERT-immortalized normal human bronchial epithelial cells (HBECs) from several individuals to study lung cancer pathogenesis by introducing combinations of common lung cancer oncogenic changes (p53, KRAS, MYC) and followed the stepwise transformation of HBECs to full malignancy. This model demonstrated that: 1) the combination of five genetic alterations (CDK4, hTERT, sh-p53, KRASV12, and c-MYC) is sufficient for full tumorigenic conversion of HBECs; 2) genetically-identical clones of transformed HBECs exhibit pronounced differences in tumor growth, histology, and differentiation; 3) HBECs from different individuals vary in their sensitivity to transformation by these oncogenic manipulations; 4) high levels of KRASV12 are required for full malignant transformation of HBECs, however prior loss of p53 function is required to prevent oncogene-induced senescence; 5) over-expression of c-MYC greatly enhances malignancy but only in the context of sh-p53+KRASV12; 6) growth of parental HBECs in serum-containing medium induces differentiation while growth of oncogenically manipulated HBECs in serum increases in vivo tumorigenicity, decreases tumor latency, produces more undifferentiated tumors, and induces epithelial-to-mesenchymal transition (EMT); 7) oncogenic transformation of HBECs leads to increased sensitivity to standard chemotherapy doublets; 8) an mRNA signature derived by comparing tumorigenic vs. non-tumorigenic clones was predictive of outcome in lung cancer patients. Collectively, our findings demonstrate this HBEC model system can be used to study the effect of oncogenic mutations, their expression levels, and serum-derived environmental effects in malignant transformation, while also providing clinically translatable applications such as development of prognostic signatures and drug response phenotypes. PMID:23449933

Sato, Mitsuo; Larsen, Jill E.; Lee, Woochang; Sun, Han; Shames, David S.; Dalvi, Maithili P.; Ramirez, Ruben D.; Tang, Hao; DiMaio, J. Michael; Gao, Boning; Xie, Yang; Wistuba, Ignacio I.; Gazdar, Adi F.; Shay, Jerry W.; Minna, John D.

2013-01-01

95

Insulin-Like Growth Factor-Type 1 Receptor Inhibitor NVP-AEW541 Enhances Radiosensitivity of PTEN Wild-Type but Not PTEN-Deficient Human Prostate Cancer Cells  

SciTech Connect

Purpose: During the past decade, many clinical trials with both monoclonal antibodies and small molecules that target the insulin-like growth factor-type 1 receptor (IGF-1R) have been launched. Despite the important role of IGF-1R signaling in radioresistance, studies of such agents in combination with radiotherapy are lagging behind. Therefore, the aim of this study was to investigate the effect of the small molecule IGF-1R kinase inhibitor NVP-AEW541 on the intrinsic radioresistance of prostate cancer cells. Methods and Materials: The effect of NVP-AEW541 on cell proliferation, cell viability, IGF-1R signaling, radiosensitivity, cell cycle distribution, and double strand break repair was determined in three human prostate cancer cell lines (PC3, DU145, 22Rv1). Moreover, the importance of the PTEN pathway status was explored by means of transfection experiments with constitutively active Akt or inactive kinase-dead Akt. Results: NVP-AEW541 inhibited cell proliferation and decreased cell viability in a time-and dose-dependent manner in all three cell lines. Radiosensitization was observed in the PTEN wild-type cell lines DU145 and 22Rv1 but not in the PTEN-deficient PC3 cell line. NVP-AEW541-induced radiosensitization coincided with downregulation of phospho-Akt levels and high levels of residual double strand breaks. The importance of PTEN status in the radiosensitization effect was confirmed by transfection experiments with constitutively active Akt or inactive kinase-dead Akt. Conclusions: NVP-AEW541 enhances the effect of ionizing radiation in PTEN wild-type, but not in PTEN-deficient, prostate cancer cells. Proper patient selection based on the PTEN status of the tumor will be critical to the achievement of optimal results in clinical trials in which the combination of radiotherapy and this IGF-1R inhibitor is being explored.

Isebaert, Sofie F., E-mail: sofie.isebaert@med.kuleuven.be [Department of Radiation Oncology, University Hospitals Leuven Campus Gasthuisberg, Leuven (Belgium); Swinnen, Johannes V. [Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven (Belgium); McBride, William H. [Department of Radiation Oncology, University of California at Los Angeles, CA (United States); Haustermans, Karin M. [Department of Radiation Oncology, University Hospitals Leuven Campus Gasthuisberg, Leuven (Belgium)

2011-09-01

96

Selective growth inhibition of human malignant melanoma cells by syringic acid-derived proteasome inhibitors  

PubMed Central

Background It has been shown that proteasome inhibition leads to growth arrest in the G1 phase of the cell cycle and/or induction of apoptosis. However, it was found that some of these inhibitors do not induce apoptosis in several human normal cell lines. This selective activity makes proteasome inhibition a promising target for new generation of anticancer drugs. Clinical validation of the proteasome, as a therapeutic target in oncology, has been provided by the dipeptide boronic acid derivative; bortezomib. Bortezomib has proven to be effective as a single agent in multiple myeloma and some forms of non-Hodgkin’s lymphoma. Syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid, 1), a known phenolic acid, was isolated from the methanol extract of Tamarix aucheriana and was shown to possess proteasome inhibitory activity. Methods Using Surflex-Dock program interfaced with SYBYL, the docking affinities of syringic acid and its proposed derivatives to 20S proteasome were studied. Several derivatives were virtually proposed, however, five derivatives: benzyl 4-hydroxy-3,5-dimethoxybenzoate (2), benzyl 4-(benzyloxy)-3,5-dimethoxybenzoate (3), 3'-methoxybenzyl 3,5-dimethoxy-4-(3'-methoxybenzyloxy)benzoate (4), 3'-methoxybenzyl 4-hydroxy-3,5-dimethoxybenzoate (5) and 3',5'-dimethoxybenzyl 4-hydroxy-3,5-dimethoxybenzoate (6), were selected based on high docking scores, synthesized, and tested for their anti-mitogenic activity against human colorectal, breast and malignant melanoma cells as well as normal human fibroblast cells. Results Derivatives 2, 5, and 6 showed selective dose-dependent anti-mitogenic effect against human malignant melanoma cell lines HTB66 and HTB68 with minimal cytotoxicity on colorectal and breast cancer cells as well as normal human fibroblast cells. Derivatives 2, 5 and 6 significantly (p???0.0001) inhibited the various proteasomal chymotrypsin, PGPH, and trypsin like activities. They growth arrested the growth of HTB66 cells at G1 and G2-phases. They also arrested the growth of HTB68 cells at S- and G2-phase, respectively. Moreover, derivatives 2, 5, and 6 markedly induced apoptosis (? 90%) in both HTB66 and HTB68. Conclusions Computer-derived syringic acid derivatives possess selective anti-mitogenic activity on human malignant melanoma cells that may be attributed to perturbation of cell cycle, induction of apoptosis and inhibition of various 26S proteasomal activities. PMID:23958424

2013-01-01

97

High-performance capillary electrophoretic analysis of hyaluronan in effusions from human malignant mesothelioma.  

PubMed

A procedure to quantify hyaluronan in effusions from human malignant mesothelioma using a highly sensitive and reproducible high-performance capillary electrophoresis (HPCE) method is presented. Following ethanol precipitation, hyaluronan and galactosaminoglycans were degraded to delta 4,5-disaccharides with a mixture of chondroitinases ABC and AC. Heparan sulphate and proteins/glycoproteins were separated by ultrafiltration on a Centricon 3 membrane, and hyaluronan-derived disaccharides were analysed by direct injection of the filtrate into a HPCE system. Determination of hyaluronan in effusions from five healthy individuals and three patients with mesothelioma gave values comparable to those found using the HPLC method. One of the advantages of the HPCE method as compared to HPLC is the low solvent consumption. The much lower detection limit (attomole level) of the HPCE method may also allow the analysis of hyaluronan content in serum. The contribution of HPCE in diagnosis of a neoplasm, such as human malignant mesothelioma, illustrates the great potential of this technique in the field of life sciences. PMID:9342681

Karamanos, N K; Hjerpe, A

1997-09-12

98

Discrimination analysis of human lung cancer cells associated with histological type and malignancy using Raman spectroscopy  

NASA Astrophysics Data System (ADS)

The Raman spectroscopic technique enables the observation of intracellular molecules without fixation or labeling procedures in situ. Raman spectroscopy is a promising technology for diagnosing cancers-especially lung cancer, one of the most common cancers in humans-and other diseases. The purpose of this study was to find an effective marker for the identification of cancer cells and their malignancy using Raman spectroscopy. We demonstrate a classification of cultured human lung cancer cells using Raman spectroscopy, principal component analysis (PCA), and linear discrimination analysis (LDA). Raman spectra of single, normal lung cells, along with four cancer cells with different pathological types, were successfully obtained with an excitation laser at 532 nm. The strong appearance of bands due to cytochrome c (cyt-c) indicates that spectra are resonant and enhanced via the Q-band near 550 nm with excitation light. The PCA loading plot suggests a large contribution of cyt-c in discriminating normal cells from cancer cells. The PCA results reflect the nature of the original cancer, such as its histological type and malignancy. The five cells were successfully discriminated by the LDA.

Oshima, Yusuke; Shinzawa, Hideyuki; Takenaka, Tatsuji; Furihata, Chie; Sato, Hidetoshi

2010-01-01

99

Heparan Sulfate-Like Proteoglycans Mediate Adhesion of Human Malignant Melanoma A375 Cells to P-Selectin  

E-print Network

of certain types of non-blood borne, "epithelial-like" human cancer cells to P-selectin. The Journal-Selectin Under Flow1 Yan-Qing Ma and Jian-Guo Geng2 Selectins, a family of cell adhesion molecules, bindHeparan Sulfate-Like Proteoglycans Mediate Adhesion of Human Malignant Melanoma A375 Cells to P

Tian, Weidong

100

Characterization of phosphodiesterase 2A in human malignant melanoma PMP cells  

PubMed Central

The prognosis for malignant melanoma is poor; therefore, new diagnostic methods and treatment strategies are urgently needed. Phosphodiesterase 2 (PDE2) is one of 21 phosphodiesterases, which are divided into 11 families (PDE1-PDE11). PDE2 hydrolyzes cyclic AMP (cAMP) and cyclic GMP (cGMP), and its binding to cGMP enhances the hydrolysis of cAMP. We previously reported the expression of PDE1, PDE3 and PDE5 in human malignant melanoma cells. However, the expression of PDE2 in these cells has not been investigated. Herein, we examined the expression of PDE2A and its role in human oral malignant melanoma PMP cells. Sequencing of RT-PCR products revealed that PDE2A2 was the only variant expressed in PMP cells. Four point mutations were detected; one missense mutation at nucleotide position 734 (from C to T) resulted in the substitution of threonine with isoleucine at amino acid position 214. The other three were silent mutations. An in vitro migration assay and a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay revealed that suppressing PDE2 activity with its specific inhibitor, erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), had no impact on cell motility or apoptosis. Furthermore, the cytotoxicity of EHNA, assessed using a trypan blue exclusion assay, was negligible. On the other hand, assessment of cell proliferation by BrdU incorporation and cell cycle analysis by flow cytometry revealed that EHNA treatment inhibited DNA synthesis and increased the percentage of G2/M-arrested cells. Furthermore, cyclin A mRNA expression was downregulated, while cyclin E mRNA expression was upregulated in EHNA-treated cells. Our results demonstrated that the PDE2A2 variant carrying point mutations is expressed in PMP cells and may affect cell cycle progression by modulating cyclin A expression. Thus, PDE2A2 is a possible new molecular target for the treatment of malignant melanoma. PMID:23381931

MORITA, HIROSHI; MURATA, TAKU; SHIMIZU, KASUMI; OKUMURA, KENYA; INUI, MADOKA; TAGAWA, TOSHIRO

2013-01-01

101

In vivo study of breast carcinoma radiosensitization by targeting eIF4E  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer eIF4E is associated with the formation and progression for breast cancer. Black-Right-Pointing-Pointer pSecX-t4EBP1 can downregulated the expression of eIF4E in direct binding. Black-Right-Pointing-Pointer We transfected pSecX-t4EBP1 into a mouse xenograft model. Black-Right-Pointing-Pointer It can significantly inhibit tumor growth and enhance the radiosensitivity. Black-Right-Pointing-Pointer The possible mechanism is downregulation of HIF-1{alpha} expression. -- Abstract: Background: Eukaryotic initiation factor eIF4E, an important regulator of translation, plays a crucial role in the malignant transformation, progression and radioresistance of many human solid tumors. The overexpression of this gene has been associated with tumor formation in a wide range of human malignancies, including breast cancer. In the present study, we attempted to explore the use of eIF4E as a therapeutic target to enhance radiosensitivity for breast carcinomas in a xenograft BALB/C mice model. Materials and methods: Ninety female BALB/C mice transfected with EMT-6 cells were randomly divided into six groups: control, irradiation (IR), pSecX-t4EBP1, pSecX-t4EBP1 + irradiation, pSecX and pSecX + irradiation. At the end of the experiments, all mice were sacrificed, the xenografts were harvested to measure the tumor volume and mass, and the tumor inhibition rates were calculated. Apoptosis was detected with a flow cytometric assay. Immunohistochemistry was used to detect the expression of HIF-1{alpha}. Results: The xenografts in pSecX-t4EBP1 mice showed a significantly delayed growth and smaller tumor volume, with a higher tumor inhibition rate compared with the control and pSecX groups. A similar result was obtained in the pSecX-t4EBP1 + IR group compared with IR alone and pSecX + irradiation. The expression of HIF-1{alpha} in the tumor cells was significantly decreased, while the apoptosis index was much higher. Conclusions: pSecX-t4EBP1 can significantly inhibit tumor growth and enhance the radiosensitivity of breast carcinoma xenografts in BALB/C mice. This is possibly associated with the downregulation of HIF-1{alpha} expression, which suggests that pSecX-t4EBP1 may serve as an ideal molecular target for the radiosensitization of breast carcinoma.

Yang, Hua [Department of Radiotherapy, Xijing Hospital, The Fourth Military Medical University, No. 17 Changle Western Road, Xi'an 710032 (China)] [Department of Radiotherapy, Xijing Hospital, The Fourth Military Medical University, No. 17 Changle Western Road, Xi'an 710032 (China); Li, Li-Wen [Department of Radiotherapy, Xijing Hospital, The Fourth Military Medical University, No. 17 Changle Western Road, Xi'an 710032 (China) [Department of Radiotherapy, Xijing Hospital, The Fourth Military Medical University, No. 17 Changle Western Road, Xi'an 710032 (China); Department of Bioscience, College of Life Sciences, Northwest University, No. 229 North Taibai Road, Xi'an 710069 (China); Shi, Mei, E-mail: mshi82@fmmu.edu.cn [Department of Radiotherapy, Xijing Hospital, The Fourth Military Medical University, No. 17 Changle Western Road, Xi'an 710032 (China)] [Department of Radiotherapy, Xijing Hospital, The Fourth Military Medical University, No. 17 Changle Western Road, Xi'an 710032 (China); Wang, Jian-Hua; Xiao, Feng; Zhou, Bin; Diao, Li-Qiong; Long, Xiao-Li; Liu, Xiao-Li; Xu, Lin [Department of Radiotherapy, Xijing Hospital, The Fourth Military Medical University, No. 17 Changle Western Road, Xi'an 710032 (China)] [Department of Radiotherapy, Xijing Hospital, The Fourth Military Medical University, No. 17 Changle Western Road, Xi'an 710032 (China)

2012-07-13

102

Isolation of alpha 1-protease inhibitor from human normal and malignant ovarian tissue.  

PubMed Central

Proteolytic enzymes are associated with normal and neoplastic tissues. Therefore protease inhibitors might also be involved in the control of cell function. alpha 1-protease antigen and antitryptic activity have been found in normal and neoplastic human ovarian homogenate. The inhibitor has been localized to ovarian stromal cells or tumor cells by immunoperoxidase staining. The protein was purified to apparent homogeneity as judged by alkaline gel and sodium dodecyl sulfate (SDS) gel electrophoresis. Immunochemical studies revealed antigenic similarity of plasma alpha 1-protease inhibitor by double immunodiffusion and similar mobility on immunoelectrophoresis and two-dimensional electroimmunodiffusion. The molecular weight was similar to that described for plasma alpha 1-protease inhibitor: 60,000 by gel filtration and 53,500 by SDS electrophoresis. Furthermore, the phenotypic pattern as determined by acid starch gel electrophoresis and immunoprecipitation was PiMM, which is the predominant genetic variant in normal plasma alpha 1-protease inhibitor. An inhibitor ws isolated and purified from an ovarian carcinoma that exhibited functional, immunochemical, and physical similarity to the normal ovarian alpha 1-protease inhibitor. alpha 1-protease inhibitor from normal and malignant ovaries competitively inhibited bovine pancreatic trypsin at incubation times of 5 min at 30 degrees C. Inhibition constant (Ki) values were calculated at 0.67 and 0.51 inhibitory units, respectively. The alpha 1-protease inhibitor in malignant cells may be a factor in the control of proliferation in this tissue. Since ovulation is in part a proteolytic event, the alpha 1-protease inhibitor in ovarian cells may play a role in the control of this specialized tissue. Persistance of this protein in malignant ovarian tissue may be a vestige of its differentiated origin. Images PMID:6161137

Bagdasarian, A; Wheeler, J; Stewart, G J; Ahmed, S S; Colman, R W

1981-01-01

103

Tumor suppressor gene alterations of spontaneously malignant transformed cells from human embryonic muscle in vitro.  

PubMed

Recent research has shown that mesenchymal stem cells (MSCs) which were cultured for long time could transform malignantly, the transformation mechanism is not clear yet, it might be associated with the activation of oncogenes and inactivation of tumor suppressor genes. In our initial investigation, we found that the cells arising from human embryonic muscle could spontaneously transform into malignancy in vitro and we obtained 6 immortalized cell lines. In this study, polymerase chain reaction (PCR) was used to assay several tumor suppressor genes of these cell lines, and homozygous deletions within chromosomal band 9p2l including MTAP (methylthioadenosine phosphorylase), p16 and p15 were detected. PCR products of p53 exons 7 and 8 of these novel tumor cell lines were assayed by sequencing, and the results showed high prevalence of mutations in these regions, the mutation rate reached as high as 8% in exon 7 and 14% in exon 8, and all of them were point mutations, the intron 7 changed more significantly, including piece deletion, insertion, frameshift and point mutation, it showed almost no similarity to that of the wt p53 sequence, that was totally different from other p53 mutation data published. All the mutation sequences were identical in 6 cell lines, this suggest that there may be a common mutation mechanism and strong selective advantage in these novel tumor cell lines over long-term culture. In conclusion, our research shows that the inactivation of tumor suppressor genes may play an important role in the process of malignant transformation of embryonic muscle cells in vitro. PMID:20596646

Wang, Xianyao; Li, Wenyu; Zheng, Jiakun; Chen, Qiang; Zou, Haiying; Ma, Lian; Lin, Guangyu; Huang, Tianhua; Huang, Ge; Yang, Liye

2010-08-01

104

Circadian rhythmometry of mammalian radiosensitivity  

NASA Technical Reports Server (NTRS)

In the case of human bone marrow, the largest number of mitoses is seen in the evening in diurnally active men, mitotic activity being at a minimum in the morning. The opposite pattern is observed for nocturnal animals such as rats and mice on a regimen of light during the daytime alternating with darkness during the night hours. The entirety of these rhythms plays an important role in the organism's responses to environmental stimuli, including its resistance to potentially harmful agents. Conditions under which circadian rhythms can be observed and validated by inferential statistical means are discussed while emphasizing how artifacts of the laboratory environment can be shown to obscure circadian periodic variations in radiosensitivity.

Haus, E.; Halberg, F.; Loken, M. K.; Kim, Y. S.

1974-01-01

105

Overexpression of CD99 Increases the Migration and Invasiveness of Human Malignant Glioma Cells  

PubMed Central

The malignant glioma is the most common primary human brain tumor, and its migration and invasiveness away from the primary tumor mass are considered a leading cause of tumor recurrence and treatment failure. Recently, gene expression profiling revealed that the transmembrane glycoprotein CD99 is more highly expressed in malignant glioma than in normal brain. Although its function is not completely understood, CD99 is implicated in cell adhesion and migration in a variety of different cell types. CD99 has wild-type and splice variant isoforms. Previous studies have shown that wild-type CD99 may be an oncosuppressor in some tumors, distinct from the role of the splice variant isoform. In this study, our data reveal that only wild-type CD99 is expressed in human glioma cells and tissues. Using a tissue microarray, we validated that gliomas demonstrate higher expression of CD99 compared with nonneoplastic brain. To assess the role of CD99 in glioma migration and invasion, we inhibited CD99 expression by siRNA and demonstrated decreased glioma migration and invasion. In contrast, when CD99 was overexpressed in glioma cells, we observed enhancement of cell migration and invasiveness. An orthotopic brain tumor model demonstrates that CD99 overexpression significantly increases invasiveness and decreases survival rate. Interestingly, Rac activity was decreased and Rho activity was increased in CD99 overexpressing glioma cells, and the proportion of amoeboid cells to mesenchymal cells was significantly increased. Taken together, our findings suggest that CD99 may play an important role in the migration and invasion of human gliomas independent of Akt, ERK, or JNK signaling pathways. Moreover, CD99 might be involved in amoeboid-mesenchymal transition in glioma migration. CD99 may be an important future target to inhibit migration and invasion, especially in CD99-expressing gliomas. PMID:23486730

Seol, Ho Jun; Chang, Jong Hee; Yamamoto, Junkoh; Romagnuolo, Rocco; Suh, Youngchul; Weeks, Adrienne; Agnihotri, Sameer; Smith, Christian A.

2012-01-01

106

Analysis of telomere length and function in radiosensitive mouse and human cells in response to DNA-PKcs inhibition  

PubMed Central

Background Telomeres, the physical ends of chromosomes, play an important role in preserving genomic integrity. This protection is supported by telomere binding proteins collectively known as the shelterin complex. The shelterin complex protects chromosome ends by suppressing DNA damage response and acting as a regulator of telomere length maintenance by telomerase, an enzyme that elongates telomeres. Telomere dysfunction manifests in different forms including chromosomal end-to-end fusion, telomere shortening and p53-dependent apoptosis and/or senescence. An important shelterin-associated protein with critical role in telomere protection in human and mouse cells is the catalytic subunit of DNA-protein kinase (DNA-PKcs). DNA-PKcs deficiency in mouse cells results in elevated levels of spontaneous telomeric fusion, a marker of telomere dysfunction, but does not cause telomere length shortening. Similarly, inhibition of DNA-PKcs with chemical inhibitor, IC86621, prevents chromosomal end protection through mechanism reminiscent of dominant-negative reduction in DNA-PKcs activity. Results We demonstrate here that the IC86621 mediated inhibition of DNA-PKcs in two mouse lymphoma cell lines results not only in elevated frequencies of chromosome end-to-end fusions, but also accelerated telomere shortening in the presence of telomerase. Furthermore, we observed increased levels of spontaneous telomeric fusions in Artemis defective human primary fibroblasts in which DNA-PKcs was inhibited, but no significant changes in telomere length. Conclusion These results confirm that DNA-PKcs plays an active role in chromosome end protection in mouse and human cells. Furthermore, it appears that DNA-PKcs is also involved in telomere length regulation, independently of telomerase activity, in mouse lymphoma cells but not in human cells. PMID:23521760

2013-01-01

107

Role of p53 family members p73 and p63 in human hematological malignancies.  

PubMed

p53, mutated in over half of human cancers and about 13% of all hematological malignancies, maintains genomic integrity and triggers cellular senescence and apoptosis of damaged cells. In contrast to p53, the homologs p73 and p63 play critical roles in development of the central nervous system and skin/limbs, respectively. Moreover, dependent on the context they can exert tumor suppressor activities that cooperate with p53. Unlike p53, p73 and p63 are rarely mutated in cancers. Instead, up-regulation of the anti-apoptotic dominant-negative ?Np73 and ?Np63 isoforms is the most frequent abnormality in solid cancers. In hematological malignancies the most frequent p73 defect is promoter methylation and loss of expression, associated with unfavorable clinical outcomes. This suggests an essential tumor suppressor role of p73 in blood cells, also supported by genetic mouse models. Many therapeutic approaches aiming to restore p73 activity are currently being investigated. In contrast, the most frequent p63 abnormality is protein overexpression, associated with higher disease grade and poorer prognosis. Surprisingly, although available data are still scarce, the emerging picture is up-regulation of transactivation-competent TAp63 isoforms, suggesting a tumor-promoting role in this context. PMID:22497596

Alexandrova, Evguenia M; Moll, Ute M

2012-11-01

108

Proton beam irradiation stimulates migration and invasion of human U87 malignant glioma cells  

PubMed Central

Migration and invasion of malignant glioma play a major role in tumor progression and can be increased by low doses of gamma or X-ray irradiation, especially when the migrated tumor cells are located at a distance from the main tumor mass or postoperative cavity and are irradiated in fractions. We studied the influence of proton beam irradiation on migration and invasion of human U87 malignant glioma (U87MG) cells. Irradiation at 4 and 8 Gy increased cell migration by 9.8% (±4, P = 0.032) and 11.6% (±6.6, P = 0.031) and invasion by 45.1% (±16.5, P = 0.04) and 40.5% (±12.7, P = 0.041), respectively. After irradiation at 2 and 16 Gy, cell motility did not differ from that at 0 Gy. We determined that an increase in proton beam irradiation dose to over 16 Gy might provide tumor growth control, although additional specific treatment might be necessary to prevent the potentially increased motility of glioma cells during proton beam therapy. PMID:24187331

Zaboronok, Alexander; Isobe, Tomonori; Yamamoto, Tetsuya; Sato, Eisuke; Takada, Kenta; Sakae, Takeji; Tsurushima, Hideo; Matsumura, Akira

2014-01-01

109

Seroprevalence of human T-lymphotropic virus antibodies among patients with lymphoid malignancies at a tertiary center in Lagos, Nigeria  

PubMed Central

Background There is a significant association of human T-lymphotropic viruses (HTLV) with lymphoid malignancies. HTLV causes a lymphoproliferative malignancy of CD4-activated cells called adult T-cell leukemia/lymphoma (ATL) and a chronic myelopathy called tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). This study aims to determine the prevalence of HTLV among patients with lymphoid malignancies at a tertiary center in Lagos. Methods A cross-sectional study was carried out at the hematology clinic of the Lagos State University Teaching Hospital. After obtaining consent, approximately 5 mL of venous blood was collected from each subject. The serum was separated and stored at ?20°C. Sera were assayed for HTLV by an enzyme-linked immunoassay (ELISA) for the determination of antibodies to HTLV-1 and -2. Western blot confirmatory testing was done on reactive samples. All patients were also screened for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) by rapid kits. Results A total of 39 patients with lymphoid malignancies were enrolled, consisting of 24 (61.5%) with solid malignancies, while 15 (38.5%) had leukemia. Only two patients (5.1%) with lymphoid malignancies were reactive on the ELISA test. On confirmatory testing with Western blot, two patients (5.1%) with lymphoid malignancies were also positive for HTLV. All patients were HIV negative, but four were positive to HBsAg and HCV. There was no association between history of previous blood transfusion and positivity to HTLV (P=0.544). Conclusion A prevalence of 5.1% of HTLV among patients with lymphoid malignancies was found in this study, and previous history of blood transfusion was not found to be a significant cause of HTLV infection.

Akinbami, Akinsegun; Durojaiye, Idris; Dosunmu, Adedoyin; John-Olabode, Sarah; Adediran, Adewumi; Oshinaike, Olajumoke; Uche, Ebele; Dada, Akinola; Odesanya, Mojeed; Okunoye, Olaitan

2014-01-01

110

Frequency analysis of multispectral photoacoustic images for differentiating malignant region from normal region in excised human prostate  

NASA Astrophysics Data System (ADS)

Frequency domain analysis of the photoacoustic (PA) radio frequency signals can potentially be used as a tool for characterizing microstructure of absorbers in tissue. This study investigates the feasibility of analyzing the spectrum of multiwavelength PA signals generated by excised human prostate tissue samples to differentiate between malignant and normal prostate regions. Photoacoustic imaging at five different wavelengths, corresponding to peak absorption coefficients of deoxyhemoglobin, whole blood, oxyhemoglobin, water and lipid in the near infrared (NIR) (700 nm - 1000 nm) region, was performed on freshly excised prostate specimens taken from patients undergoing prostatectomy for biopsy confirmed prostate cancer. The PA images were co-registered with the histopathology images of the prostate specimens to determine the region of interest (ROI) corresponding to malignant and normal tissue. The calibrated power spectrum of each PA signal from a selected ROI was fit to a linear model to extract the corresponding slope, midband fit and intercept parameters. The mean value of each parameter corresponding to malignant and adjacent normal prostate ROI was calculated for each of the five wavelengths. The results obtained for 9 different human prostate specimens, show that the mean values of midband fit and intercept are significantly different between malignant and normal regions. In addition, the average midband fit and intercept values show a decreasing trend with increasing wavelength. These preliminary results suggest that frequency analysis of multispectral PA signals can be used to differentiate malignant region from the adjacent normal region in human prostate tissue.

Sinha, Saugata; Rao, Navalgund A.; Valluru, Keerthi S.; Chinni, Bhargava K.; Dogra, Vikram S.; Helguera, Maria

2014-03-01

111

Radiosensitization of Human Cervical Cancer Cells by Inhibiting Ribonucleotide Reductase: Enhanced Radiation Response at Low-Dose Rates  

SciTech Connect

Purpose: To test whether pharmacologic inhibition of ribonucleotide reductase (RNR) by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC no. 663249) enhances radiation sensitivity during low-dose-rate ionizing radiation provided by a novel purpose-built iridium-192 cell irradiator. Methods and Materials: The cells were exposed to low-dose-rate radiation (11, 23, 37, 67 cGy/h) using a custom-fabricated cell irradiator or to high-dose-rate radiation (330 cGy/min) using a conventional cell irradiator. The radiation sensitivity of human cervical (CaSki, C33-a) cancer cells with or without RNR inhibition by 3-AP was evaluated using a clonogenic survival and an RNR activity assay. Alteration in the cell cycle distribution was monitored using flow cytometry. Results: Increasing radiation sensitivity of both CaSki and C33-a cells was observed with the incremental increase in radiation dose rates. 3-AP treatment led to enhanced radiation sensitivity in both cell lines, eliminating differences in cell cytotoxicity from the radiation dose rate. RNR blockade by 3-AP during low-dose-rate irradiation was associated with low RNR activity and extended G{sub 1}-phase cell cycle arrest. Conclusions: We conclude that RNR inhibition by 3-AP impedes DNA damage repair mechanisms that rely on deoxyribonucleotide production and thereby increases radiation sensitivity of human cervical cancers to low-dose-rate radiation.

Kunos, Charles A., E-mail: charles.kunos@UHhospitals.org [Department of Radiation Oncology, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH (United States); Colussi, Valdir C. [Department of Radiation Oncology, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH (United States); Pink, John [Department of General Medical Sciences, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH (United States); Radivoyevitch, Tomas [Department of Epidemiology and Biostatistics, Case Comprehensive Cancer Center, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH (United States); Oleinick, Nancy L. [Department of Radiation Oncology, University Hospitals Case Medical Center and Case Western Reserve School of Medicine, Cleveland, OH (United States)

2011-07-15

112

FTIR microscopic comparative study on normal, premalignant, and malignant tissues of human intenstine  

NASA Astrophysics Data System (ADS)

Fourier-Transform Infrared Spectroscopy (FTIR) employs a unique approach to optical diagnosis of tissue pathology based on the characteristic molecular vibrational spectra of the tissue. The architectural changes in the cellular and sub-cellular levels developing in abnormal tissue, including a majority of cancer forms, manifest themselves in different optical signatures, which can be detected in infrared spectroscopy. The biological systems we have studied include normal, premalignant (polyp) and malignant human colonic tissues from three patients. Our method is based on microscopic infrared study (FTIR-microscopy) of thin tissue specimens and a direct comparison with normal histopathological analysis, which serves as a `gold' reference. The normal intestine tissue has a stronger absorption than polyp and cancerous types over a wide region in all three cases. The detailed analysis showed that there is a significant decrease in total phosphate and creatine contents for polyp and cancerous tissue types in comparison to the controls.

Mordechai, Shaul; Argov, Shmuel; Salman, Ahmad O.; Cohen, Beny; Ramesh, Jagannathan; Erukhimovitch, Vitaly; Goldstein, Jed; Sinelnikov, Igor

2000-07-01

113

Knockdown of NOB1 expression inhibits the malignant transformation of human prostate cancer cells.  

PubMed

Nin one binding-1 protein (NOB1) is a kind of zinc protein involved in ribosome biogenesis and controlled proteolysis. To explore the function of NOB1 in human prostate malignancy, we analyzed the expression of NOB1 in prostate cancer and found that NOB1 was elevated in prostate cancer tissues compared to the adjacent normal tissues. Knockdown of NOB1 by lentivirus-shRNA inhibited the proliferation and colony-formation ability of PC-3 and DU145 prostate cancer cells. Cell cycle analysis showed that silencing of NOB1 caused G0/G1 phase arrest and a slight decrease in S phase (P < 0.05). Furthermore, knockdown of NOB1 significantly suppressed the mobility of PC-3 and DU145 prostate cancer cells (P < 0.05). Collectively, these findings suggested that NOB1 might be involved in tumorigenecity of prostate cancer, and could be a potential molecular target for prostate cancer gene therapy. PMID:25169742

Zhang, Xiangmin; Zhang, Dongxu; Qu, Fajun; Hong, Yi; Cao, Jianwei; Pan, Xiuwu; Li, Lin; Huang, Yi; Huang, Hai; Yin, Lei; Chen, Lu; Ren, Jizhong; Wang, Zhijun; Xu, Danfeng; Cui, Xingang

2014-11-01

114

Human colon adenocarcinoma cell lines display infrared spectroscopic features of malignant colon tissues.  

PubMed

Seven human colon cell lines were studied by infrared spectroscopy including study of several spectral parameters under high pressure (pressure tuning spectroscopy). The results were compared to those obtained from the study of normal and malignant colon tissues (B. Rigas et al., Proc. Natl. Acad. Sci. USA, 87: 8140-8144, 1990; P. T. T. Wong and B. Rigas., Appl. Spectrosc., 44: 1715, 1990). The seven adenocarcinoma cell lines displayed almost all of the important spectroscopic features of colon cancer tissues: (a) increased hydrogen-bonding of the phosphodiester groups of nucleic acids; (b) decreased hydrogen-bonding of the C--OH groups of carbohydrates and proteins; (c) a prominent band at 972 cm-1; and (d) a shift of the band normally appearing at 1082 cm-1 to 1086 cm-1. These cell lines differed spectroscopically from the colon cancer tissues in that: (a) they displayed a band at 991 cm-1, which is weak in colon tissues; and (b) the packing and degree of disorder of membrane lipids were close to those observed in normal colonic tissues. These findings (i) establish IR spectroscopy, used in combination with pressure tuning, as a useful method to address problems of tumor biology in cell culture systems, (ii) indicate that these cell lines offer a useful experimental model to explore the origin of the spectroscopic changes that we observed in colon cancer tissues, and (iii) support the idea that the malignant colonocyte is the likely source of all or most spectroscopic abnormalities of human colon cancer. PMID:1727389

Rigas, B; Wong, P T

1992-01-01

115

Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy  

PubMed Central

Background The epidermal specific ablation of Trp53 gene leads to the spontaneous development of aggressive tumors in mice through a process that is accelerated by the simultaneous ablation of Rb gene. Since alterations of p53-dependent pathway are common hallmarks of aggressive, poor prognostic human cancers, these mouse models can recapitulate the molecular features of some of these human malignancies. Results To evaluate this possibility, gene expression microarray analysis was performed in mouse samples. The mouse tumors display increased expression of cell cycle and chromosomal instability associated genes. Remarkably, they are also enriched in human embryonic stem cell gene signatures, a characteristic feature of human aggressive tumors. Using cross-species comparison and meta-analytical approaches, we also observed that spontaneous mouse tumors display robust similarities with gene expression profiles of human tumors bearing mutated TP53, or displaying poor prognostic outcome, from multiple body tissues. We have obtained a 20-gene signature whose genes are overexpressed in mouse tumors and can identify human tumors with poor outcome from breast cancer, astrocytoma and multiple myeloma. This signature was consistently overexpressed in additional mouse tumors using microarray analysis. Two of the genes of this signature, AURKA and UBE2C, were validated in human breast and cervical cancer as potential biomarkers of malignancy. Conclusions Our analyses demonstrate that these mouse models are promising preclinical tools aimed to search for malignancy biomarkers and to test targeted therapies of prospective use in human aggressive tumors and/or with p53 mutation or inactivation. PMID:20630075

2010-01-01

116

Micro-RNAs as diagnostic or prognostic markers in human epithelial malignancies  

PubMed Central

Micro-RNAs (miRs) are important regulators of mRNA and protein expression; the ability of miR expression profilings to distinguish different cancer types and classify their sub-types has been well-described. They also represent a novel biological entity with potential value as tumour biomarkers, which can improve diagnosis, prognosis, and monitoring of treatment response for human cancers. This endeavour has been greatly facilitated by the stability of miRs in formalin-fixed paraffin-embedded (FFPE) tissues, and their detection in circulation. This review will summarize some of the key dysregulated miRs described to date in human epithelial malignancies, and their potential value as molecular bio-markers in FFPE tissues and blood samples. There remain many challenges in this domain, however, with the evolution of different platforms, the complexities of normalizing miR profiling data, and the importance of evaluating sufficiently-powered training and validation cohorts. Nonetheless, well-conducted miR profiling studies should contribute important insights into the molecular aberrations driving human cancer development and progression. PMID:22128797

2011-01-01

117

Apoptotic effects of ?-mangostin from the fruit hull of Garcinia mangostana on human malignant glioma cells.  

PubMed

Gliomas are a common type of primary brain tumor with glioblastoma multiforme accounting for the majority of human brain tumors. In this paper, high grade human malignant glioblastomas (MGs) including U87 MG and GBM 8401 were used to evaluate the antitumor effects of ?-mangostin, a xanthone derivative isolated and purified from the hull of the tropical fruit Garcinia mangostana. The ?-mangostin showed potent antiproliferative activity toward MGs in dose- and time-dependent manners. In addition, flow cytometric analysis of cell morphology in the apoptotic cells revealed an increase in hypodiploid cells in ?-mangostin treated U87 MG and GBM 8401 cells, while significant enhancement of intracellular peroxide production was detected in the same ?-mangostin treated cells by DCHDA assay and DiOC(6)(3) stain. g-Mangostin induced apoptosis, which in turn mediates cytotoxicity in human MG cells was prevented by the addition of catalase. Naturally derived medicines and herbal therapies are drawing increasing attention in regard to the treatment of many health issues, and this includes the testing of new phytochemicals or nutrients for brain tumor patients. This has led to ?-mangostin being identified as a potential leading compound for the development of an anti-brain tumor agent. PMID:21139533

Chang, Hui-Fang; Huang, Wen-Tsung; Chen, Hui-Ju; Yang, Ling-Ling

2010-01-01

118

Intrinsic radiosensitivity of human pancreatic tumour cells and the radiosensitising potency of the nitric oxide donor sodium nitroprusside.  

PubMed Central

A panel of eight human pancreatic tumour cell lines displayed high intrinsic radioresistance, with mean inactivation doses between 2.4 and 6.5 Gy, similar to those reported for melanoma and glioblastoma. The radiosensitising potency of sodium nitroprusside, a bioreductive nitric oxide donor, was assessed in a model of metabolism-induced hypoxia in a cell micropellet. Sodium nitroprusside at 0.1 mM revealed a radiosensitising effect with an overall enhancement ratio of 1.9 compared with 2.5 for oxygen. Radiosensitising activity correlated with the enhancement of single-strand DNA breakage caused by radiation. In suspensions with cell densities of between 3% and 30% (v/v), the half-life of sodium nitroprusside decreased from 31 to 3.2 min, suggesting a value of around 1 min for micropellets. Despite this variation, the radiosensitising activity was similar in micropellets and in diluted cell suspensions. S-nitroso-L-glutathione was found to possess radiosensitising activity, consistent with a possible role of natural thiols in the storing of radiobiologically active nitric oxide adducts derived from sodium nitroprusside. As measured by a nitric oxide-specific microsensor, activation of sodium nitroprusside occurred by bioreduction, whereas S-nitroso-L-glutathione showed substantial spontaneous decomposition. Both agents appear to exert radiosensitising action through nitric oxide as its scavenging by carboxy phenyltetramethylimidazolineoxyl N-oxide (carboxy-PTI0) and oxyhaemoglobin resulted in attenuated radiosensitisation. Sodium nitroprusside was at least 10-fold more potent than etanidazole, a 2-nitroimidazole used as a reference. Our data suggest that sodium nitroprusside, a drug currently used for the treatment of hypertension, is a potential tumour radioresponse modifier. PMID:8956786

Verovski, V. N.; Van den Berge, D. L.; Soete, G. A.; Bols, B. L.; Storme, G. A.

1996-01-01

119

Short telomeres result in chromosomal instability in hematopoietic cells and precede malignant evolution in human aplastic anemia  

Microsoft Academic Search

In cell and animal models, telomere erosion promotes chromosomal instability via breakage-fusion-bridge cycles, contributing to the early stages of tumorigenesis. However, evidence involving short telomeres in cancer development in humans is scarce, epidemiological and indirect. Here we directly implicate telomere shortening as a critical molecular event for malignant evolution in aplastic anemia (AA). Patients’ telomere lengths at diagnosis of AA,

R T Calado; J N Cooper; H M Padilla-Nash; E M Sloand; C O Wu; P Scheinberg; T Ried; N S Young

2012-01-01

120

Human cerebral endothelium: Isolation and characterization of cells derived from microvessels of non-neoplastic and malignant glial tissue  

Microsoft Academic Search

Human microvessels were isolated and cultured from non-neoplastic cerebral tissue specimens resected for the treatment of seizure disorders and from malignant glial tumors. After 1–2 weeks, cobblestone patterned plaques of cells were isolated and cultured from these microvessels. Cell lines positive for Factor VIII antigen and negative for glial fibrillary acidic protein were designated as endothelium. Endothelium from both tissue

Penny Costello; Rolando Del Maestro

1990-01-01

121

Human hepatocellular carcinoma: cross-reactive and idiotypic antigens associated with malignant transformation of epithelial cells.  

PubMed

Monoclonal antibodies were isolated following immunization with the HBsAg and alpha-fetoprotein-secreting human hepatoma PLC/PRF/5 ("Alexander") cell line. Three antibodies (K-PLC1, K-PLC2 and K-PLC3) showed evidence of carcinoma-associated reactivity by indirect immunofluorescence. Antibodies K-PLC2 and K-PLC3 reacted only with PLC/PRF/5 cells, but not with any other normal or malignant cell type tested, including the Hep/G2 hepatoma cell line. The reactivity of these antibodies was not removed by absorption with homogenates of either normal liver or a primary hepatocellular carcinoma. These results suggest that K-PLC2 and K-PLC3 identify PLC/PRF/5 idiospecific determinants. Following surface iodination of PLC/PRF/5 cells, immunoprecipitation and analysis on polyacrylamide gels, these specific determinants were found to be of 200,000 and 76,000 daltons, respectively. On the other hand, antibody K-PLC1, although unreactive by immunofluorescence on the majority of normal cell types, including those of lymphoid organs and bone marrow liver cells and most epithelia, was weakly positive on some normal ductal secretory epithelia and was positive on vascular endothelium. However, K-PLC1 reacted strongly with all carcinoma specimens tested, and with most carcinoma-derived cell lines, indicating a large increase in K-PLC1 antigen expression by epithelial cells after malignant transformation. Absorption of K-PLC1 with normal liver homogenate had no affect, but absorption with a hepatocarcinoma homogenate abolished its activity. The K-PLC1 antigen could not be immunoblotted or immunoprecipitated and resolved on polyacrylamide gels; yet it showed the properties of a phospholipid, namely resistance to proteases, extractability with organic solvents and sensitivity to phospholipase C. PMID:2437001

Wiedmann, K H; Trejdosiewicz, L K; Southgate, J; Thomas, H C

1987-01-01

122

Aberrant Expression of Interleukin-1? and Inflammasome Activation in Human Malignant Gliomas  

PubMed Central

Objective Glioblastoma is the most frequent and malignant form of primary brain tumor with grave prognosis. Mounting evidence supports that chronic inflammation (such as chronic overactivation of IL-1 system) is a crucial event in carcinogenesis and tumor progression. IL-1 also is an important cytokine with species-dependent regulations and roles in CNS cell activation. While much attention is paid to specific anti-tumor immunity, little is known about the role of chronic inflammation/innate immunity in glioma pathogenesis. In this study, we examined whether human astrocytic cells (including malignant gliomas) can produce IL-1 and its role in glioma progression. Methods We used a combination of cell culture, real-time PCR, ELISA, western blot, immunocytochemistry, siRNA and plasmid transfection, micro-RNA analysis, angiogenesis (tube formation) assay, and neurotoxicity assay. Results Glioblastoma cells produced large quantities of IL-1 when activated, resembling macrophages/microglia. The activation signal was provided by IL-1 but not the pathogenic components LPS or poly IC. Glioblastoma cells were highly sensitive to IL-1 stimulation, suggesting its relevance in vivo. In human astrocytes, IL-1? mRNA was not translated to protein. Plasmid transfection also failed to produce IL-1 protein, suggesting active repression. Suppression of microRNAs that can target IL-1?/? did not induce IL-1 protein. Glioblastoma IL-1? processing occurred by the NLRP3 inflammasome, and ATP and nigericin increased IL-1? processing by upregulating NLRP3 expression, similar to macrophages. RNAi of annexin A2, a protein strongly implicated in glioma progression, prevented IL-1 induction, demonstrating its new role in innate immune activation. IL-1 also activated Stat3, a transcription factor crucial in glioma progression. IL-1 activated glioblastoma-conditioned media enhanced angiogenesis and neurotoxicity. Conclusions Our results demonstrate unique, species-dependent immune activation mechanisms involving human astrocytes and astrogliomas. Specifically, the ability to produce IL-1 by glioblastoma cells may confer them a mesenchymal phenotype including increased migratory capacity, unique gene signature and proinflammatory signaling. PMID:25054228

Tarassishin, Leonid; Casper, Diana; Lee, Sunhee C.

2014-01-01

123

Expression of targeting protein for Xenopus kinesin-like protein 2 is associated with progression of human malignant astrocytoma  

Microsoft Academic Search

In humans, the targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a cell cycle-associated protein, and altered TPX2 expression has been found in various malignancies. However, the contribution of TPX2 expression to astrocytoma progression is unclear. The aim of this study was to investigate TPX2 expression in human astrocytoma samples and cell lines. TPX2 protein expression was detected in

Bin Li; Xiang-Qian Qi; Xin Chen; Xin Huang; Guo-Ying Liu; Huai-Rui Chen; Cheng-Guang Huang; Chun Luo; Yi-Cheng Lu

2010-01-01

124

Involvement of placental/umbilical cord blood acid-base status and gas values on the radiosensitivity of human fetal/neonatal hematopoietic stem/progenitor cells  

PubMed Central

Arterial cord blood (CB) acid–base status and gas values, such as pH, PCO2, PO2, HCO3?and base excess, provide useful information on the fetal and neonatal condition. However, it remains unknown whether these values affect the radiosensitivity of fetal/neonatal hematopoiesis. The present study evaluated the relationship between arterial CB acid–base status, gas values, and the radiosensitivity of CB hematopoietic stem/progenitor cells (HSPCs). A total of 25 CB units were collected. The arterial CB acid–base status and gas values were measured within 30 min of delivery. The CD34+HSPCs obtained from CB were exposed to 2 Gy X-irradiation, and then assayed for colony-forming unit-granulocyte-macrophage, burst-forming unit-erythroid (BFU-E), and colony-forming unit-granulocyte erythroid, macrophage and megakaryocyte cells. Acid–base status and gas values for PCO2and HCO3?showed a statistically significant negative correlation with the surviving fraction of BFU-E. In addition, a significant positive correlation was observed between gestational age and PCO2. Moreover, the surviving fraction of BFU-E showed a significant negative correlation with gestational age. Thus, HSPCs obtained from CB with high PCO2/HCO3?levels were sensitive to X-irradiation, which suggests that the status of arterial PCO2/HCO3?influences the radiosensitivity of fetal/neonatal hematopoiesis, especially erythropoiesis. PMID:23263728

Yamaguchi, Masaru; Ebina, Satoko; Kashiwakura, Ikuo

2013-01-01

125

Antisense-mediated reduction in thrombospondin reverses the malignant phenotype of a human squamous carcinoma.  

PubMed Central

Thrombospondin (TSP) is a trimeric glycoprotein which is synthesized and incorporated into the extracellular matrix by a wide variety of cells. TSP is involved in a number of cellular processes which govern tumor cell behavior including mitogenesis, attachment, migration, and differentiation. To directly assess the role of TSP in tumor cell growth and spread, a human squamous carcinoma cell line, with high TSP production and an invasive phenotype, was transfected with a TSP cDNA antisense expression vector. Five unique transfected clones were obtained with reduced TSP production. Expression of the transfected antisense sequence in these clones was verified by a ribonuclease protection assay. These clones demonstrated reduced growth rates in vitro when compared with a vector transfected control. After subcutaneous inoculation into athymic mice, the antisense clones formed either no tumors or tumors that were slow growing and highly differentiated. This contrasted with the vector-transfected clone which produced poorly differentiated, rapidly growing, invasive tumors. Our results argue in favor of a direct role for TSP in determining the malignant phenotype of certain human tumors. Images PMID:2040684

Castle, V; Varani, J; Fligiel, S; Prochownik, E V; Dixit, V

1991-01-01

126

Phase-I trial of Ultrapure ™ human leukocyte interferon in human malignancy  

Microsoft Academic Search

A phase-I trial of Ultrapure™ human leukocyte (a) interferon was performed, in which 15 patients were treated according to a dose-ranging protocol. Five patients were treated at each of three dosage levels: 3×106 IU\\/dose, 9×106 IU\\/dose, and 15×106 IU\\/dose. Doses were given on days 1–5 and 8–12 of a 28-day study period. Serial NK-cell assays were performed in all patients,

G. Thomas Budd; R. M. Bukowski; L. Miketo; B. Yen-Lieberman; M. R. Proffitt

1984-01-01

127

Frequency-domain photon migration measurements of normal and malignant tissue optical properties in a human subject  

SciTech Connect

A 1-GHz multifrequency, multiwavelength frequency-domain photon migration instrument is used to measure quantitatively the optical absorption ({mu}{sub a}) and effective optical scattering ({mu}{sub s}{sup {prime}}) of normal and malignant tissues in a human subject. Large ellipsoidal ({approximately}10-cm major axis, {approximately}6-cm minor axes) subcutaneous malignant lesions were compared with adjacent normal sites in the abdomen and back. Absorption coefficients recorded at 674, 811, 849, and 956 nm were used to calculate tissue hemoglobin concentration (oxyhemoglobin, deoxyhemoglobin, and total), water concentration, hemoglobin oxygen saturation, and blood volume fraction {ital in vivo}. Our results show that the normal and the malignant tissues measured in the patient have clearly resolvable optical and physiological property differences that may be broadly useful in identifying and characterizing tumors.{copyright} 1997 Optical Society of America

Fishkin, J.B.; Coquoz, O.; Anderson, E.R.; Brenner, M.; Tromberg, B.J. [Beckman Laser Institute and Medical Clinic, University of California at Irvine, 1002 Health Sciences Road East, Irvine, California 92612 (United States)]|[EA Photonics, 2515 Fisk Lane, Redondo Beach, California 90278 (United States)

1997-01-01

128

Increased Wild-Type N-Ras Activation by Neurofibromin Down-Regulation Increases Human Neuroblastoma Stem Cell Malignancy  

PubMed Central

Cellular heterogeneity is a well-known feature of human neuroblastoma tumors and cell lines. Of the 3 phenotypes (N-, I-, and S-type) isolated and characterized, the I-type cancer stem cell of neuroblastoma is the most malignant. Here, we report that, although wild-type N-Ras protein is expressed at the same level in all 3 neuroblastoma cell phenotypes, activated N-Ras–GTP level is significantly higher in I-type cancer stem cells. When activated N-Ras levels were decreased by transfection of a dominant-negative N-Ras construct, the malignant potential of I-type cancer stem cells decreased significantly. Conversely, when weakly malignant N-type cells were transfected with a constitutively active N-Ras construct, activated N-Ras levels, and malignant potential, were significantly increased. Thus, high levels of N-Ras–GTP are required for the increased malignancy of I-type neuroblastoma cancer stem cells. Moreover, increased activation of N-Ras results from significant down-regulation of neurofibromin (NF1), an important RasGAP. This specific down-regulation is mediated by an ubiquitin-proteasome–dependent pathway. Thus, decreased expression of NF1 in I-type neuroblastoma cancer stem cells causes a high level of activated N-Ras that is, at least in part, responsible for their higher tumorigenic potential. PMID:22737269

Han, Dan; Spengler, Barbara A.

2011-01-01

129

Expression of peroxiredoxin 1 and 4 promotes human lung cancer malignancy.  

PubMed

Members of the Peroxiredoxin (Prx) family are major cellular antioxidants that scavenge hydrogen peroxide and play essential roles in oxidative stress and cell signaling. 2-Cys Prxs, including Prx1, 2, 3 and 4, have been indicated in multiple oncogenic signaling pathways and thus may contribute to various processes of cancer development. The significance of 2-Cys Prxs in lung cancer development and their biological function in signal transduction have not been fully investigated. In this study we analyzed the expression of 2-Cys Prxs in lung cancer, and examined their levels of expression in a variety of cell lines established from human lung normal or cancer tissues. We found that 2-Cys Prxs, in particular, Prx1 and Prx4, were preferentially expressed in cell lines derived from human lung cancer. Through isoform specific knockdown of individual Prx, we demonstrated that Prx1 and Prx4 (but not Prx3) were required for human lung cancer A549 cells to form soft agar colony and to invade through matrigel in culture. Knockdown of Prx1 or Prx4 significantly reduced the activation of c-Jun and repressed the AP-1 mediated promoter activity. In mouse xenograft models, knockdown of Prx4 in A549 cells reduced subcutaneous tumor growth and blocked metastasis formation initiated through tail vein injection. Moreover, overexpression of Prx1 or Prx4 further enhanced the malignancy of A549 cells both in culture and in mouse xenografts in vivo. These data provide an in-depth understanding of the contribution of Prx1 and Prx4 to lung cancer development and are of importance for future development of therapeutic methods that targeting 2-Cys Prxs. PMID:25232487

Jiang, Hong; Wu, Lisha; Mishra, Murli; Chawsheen, Hedy A; Wei, Qiou

2014-01-01

130

Phase-I trial of UltrapureTM human leukocyte interferon in human malignancy.  

PubMed

A phase-I trial of UltrapureTM human leukocyte (alpha) interferon was performed, in which 15 patients were treated according to a dose-ranging protocol. Five patients were treated at each of these dosage levels: 2 X 10(6) IU/dose, 9 X 10(6) IU/dose, and 15 X 10(6) IU/dose. Doses were given on days 1-5 and 8-12 of a 28-day study period. Serial NK-cell assays were performed in all patients, and failed to show consistent effects referable to treatment. Serum interferon levels were assayed on one patient at the 9 X 10(6) IU and one patient at the 15 X 10(6) IU dose level. In both cases, a significant interferon titer (greater than or equal to 160) was detected in the serum, and this persisted for as long as 12 h. Fever, malaise, and myalgias were associated with therapy. The dose-limiting toxicity was a dose-related leukopenia, with median white blood cell nadirs of 6,500/mm3 (3 X 10(6) IU/dose), 3,200/mm3 (9 X 10(6) IU/dose), and 1,800/mm3 (15 X 10(6) IU/dose) being produced. One patient died in ventricular fibrillation while suffering chest pain after receiving 5 days of treatment at the 15 X 10(6) IU/dose level. Three patients showed minor responses, insufficient to be called partial responses, in association with interferon therapy. We conclude that dose-limiting leukopenia occurs with this schedule of administration of UltrapureTM human leukocyte interferon at 15 X 10(6) IU/dose. PMID:6690072

Budd, G T; Bukowski, R M; Miketo, L; Yen-Lieberman, B; Proffitt, M R

1984-01-01

131

Glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) expression correlates with malignant choline phospholipid metabolite profiles in human breast cancer  

PubMed Central

Altered choline phospholipid metabolism is a hallmark of cancer, leading to malignant choline metabolite profiles consisting of low glycerophosphocholine (GPC) and high phosphocholine (PC) in human breast cancers. Glycerophosphocholine phosphodiesterase (GPC-PDE) catalyzes the degradation of GPC to free choline and glycerol-3-phosphate. The gene(s) encoding for the GPC-PDE(s) responsible for GPC degradation in breast cancers have not yet been identified. Here we have demonstrated for the first time that the GPC-PDE encoded by glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) is associated with breast cancer malignancy. Two human breast cancer cell lines (n=8 and 10) and primary human breast tumor samples (n=19) were studied with combined magnetic resonance spectroscopy (MRS) and qRT-PCR to investigate several isoforms of GDPD expression with respect to choline phospholipid metabolite levels. Out of five GDPDs tested, GDPD5 was found to be significantly overexpressed in highly malignant estrogen receptor negative (ER?) compared to weakly malignant estrogen receptor positive (ER+) human breast cancer cells (P=0.027) and breast tumors from patients (P=0.015). GDPD5 showed significantly positive correlations with PC (P<0.001), total choline (tCho) (P=0.007) and PC/GPC (P<0.001) levels in human breast tumors. GDPD5 showed a trend towards negative correlation with GPC levels (P=0.130). Human breast cancers with malignant choline metabolite profiles consisting of low GPC and high PC levels highly co-expressed GDPD5, choline kinase alpha (CHKA), and phosphatidylcholine-specific phospholipase D1 (PLD1), while cancers containing high GPC and relatively low PC levels displayed low co-expression of GDPD5, CHKA, and PLD1. GDPD5, CHKA and PLD1 were significantly overexpressed in highly malignant ER? tumors in our patient cohort. Our study identified GDPD5 as a GPC-PDE that likely participates in regulating choline phospholipid metabolism in breast cancer, which possibly occurs in cooperation with CHKA and PLD1. PMID:22279038

Cao, Maria D.; Dopkens, Mailin; Krishnamachary, Balaji; Vesuna, Farhad; Gadiya, Mayur M.; Loenning, Per E.; Bhujwalla, Zaver M.; Gribbestad, Ingrid S.; Glunde, Kristine

2012-01-01

132

Immunophenotype of human ovarian malignancies (cystadenocarcinomata and mixed müllerian tumor) established in SCID mice.  

PubMed

Human ovarian malignancies from three different patients (histology: two serous cystadenocarcinomata and one mixed Müllerian tumor, homologous type) were successfully serially transplanted intraperitoneally into severe combined immunodeficient (SCID) mice where the tumor cells spread around the peritoneal cavity. If the ascites derived from cystadenocarcinoma cells engrafted in the female genital tract of the SCID mice, they formed cystic tumors resembling remarkably well the original tumors in the patients. Immunohistochemical analysis revealed that the immunophenotype of the patients' original tumor and those grown in SCID mice were similar in the case of the two cystadenocarcinomata; in addition, the marker expression in general was stable during serial transplantation. If distant metastases occurred in the lungs, they immunophenotypically resembled those grown intraperitoneally. In contrast, the cells derived from the mixed Müllerian tumor shifted during serial transplantation from a spindle cell morphology toward a morphology characterized by cuboidal cells. The transition toward a more epithelial phenotype was accompanied by a changed immunophenotype of the tumor cells which became positive for epithelial cell markers such as carcinoembryonic antigens, CA 19-9 and CA 125. Concurrently with this differentiation, the p53 immunophenotype changed from positive to negative, indicating a further mutation in the p53 gene during serial passages. PMID:9316588

Schumacher, U; Adam, E; Dietl, J; Horny, H P

1997-04-01

133

A three-dimensional tissue culture model to study primary human bone marrow and its malignancies.  

PubMed

Tissue culture has been an invaluable tool to study many aspects of cell function, from normal development to disease. Conventional cell culture methods rely on the ability of cells either to attach to a solid substratum of a tissue culture dish or to grow in suspension in liquid medium. Multiple immortal cell lines have been created and grown using such approaches, however, these methods frequently fail when primary cells need to be grown ex vivo. Such failure has been attributed to the absence of the appropriate extracellular matrix components of the tissue microenvironment from the standard systems where tissue culture plastic is used as a surface for cell growth. Extracellular matrix is an integral component of the tissue microenvironment and its presence is crucial for the maintenance of physiological functions such as cell polarization, survival, and proliferation. Here we present a 3-dimensional tissue culture method where primary bone marrow cells are grown in extracellular matrix formulated to recapitulate the microenvironment of the human bone (rBM system). Embedded in the extracellular matrix, cells are supplied with nutrients through the medium supplemented with human plasma, thus providing a comprehensive system where cell survival and proliferation can be sustained for up to 30 days while maintaining the cellular composition of the primary tissue. Using the rBM system we have successfully grown primary bone marrow cells from normal donors and patients with amyloidosis, and various hematological malignancies. The rBM system allows for direct, in-matrix real time visualization of the cell behavior and evaluation of preclinical efficacy of novel therapeutics. Moreover, cells can be isolated from the rBM and subsequently used for in vivo transplantation, cell sorting, flow cytometry, and nucleic acid and protein analysis. Taken together, the rBM method provides a reliable system for the growth of primary bone marrow cells under physiological conditions. PMID:24637629

Parikh, Mukti R; Belch, Andrew R; Pilarski, Linda M; Kirshner, Julia

2014-01-01

134

Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells.  

PubMed

Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor-derived angiogenesis and commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering insights into the successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3? activation, while p38? phosphorylation levels were increased. Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors. PMID:24789042

Ruma, I Made Winarsa; Putranto, Endy Widya; Kondo, Eisaku; Watanabe, Risayo; Saito, Ken; Inoue, Yusuke; Yamamoto, Ken-Ichi; Nakata, Susumu; Kaihata, Masaji; Murata, Hitoshi; Sakaguchi, Masakiyo

2014-07-01

135

Analysis and significance of the malignant 'eclipse' during the progression of primary cutaneous human melanomas.  

PubMed

Why is it that primary melanomas which are less than 0.76 mm in thickness are almost always curable by surgery whereas thicker lesions are associated with a worse prognosis? Put in another way, why is it that such small increases in tumor thickness beyond 0.76 mm are often associated with the eventual formation of distant metastases and death? Part of the answer lies in the dramatic qualitative changes which can accompany small increases in the size of primary human melanomas. Thus, primary melanomas less than 0.76 mm in thickness usually contain very low proportions of metastatically competent tumor cells, whereas slightly thicker lesions can contain very high proportions of such cells, resulting from a selective growth advantage of the latter in the dermal mesenchyme. This overgrowth process is akin to a 'malignant eclipse' phenomenon (by analogy with a solar eclipse). We have been studying the causes of the malignant eclipse in melanoma, for which there are at least four possibilities: 1) an increase in autocrine, mitogenic growth factors by melanoma cells; 2) a decreased rate of apoptosis in the same population; 3) an acquired resistance to paracrine growth inhibitory factors; and 4) an increased ability to induce an angiogenic response. Evidence exists for all four possibilities. Our experimental approach to studying this problem has relied heavily on the use of cell lines obtained from early stage radial growth phase or vertical growth phase lesions which have a clinical-like inability to grow progressively in nude mice, and variants obtained from such lines which are aggressively tumorigenic. Using such paired lines, and other experimental systems, we have obtained evidence that shows early stage melanoma cell lines may be deficient in inducing angiogenesis, are highly sensitive to the growth inhibitory effects of a plethora of cytokines, including transforming growth factor beta, interleukin-6, and oncostatin M, and are more sensitive to undergoing spontaneous apoptosis in several conditions including when growth in anchor-age-independent, 3-dimensional tissue culture. How this information may impact tumor prognosis and the design and effects of new strategies to treat melanoma, especially antiangiogenesis strategies, is discussed. PMID:9627714

Kerbel, R S; Kobayashi, H; Graham, C H; Lu, C

1996-04-01

136

Phytoestrogens induce differential effects on both normal and malignant human breast cells in vitro.  

PubMed

Abstract Objective To explore the effect and pathway of phytoestrogens in vitro on the growth of both normal and malignant breast cells. Methods Normal breast MCF-10A cells and breast cancer MCF-7 cells were incubated with 10 (- 10)-10 (- 4)? mol/l genistein, resveratrol, and quercetin (plasma concentrations in human: 10 nmol/l-10 ?mol/l) for 48 h and were then extracted for a cell proliferation assay (MTT), and for a cell death assay (TUNEL) assay. The proteins involved in the proliferative and apoptotic pathways were evaluated by Western blot analysis. Additionally, a comparison with 17?-estradiol as well as an evaluation of the differential effects on estrogen receptors (ER) ? and ? were performed. Results MCF-7 cell proliferation was significantly inhibited at the concentrations greater than 10(-4) mol/l for all three phytoestrogens and from 10 (- 5) mol/l for resveratrol and quercetin. MCF-10A cell proliferation was significantly increased at the concentrations from 10 (- 8) to 10 (- 5) mol/l for genistein and resveratrol and only at 10 (- 5) mol/l for quercetin. Apoptotic cells were significantly increased by these phytoestrogens in the MCF-7 cells. At a concentration of 10 (- 7)? mol/l of these phytoestrogens, a significant reduction of PI3K and Akt and an increase of Fas ligand, Fas-associated protein with death domain, cytochrome C, truncated Bid, caspase-9, and caspase-3 were noted in the MCF-7; PI3K and Akt were significantly increased in the MCF-10A. ER? expression was significantly elevated in MCF-10A and MCF-7 with these phytoestrogens. The effects of estradiol on normal and malignant breast cells were completely opposite to those of phytoestrogens. Conclusions This study demonstrates that phytoestrogens have antiproliferative effects on breast cancer cells via an ER-dependent mechanism, even at low concentrations, but are also capable of maintaining the survival of normal breast cell via ER-independent or other mechanisms. PMID:24978400

Chen, F-P; Chien, M-H

2014-12-01

137

Pediatric Malignancies: Synopsis of Current Imaging Techniques  

Microsoft Academic Search

The imaging evaluation of malignancies is directed towards the assessment of size, location and characterization of the neoplasm.\\u000a Imaging children necessitates additional attention to the dose of radiation, given the radiosensitivity and the expected longevity\\u000a of children. This chapter will present some of the latest technologies used to image pediatric malignancies, as well as methods\\u000a to evaluate the most common

Sabah Servaes; Monica Epelman; Avrum Pollock; Karuna Shekdar

138

Radioimmunoassay for human pancreatic ribonuclease and measurement of serum immunoreactive pancreatic ribonuclease in patients with malignant tumors  

SciTech Connect

A method for radioimmunoassay of human pancreatic RNase was developed. The method is sensitive, reproducible, and specific. Almost no cross-reactivity exists between human pancreatic and liver RNases. A good correlation was observed between the serum concentration of pancreatic RNase as measured by radioimmunoassay and its enzymatic activity using polycytidylic acid as substrate. The concentration of serum pancreatic RNase correlates well with age, blood urea nitrogen, and albumin contents but does not correlate with serum amylase activity. Using the data of 52 patients with malignant tumors except pancreatic cancer, serum RNase level could be expressed by a multiple regression equation: Immunoreactive RNase content in pancreatic cancer was elevated in patients with complications from renal failure. Serum pancreatic RNase contents in patients with pancreatic cancer measured by radioimmunoassay agreed well with the values calculated using the equation derived from the data of patients with other malignant tumors.

Kurihara, M.; Ogawa, M.; Ohta, T.; Kurokawa, E.; Kitahara, T.; Murata, A.; Matsuda, K.; Kosaki, G.; Watanabe, T.; Wada, H.

1984-05-01

139

Early Stimulation of Human Chorionic Gonadotropin Secretion by Dibutyryl Cyclic AMP and Theophylline in Human Malignant Trophoblast Cells in vitro: Inhibition by Actinomycin D, ?-Amanitin, and Cordycepin  

Microsoft Academic Search

Human malignant trophoblast cells (BeWo line) in culture were employed to investigate the early stimulation of human chorionic gonadotropin (hCG) secretion by 1 mM dibutyryl cyclic AMP and 1 mM theophylline (dbT). The earliest increase in secreted immunoreactive hCG occurred at least 3½ h following addition of dbT, and was preceded by an increase in intracellular hCG. These results suggested

Roland A Pattillo; Robert O. Hussa

1975-01-01

140

ZAP70 is expressed by normal and malignant human B-cell subsets of different maturational stage  

Microsoft Academic Search

ZAP-70 tyrosine kinase is involved in signalling pathways following T-cell receptor stimulation and was originally described only in T cells and natural killer cells. ZAP-70 expression has been reported in normal mouse B lineage cells and in human malignant B lymphocytes, mainly in chronic lymphocytic leukemia (CLL) where it correlates with clinical outcome. We analyzed several B-cell lines and ex

C Scielzo; A Camporeale; M Geuna; M Alessio; A Poggi; M R Zocchi; M Chilosi; F Caligaris-Cappio; P Ghia

2006-01-01

141

Coexpression of stem cell factor and its receptor c-Kit in human malignant glioma cell lines  

Microsoft Academic Search

Stem cell factor (SCF), a hematopoietic growth factor, is the ligand of the tyrosine kinase receptor encoded by the c-kit proto-oncogene. Beside the important role of this receptor-ligand complex in hematopoiesis, gametogenesis and melanogenesis, SCF and its receptor have been shown to be expressed in the brain. We have studied the expression of SCF and c-kit in 20 human malignant

Martin Stanulla; Karl Welte; Martin R. Hadam; Torsten Pietsch

1995-01-01

142

Association between chronic exposure to pesticides and recorded cases of human malignancy in Gaza Governorates (1990–1999)  

Microsoft Academic Search

Epidemiological association between chronic exposure to pesticides and recorded cases of human malignancy in Gaza Governorates during the years 1990–1999 was studied. The pesticide usage in Gaza Governorates was recorded in detail. It ranged from 216.9 to 393.3 t from 1990 to 1999, respectively. Banned and extremely hazardous pesticides are identified according to their carcinogenicity, genotoxicity and cytotoxicity. Hospital cases

Jamal M. Safi

2002-01-01

143

The Guanine Nucleotide Exchange Factor SWAP-70 Modulates the Migration and Invasiveness of Human Malignant Glioma Cells12  

PubMed Central

The malignant glioma is the most common primary human brain tumor. Its tendency to invade away from the primary tumor mass is considered a leading cause of tumor recurrence and treatment failure. Accordingly, the molecular pathogenesis of glioma invasion is currently under investigation. Previously, we examined a gene expression array database comparing human gliomas to nonneoplastic controls and identified several Rac guanine nucleotide exchange factors with differential expression. Here, we report that the guanine nucleotide exchange factor SWAP-70 has increased expression in malignant gliomas and strongly correlates with lowered patient survival. SWAP-70 is a multifunctional signaling protein involved in membrane ruffling that works cooperatively with activated Rac. Using a glioma tissue microarray, we validated that SWAP-70 demonstrates higher expression in malignant gliomas compared with low-grade gliomas or nonneoplastic brain tissue. Through immunofluorescence, SWAP-70 localizes to membrane ruffles in response to the growth factor, epidermal growth factor. To assess the role of SWAP-70 in glioma migration and invasion, we inhibited its expression withsmall interfering RNAs and observed decreased glioma cell migration and invasion. SWAP-70 overexpression led to increased levels of active Rac even in low-serum conditions. In addition, when SWAP-70 was overexpressed in glioma cells, we observed enhanced membrane ruffle formation followed by increased cellmigration and invasiveness. Taken together, our findings suggest that the guanine nucleotide exchange factor SWAP-70 plays an important role in the migration and invasion of human gliomas into the surrounding tissue. PMID:19956392

Seol, Ho Jun; Smith, Christian A; Salhia, Bodour; Rutka, James T

2009-01-01

144

Emergence of fractal behavior and other changes of cell surface during malignant transformation: AFM study of human cervical epithelial cells  

NASA Astrophysics Data System (ADS)

Fractal behavior, self-similarity when zooming in or out, is frequently found in natural patterns emerged from chaos or any far from equilibrium systems. While expected and observed for tissues, the emergence of fractal behavior associated with malignant transformations was not observed at the level of single cell. Here report on the appearance of fractal behavior when normal human cervical epithelial cells become malignant. This was found by analyzing the adhesion maps imaged with AFM working in HarmoniX mode. Normal and malignant (a mix of cancerous and precancerous) cells were enzymatic only extracted from cervical tissue of healthy individuals and cancer patients, respectively. A surprising 100% discrimination of malignant and normal cells was observed. Although we previously reported differences in surface (brush) layer of cancer cells, the unambiguous quantitative divergence of the fractal behavior of the adhesion maps is a surprise (in particular, when compared to no difference found in the regular AFM images). The nature of the observed difference in the adhesion behavior will be discussed. These results may suggest that the fractal dimensionality can be treated as a new potential ``physicomarker'' for detection of individual cervical cancer cells.

Dokukin, Maxim; Guz, Nataliia; Woodworth, Craig; Sokolov, Igor

2012-02-01

145

The Methanol Extract of Angelica sinensis Induces Cell Apoptosis and Suppresses Tumor Growth in Human Malignant Brain Tumors  

PubMed Central

Glioblastoma multiforme (GBM) is a highly vascularized and invasive neoplasm. The methanol extract of Angelica sinensis (AS-M) is commonly used in traditional Chinese medicine to treat several diseases, such as gastric mucosal damage, hepatic injury, menopausal symptoms, and chronic glomerulonephritis. AS-M also displays potency in suppressing the growth of malignant brain tumor cells. The growth suppression of malignant brain tumor cells by AS-M results from cell cycle arrest and apoptosis. AS-M upregulates expression of cyclin kinase inhibitors, including p16, to decrease the phosphorylation of Rb proteins, resulting in arrest at the G0-G1 phase. The expression of the p53 protein is increased by AS-M and correlates with activation of apoptosis-associated proteins. Therefore, the apoptosis of cancer cells induced by AS-M may be triggered through the p53 pathway. In in vivo studies, AS-M not only suppresses the growth of human malignant brain tumors but also significantly prolongs patient survival. In addition, AS-M has potent anticancer effects involving cell cycle arrest, apoptosis, and antiangiogenesis. The in vitro and in vivo anticancer effects of AS-M indicate that this extract warrants further investigation and potential development as a new antibrain tumor agent, providing new hope for the chemotherapy of malignant brain cancer. PMID:24319475

Lai, Wen-Lin; Harn, Horng-jyh; Hung, Pei-Hsiu; Hsieh, Ming-Chang; Chang, Kai-Fu; Huang, Xiao-Fan; Liao, Kuang-Wen; Lee, Ming-Shih; Tsai, Nu-Man

2013-01-01

146

Catalase ameliorates polychlorinated biphenyl-induced cytotoxicity in non-malignant human breast epithelial cells  

PubMed Central

Polychlorinated biphenyls (PCBs) are environmental chemical contaminants believed to adversely affect cellular processes. We investigated the hypothesis that PCB-induced changes in the levels of cellular reactive oxygen species (ROS) induce DNA damage resulting in cytotoxicity. Exponentially growing cultures of human non-malignant breast epithelial cells (MCF10A) were incubated with PCBs for 3 days and assayed for cell number, ROS levels, DNA damage, and cytotoxicity. Exposure to 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) or 2-(4-chlorophenyl)benzo-1,4-quinone (4-Cl-BQ), a metabolite of 4-chlorobiphenyl (PCB3) significantly decreased cell number, MTS reduction, and increased the percentage of cells with sub G1 DNA content. Results from electron paramagnetic resonance (EPR) spectroscopy showed a 4-fold increase in the steady-state levels of ROS, which was suppressed in cells pre-treated with catalase. EPR measurements in cells treated with 4-Cl-BQ detected the presence of a semiquinone radical, suggesting that the increased levels of ROS could be due to the redox-cycling of 4-Cl-BQ. A dose-dependent increase in micronuclei frequency was observed in PCB-treated cells, consistent with an increase in histone 2AX-phosphorylation. Treatment of cells with catalase blunted the PCB-induced increase in micronuclei frequency and H2AX phosphorylation that was consistent with an increase in cell survival. Our results demonstrate a PCB-induced increase in cellular levels of ROS causing DNA damage, resulting in cell killing. PMID:18691649

Venkatesha, Venkatasubbaiah A.; Venkataraman, Sujatha; Sarsour, Ehab H.; Kalen, Amanda L.; Buettner, Garry R.; Robertson, Larry W.; Lehmler, Hans-Joachim; Goswami, Prabhat C.

2008-01-01

147

Virus-like particles for the prevention of human papillomavirus-associated malignancies  

PubMed Central

As compared to peptide/protein-based vaccines, naked DNA vectors and even traditional attenuated or inactived virus vaccines, virus-like particles (VLPs) are an attractive vaccine platform because they offer a combination of safety, ease of production, and both high density B cell epitope display and intracellular presentation of T cell epitopes that induce potent humoral and cellular immune responses respectively. Indeed, human papillomavirus (HPV) vaccines based on VLP production by recombinant expression of major capsid antigen L1 in yeast (Gardasil®, Merck & Co.) or insect cells (Cervarix®, GlaxoSmithKline) have been licensed for the prevention of cervical and anogenital infection and disease associated with the genotypes targeted by each vaccine. These HPV vaccines however have not been demonstrated as effective to treat existing infections, and efforts to develop a therapeutic HPV vaccine continue. Furthermore, current HPV L1-VLP vaccines provide type-restricted protection, requiring highly multivalent formulations to broaden coverage to the dozen or more oncogenic HPV genotypes. This raises the complexity and cost of vaccine production. The lack of access to screening and high disease burden in developing countries has spurred efforts to develop second generation HPV vaccines that are more affordable, induce wider protective coverage and offer therapeutic coverage against HPV-associated malignancies. Given the previous success with L1 VLP-based vaccines against HPV, VLPs have been also adopted as platforms for many second generation HPV and non-HPV vaccine candidates with both prophylactic and therapeutic intent. Here we examine the progress and challenges of these efforts, with a focus on how they inform VLP vaccine design. PMID:23414405

Wang, Joshua W.; Roden, Richard B.S.

2013-01-01

148

p53: Biology and Role for Cellular Radiosensitivity  

Microsoft Academic Search

Purpose: p53 is the most commonly mutated gene in human tumors with large impact on cellular biology and response to radiation. Many excellent reviews are available on various aspects but for several years none about the role of p53 for radiosensitivity. The latter is the aim of the present paper. Methods: Review of the literature. Results: p53 is a regulator

Jochen Dahm-Daphi

2000-01-01

149

Mutational Analysis of Hedgehog Signaling Pathway Genes in Human Malignant Mesothelioma  

PubMed Central

Background The Hedgehog (HH) signaling pathway is critical for embryonic development and adult homeostasis. Recent studies have identified regulatory roles for this pathway in certain cancers with mutations in the HH pathway genes. The extent to which mutations of the HH pathway genes are involved in the pathogenesis of malignant mesothelioma (MMe) is unknown. Methodology/Principal Findings Real-time PCR analysis of HH pathway genes PTCH1, GLI1 and GLI2 were performed on 7 human MMe cell lines. Exon sequencing of 13 HH pathway genes was also performed in cell lines and human MMe tumors. In silico programs were used to predict the likelihood that an amino-acid substitution would have a functional effect. GLI1, GLI2 and PTCH1 were highly expressed in MMe cells, indicative of active HH signaling. PTCH1, SMO and SUFU mutations were found in 2 of 11 MMe cell lines examined. A non-synonymous missense SUFU mutation (p.T411M) was identified in LO68 cells. In silico characterization of the SUFU mutant suggested that the p.T411M mutation might alter protein function. However, we were unable to demonstrate any functional effect of this mutation on Gli activity. Deletion of exons of the PTCH1 gene was found in JU77 cells, resulting in loss of one of two extracellular loops implicated in HH ligand binding and the intracellular C-terminal domain. A 3-bp insertion (69_70insCTG) in SMO, predicting an additional leucine residue in the signal peptide segment of SMO protein was also identified in LO68 cells and a MMe tumour. Conclusions/Significance We identified the first novel mutations in PTCH1, SUFU and SMO associated with MMe. Although HH pathway mutations are relatively rare in MMe, these data suggest a possible role for dysfunctional HH pathway in the pathogenesis of a subgroup of MMe and help rationalize the exploration of HH pathway inhibitors for MMe therapy. PMID:23826113

Lim, Chuan Bian; Prele, Cecilia M.; Cheah, Hui Min; Cheng, Yuen Yee; Klebe, Sonja; Reid, Glen; Watkins, D. Neil; Baltic, Svetlana; Thompson, Philip J.; Mutsaers, Steven E.

2013-01-01

150

Synergism of BARF1 with Ras induces malignant transformation in primary primate epithelial cells and human nasopharyngeal epithelial cells.  

PubMed

Although it is well known that nasopharyngeal carcinoma (NPC) is closely related with Epstein-Barr virus (EBV), few data are available about which and how EBV-expressed gene is involved in the carcinogenesis of human nasopharyngeal epithelial cells. EBV-encoded BARF1 (BamH I-A right frame 1) gene has been shown to be oncogenic and capable of inducing malignant transformation in BALB/c3T3 and NIH3T3 cells as well as in human B-cell lines Louckes and Akata. It remains unclear, however, whether BARF1 can transform primate or human epithelial cells. Here, we have shown that overexpression of H-Ras gene transformed BARF1-immortalized PATAS cells into malignant cell line. Furthermore, we found that cooperation of BARF1 with H-Ras and SV40 T antigens was sufficient to transform nonmalignant human nasopharyngeal epithelial NP69 cells when serially introduced BARF1 and H-Ras into the SV40 T antigens-immortalized NP69 cells. Taken together, these results demonstrated that the cooperation of BARF1 with Ras suffices to transform primary primate epithelial cell PATAS. Similarly, BARF1 together with H-Ras and SV40 T can transform human epithelial cell NP69, thereby indicating that BARF1 could be involved in the NPC pathogenesis in combination with additional genetic changes. PMID:19724690

Jiang, Richeng; Cabras, Giulia; Sheng, Wang; Zeng, Yixin; Ooka, Tadamasa

2009-09-01

151

Synergism of BARF1 with Ras Induces Malignant Transformation in Primary Primate Epithelial Cells and Human Nasopharyngeal Epithelial Cells1  

PubMed Central

Although it is well known that nasopharyngeal carcinoma (NPC) is closely related with Epstein-Barr virus (EBV), few data are available about which and how EBV-expressed gene is involved in the carcinogenesis of human nasopharyngeal epithelial cells. EBV-encoded BARF1 (BamH I-A right frame 1) gene has been shown to be oncogenic and capable of inducing malignant transformation in BALB/c3T3 and NIH3T3 cells as well as in human B-cell lines Louckes and Akata. It remains unclear, however, whether BARF1 can transform primate or human epithelial cells. Here, we have shown that overexpression of H-Ras gene transformed BARF1-immortalized PATAS cells into malignant cell line. Furthermore, we found that cooperation of BARF1 with H-Ras and SV40 T antigens was sufficient to transform nonmalignant human nasopharyngeal epithelial NP69 cells when serially introduced BARF1 and H-Ras into the SV40 T antigens-immortalized NP69 cells. Taken together, these results demonstrated that the cooperation of BARF1 with Ras suffices to transform primary primate epithelial cell PATAS. Similarly, BARF1 together with H-Ras and SV40 T can transform human epithelial cell NP69, thereby indicating that BARF1 could be involved in the NPC pathogenesis in combination with additional genetic changes. PMID:19724690

Jiang, Richeng; Cabras, Giulia; Sheng, Wang; Zeng, Yixin; Ooka, Tadamasa

2009-01-01

152

The activation of human endogenous retrovirus K (HERV-K) is implicated in melanoma cell malignant transformation  

SciTech Connect

Melanoma development is a multi-step process arising from a series of genetic and epigenetic events. Although the sequential stages involved in progression from melanocytes to malignant melanoma are clearly defined, our current understanding of the mechanisms leading to melanoma onset is still incomplete. Growing evidence show that the activation of endogenous retroviral sequences might be involved in transformation of melanocytes as well as in the increased ability of melanoma cells to escape immune surveillance. Here we show that human melanoma cells in vitro undergo a transition from adherent to a more malignant, non-adherent phenotype when exposed to stress conditions. Melanoma-derived non-adherent cells are characterized by an increased proliferative potential and a decreased expression of both HLA class I molecules and Melan-A/MART-1 antigen, similarly to highly malignant cells. These phenotypic and functional modifications are accompanied by the activation of human endogenous retrovirus K expression (HERV-K) and massive production of viral-like particles. Down-regulation of HERV-K expression by RNA interference prevents the transition from the adherent to the non-adherent growth phenotype in low serum. These results implicate HERV-K in at least some critical steps of melanoma progression.

Serafino, A. [Institute of Neurobiology and Molecular Medicine - ARTOV, CNR via Fosso del Cavaliere 100, 00133 - Rome (Italy)], E-mail: annalucia.serafino@artov.inmm.cnr.it; Balestrieri, E. [Department of Experimental Medicine and Biochemical Science - University of Rome 'Tor Vergata', via Montpellier, 00133 - Rome (Italy); Pierimarchi, P. [Institute of Neurobiology and Molecular Medicine - ARTOV, CNR via Fosso del Cavaliere 100, 00133 - Rome (Italy); Matteucci, C.; Moroni, G. [Department of Experimental Medicine and Biochemical Science - University of Rome 'Tor Vergata', via Montpellier, 00133 - Rome (Italy); Oricchio, E. [Department of Experimental Medicine and Biochemical Science - University of Rome 'Tor Vergata', via Montpellier, 00133 - Rome (Italy); Istituto Superiore di Sanita, Viale Regina Elena, 299, 00161 - Rome (Italy); Rasi, G. [Institute of Neurobiology and Molecular Medicine - ARTOV, CNR via Fosso del Cavaliere 100, 00133 - Rome (Italy); Mastino, A. [Department of Life Sciences, University of Messina, Salita Sperone 31, 98166 - Messina (Italy); Spadafora, C. [Istituto Superiore di Sanita, Viale Regina Elena, 299, 00161 - Rome (Italy); Garaci, E.; Vallebona, P. Sinibaldi [Department of Experimental Medicine and Biochemical Science - University of Rome 'Tor Vergata', via Montpellier, 00133 - Rome (Italy)

2009-03-10

153

Extract of Coptidis rhizoma induces cytochrome-c dependent apoptosis in immortalized and malignant human oral keratinocytes.  

PubMed

Coptidis rhizoma (C. rhizoma) had been demonstrated as an antioxidant and anticancer agent, however, its antioral cancer mechanism still remains unclear. Using water extracts of C. rhizoma, growth and apoptosis-related experiments for the treatment of multi-stage of oral cancer were carried out on immortalized human oral keratinocytes (IHOK), primary oral cancer cells (HN4), metastatic oral cancer cells (HN12) and human skin keratinocytes (HaCaT) by MTT assay, three-dimensional (3-D) raft cultures, western blotting, cell cycle analysis, nuclear staining and cytochrome c expression related to the apoptosis signaling pathway. C. rhizoma inhibited the proliferation of immortalized and malignant oral keratinocytes in a dose- and time-dependent manner. In 3-D organotypic culture, C. rhizoma-treated cells showed less maturation than the control cells, displaying low surface keratinization and decreased epithelial thickness. The major mechanism of growth inhibition by C. rhizoma appears to be the induction of apoptosis, which is supported by the results of the cell cycle analysis, FITC-annexin V staining, DNA fragmentation assay and DAPI staining. The induction of apoptosis by C. rhizoma was more prominent in immortalized keratinocytes than in malignant oral keratinocytes. Cytochrome-c release from mitochondria, accompanied by the activation of caspase-3, was observed in C. rhizoma-treated IHOK and oral cancer cells. These results suggest that C. rhizoma has apoptotic effects in immortalized and malignant oral keratinocytes via the mitochondrial signaling pathway. PMID:16807885

Lee, Hwa-Jeong; Son, Dae-Hyung; Lee, Sun-Kyung; Lee, Jun; Jun, Chang-Duk; Jeon, Byung-Hun; Lee, Suk-Keun; Kim, Eun-Cheol

2006-09-01

154

Toll-like receptors in the pathogenesis of human B cell malignancies  

PubMed Central

Toll-like receptors (TLRs) are important players in B-cell activation, maturation and memory and may be involved in the pathogenesis of B-cell lymphomas. Accumulating studies show differential expression in this heterogeneous group of cancers. Stimulation with TLR specific ligands, or agonists of their ligands, leads to aberrant responses in the malignant B-cells. According to current data, TLRs can be implicated in malignant transformation, tumor progression and immune evasion processes. Most of the studies focused on multiple myeloma and chronic lymphocytic leukemia, but in the last decade the putative role of TLRs in other types of B-cell lymphomas has gained much interest. The aim of this review is to discuss recent findings on the role of TLRs in normal B cell functioning and their role in the pathogenesis of B-cell malignancies. PMID:25112836

2014-01-01

155

ErbB receptor tyrosine kinase network inhibition radiosensitizes carcinoma cells  

SciTech Connect

Purpose The expression of epidermal growth factor receptor (EGFR)-CD533, a truncation mutant of the wild-type EGFR, radiosensitizes carcinoma and malignant glioma cell lines. This deletion mutant disrupts EGFR activation and downstream signaling through the formation of inhibitory dimerizations. In this study, the effects of EGFR-CD533 on other ErbB receptor tyrosine kinase (RTK) family members were quantified to better understand the mechanism of EGFR-CD533-mediated radiosensitization. Methods and Materials Breast carcinoma cell lines with different ErbB RTK expression profiles were transduced with EGFR or ErbB2 deletion mutants (EGFR-CD533 and ErbB2-CD572) using an adenoviral vector. ErbB RTK activation, mitogen activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/p70S6K signaling, and clonogenic survival were determined for expression of each deletion mutant. Results EGFR-CD533 radiosensitizes carcinoma cells with either high EGFR expression (MDA-MB231) or low EGFR expression (T47D) through significant blockade of the ErbB RTK network. Analysis of clonogenic survival demonstrate significant enhancement of the {alpha}/{beta} ratios, as determined by the linear-quadratic model. Split-dose survival experiments confirm that EGFR-CD533 reduces the repair of cellular damage after ionizing radiation. Conclusion Expression of EGFR-CD533 inhibits the ErbB RTK network and radiosensitizes carcinoma cells irrespective of the ErbB RTK expression patterns, and ErbB2-CD572 does not radiosensitize cells with low EGFR expression. These studies demonstrate that the mechanism of action for EGFR-CD533-mediated radiosensitization is inhibition of the ErbB RTK network, and is an advantage for radiosensitizing multiple malignant cell types.

Contessa, Joseph N. [Department of Radiation Oncology, Medical College of Virginia/Virginia Commonwealth University, Richmond VA (United States)]. E-mail: jcontess@med.umich.edu; Abell, Angela [Department of Radiation Oncology, Medical College of Virginia/Virginia Commonwealth University, Richmond VA (United States); Valerie, Kristoffer [Department of Radiation Oncology, Medical College of Virginia/Virginia Commonwealth University, Richmond VA (United States); Lin, Peck-Sun [Department of Radiation Oncology, Medical College of Virginia/Virginia Commonwealth University, Richmond VA (United States); Schmidt-Ullrich, Rupert K. [Department of Radiation Oncology, Medical College of Virginia/Virginia Commonwealth University, Richmond VA (United States)

2006-07-01

156

[Changes in cellular radiosensitivity after low dose irradiation].  

PubMed

When the adaptive response (AR) was studied on human blood lymphocytes, a new dependence was discovered. This dependence defines the direction of the radiosensitivity change after a low dose of irradiation. Using micronucleus (MN) test with cytochalasin B the dependence between the cell reaction after low level irradiation and radiosensititvity (the effect after irradiation at the dose of 1 Gy) was observed. The negative correlation between the frequency of AR manifestation, sensibilization, intermediate links and radiosensitivity was discovered. This regularity is observed in the population of Moscow, Obninsk, Chelyabinsk region (irradiated and control) inhabitants, Chernobyl accident liquidators, Moscow children, in individuals with Hodgkin's lymphoma before and during treatment. The negative correlation is also noted by AR determination with two irradiation schemes: in one or two different cell cycle phases (G1-G1 or G1-G2). Similar links are observed using the chromosome methaphase analysis (the frequency of cells with chromosome aberrations). So, the results of the experiments conducted allow us to suppose that the connection between the cell radiosensitivity and a different type of reaction after low dose irradiation--from AR to the increase in radiosensitivity (sensibilization) is a general regularity. AR is induced by low level irradiation and high cell radiosensitivity, while sensibilization is induced by low radiosensitivity. Since AR and sensibilization can be induced not only by irradiation, but many different chemicals and physical agents, the described correlation can be observed in the case of different exposures. Cellular AR and sensibilization are integral indexes depending on many genetic and epigenetic factors, as well as on the initiation of a large number of events. However, the discovered mechanisms of interrelations are still difficult to explain. PMID:23227711

Pelevina, I I; Aleshchenko, A V; Antoshchina, M M; Kudriashova, O V; Riabchenko, N I; Akleev, A V

2012-01-01

157

A Hypermutation Phenotype and Somatic MSH6 Mutations in Recurrent Human Malignant Gliomas after Alkylator Chemotherapy  

Microsoft Academic Search

Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statis- tically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents. We

Chris Hunter; Raffaella Smith; Daniel P. Cahill; Philip Stephens; Claire Stevens; Jon Teague; Chris Greenman; Sarah Edkins; Graham Bignell; Helen Davies; Sarah O'Meara; Adrian Parker; Tim Avis; Syd Barthorpe; Lisa Brackenbury; Gemma Buck; Adam Butler; Jody Clements; Jennifer Cole; Ed Dicks; Simon Forbes; Matthew Gorton; Kristian Gray; Kelly Halliday; Rachel Harrison; Katy Hills; Jonathon Hinton; Andy Jenkinson; David Jones; Vivienne Kosmidou; Ross Laman; Richard Lugg; Andrew Menzies; Janet Perry; Robert Petty; Keiran Raine; David Richardson; Rebecca Shepherd; Alexandra Small; Helen Solomon; Calli Tofts; Jennifer Varian; Sofie West; Sara Widaa; Andy Yates; Douglas F. Easton; Gregory Riggins; Jennifer E. Roy; Kymberly K. Levine; Wolf Mueller; Tracy T. Batchelor; David N. Louis; Michael R. Stratton; P. Andrew Futreal; Richard Wooster

2006-01-01

158

The Role of the Focal Adhesion Protein PINCH1 for the Radiosensitivity of Adhesion and Suspension Cell Cultures  

PubMed Central

Focal adhesion (FA) signaling mediated by adhesion to extracellular matrix and growth factor receptors contributes to the regulation of the cellular stress response to external stimuli. Critical to focal adhesion assembly and signaling is the adapter protein PINCH1. To evaluate whether the prosurvival function of PINCH1 in radiation cell survival depends on cell adhesion, we examined PINCH1fl/fl and PINCH1?/? mouse embryonic fibroblasts and human cancer cell lines. Here, we found that the enhanced cellular radiosensitivity mediated by PINCH1 depletion observed under adhesion conditions is conserved when cells are irradiated under suspension conditions. This unsuspected finding could not be explained by the observed modification of adhesion and growth factor associated signaling involving FAK, Paxillin, p130CAS, Src, AKT, GSK3? and ERK1/2 under suspension and serum withdrawal relative to adhesion conditions with serum. Our data suggest that the adapter protein PINCH1 critically participates in the regulation of the cellular radiosensitivity of normal and malignant cells similarly under adhesion and suspension conditions. PMID:20927395

Sandfort, Veit; Eke, Iris; Cordes, Nils

2010-01-01

159

Short Alternative Splice Transcripts of the mdm2 Oncogene Correlate to Malignancy in Human Astrocytic Neoplasms  

Microsoft Academic Search

The inilnû oncogene encodes a 90-kDa nuclear phosphoprotein that binds and inhibits the function of the p53 tumor suppressor protein. It was recently reported that the expression of alternatively spliced variants of uiclm2 correlated with malignancy in ovarian tumors and bladder carci nomas. We analyzed the presence of alternatively spliced mdm2 variants and studied their correlation to p53 status in

Ryoji Matsumoto; Mitsuhiro Tada; Michimasa Nozaki; Chang-Liang Zhang; Yutaka Sawamura; Hiroshi Abe

1998-01-01

160

Autocrine Tumor Cell Growth-inhibiting Activities from Human Malignant Melanoma  

Microsoft Academic Search

Autocrine-secreted tumor cell growth-inhibiting activities were isolated from supernatants of a malignant melanoma cell line, HTZ 19-dM, established from a central nervous system melanoma metastasis. HTZ 19-dM was characterized by cyto- and immunocytochemistry and kary- otyping; cells were propagated in defined serum-free tissue culture me dium for up to 8 months. Supernatants were ultrafiltrated, dialyzed, lyophilized, and purified by Bio-Gel

U. Bogdahn; R. Apfel; M. Hahn; M. Gerlach; C. Behl; J. Hoppe; R. Martin

2000-01-01

161

Activating FGFR3 mutations cause mild hyperplasia in human skin, but are insufficient to drive benign or malignant skin tumors.  

PubMed

Fibroblast growth factor receptor 3 (FGFR3) activating mutations are drivers of malignancy in several human tissues, including bladder, lung, cervix, and blood. However, in skin, these mutations are associated predominantly with benign, common epidermal growths called seborrheic keratoses (SKs). How epidermis resists FGFR3 mediated transformation is unclear, but previous studies have suggested that FGFR3 activation in skin keratinocytes may serve a tumor-suppressive role by driving differentiation and antagonizing Ras signaling. To define the role of FGFR3 in human normal and neoplastic epidermis, and to directly test the hypothesis that FGFR3 antagonizes Ras, we engineered human skin grafts in vivo with mutant active FGFR3 or shRNA FGFR3 knockdown. We show that FGFR3 active mutants drive mild hyperproliferation, but are insufficient to support benign or malignant tumorigenesis, either alone, or in combination with G 1-S checkpoint release. This suggests that additional cell-intrinsic or stromal cues are required for formation of benign SKs with FGFR3 mutations. Further, FGFR3 activation does not alter the growth kinetics or differentiation status of engineered human epidermal SCCs driven by Ras, and FGFR3 protein itself is dispensable for Ras-driven SCC. To extend these findings to patients, we examined a uniquely informative human tumor in which SCC developed in continuity with a SK, raising the hypothesis that one of the tumors evolved from the other. However, mutational analysis from each tumor indicates that the overlapping SK and SCC evolved independently and supports our conclusion that FGFR3 activation is insufficient to drive SCC. PMID:24626198

Duperret, Elizabeth K; Oh, Seung Ja; McNeal, Andrew; Prouty, Stephen M; Ridky, Todd W

2014-05-15

162

Complete regression of human malignant mesothelioma xenografts following local injection of midkine promoter-driven oncolytic adenovirus  

PubMed Central

Background Malignant mesothelioma is a highly aggressive tumor with poor prognosis. Conventional therapies for mesothelioma are generally non-curative, and new treatment paradigms are urgently needed. We hypothesized that the tumor-specific midkine (Mdk) promoter could confer transcriptional targeting to oncolytic adenoviruses for effective treatment of malignant mesothelioma. Methods We analyzed Mdk expression by quantitative RT-PCR in six human mesothelioma cell lines, and tested Mdk promoter activity by luciferase reporter assay. Based on these data, we constructed a replication-selective oncolytic adenovirus, designated AdMdk-E1-iresTK, which contains an Mdk promoter-driven adenoviral E1 gene and HSV-thymidine kinase (TK) suicide gene, and CMV promoter-driven green fluorescent protein (GFP) marker gene. Selectivity of viral replication and cytolysis were characterized in normal vs. mesothelioma cells in vitro, and intratumoral spread and antitumor efficacy were investigated in vivo. Results Mdk promoter activity was restricted in normal cells, but highly activated in mesothelioma cell lines. AdMdk-E1-iresTK was seen to efficiently replicate, produce viral progeny, and spread in multiple mesothelioma cell lines. Lytic spread of AdMdk-E1-iresTK mediated efficient killing of these mesothelioma cells, and its in vitro cytocidal effect was significantly enhanced by treatment with the prodrug, ganciclovir. Intratumoral injection of AdMdk-E1-iresTK caused complete regression of MESO4 and MSTO human mesothelioma xenografts in athymic mice. In vivo fluorescence imaging demonstrated intratumoral spread of AdMdk-E1-iresTK-derived signals, which vanished after tumor eradication. Conclusions These data indicate that transcriptional targeting of viral replication by the Mdk promoter represents a promising general strategy for oncolytic virotherapy of cancers with upregulated Mdk expression, including malignant mesothelioma. PMID:20635326

Kubo, Shuji; Kawasaki, Yoshiko; Yamaoka, Norie; Tagawa, Masatoshi; Kasahara, Noriyuki; Terada, Nobuyuki; Okamura, Haruki

2010-01-01

163

GPER mediates estrogen-induced signaling and proliferation in human breast epithelial cells and normal and malignant breast.  

PubMed

17?-Estradiol (estrogen), through receptor binding and activation, is required for mammary gland development. Estrogen stimulates epithelial proliferation in the mammary gland, promoting ductal elongation and morphogenesis. In addition to a developmental role, estrogen promotes proliferation in tumorigenic settings, particularly breast cancer. The proliferative effects of estrogen in the normal breast and breast tumors are attributed to estrogen receptor ?. Although in vitro studies have demonstrated that the G protein-coupled estrogen receptor (GPER, previously called GPR30) can modulate proliferation in breast cancer cells both positively and negatively depending on cellular context, its role in proliferation in the intact normal or malignant breast remains unclear. Estrogen-induced GPER-dependent proliferation was assessed in the immortalized nontumorigenic human breast epithelial cell line, MCF10A, and an ex vivo organ culture model employing human breast tissue from reduction mammoplasty or tumor resections. Stimulation by estrogen and the GPER-selective agonist G-1 increased the mitotic index in MCF10A cells and proportion of cells in the cell cycle in human breast and breast cancer explants, suggesting increased proliferation. Inhibition of candidate signaling pathways that may link GPER activation to proliferation revealed a dependence on Src, epidermal growth factor receptor transactivation by heparin-bound EGF and subsequent ERK phosphorylation. Proliferation was not dependent on matrix metalloproteinase cleavage of membrane-bound pro-HB-EGF. The contribution of GPER to estrogen-induced proliferation in MCF10A cells and breast tissue was confirmed by the ability of GPER-selective antagonist G36 to abrogate estrogen- and G-1-induced proliferation, and the ability of siRNA knockdown of GPER to reduce estrogen- and G-1-induced proliferation in MCF10A cells. This is the first study to demonstrate GPER-dependent proliferation in primary normal and malignant human tissue, revealing a role for GPER in estrogen-induced breast physiology and pathology. PMID:24718936

Scaling, Allison L; Prossnitz, Eric R; Hathaway, Helen J

2014-06-01

164

Angiopoietin-like protein 2 induces androgen-independent and malignant behavior in human prostate cancer cells.  

PubMed

Angiopoietin-like proteins (ANGPTLs), which comprise 7 members (ANGPTL1-ANGPTL7), structurally resemble angiopoietins. We investigated the roles of ANGPTLs in the acquisition of androgen independence and the malignant behavior of human prostate cancer cells. Expression of ANGPTL messenger RNA (mRNA) and proteins were ascertained using RT-qPCR and western blot analysis in human prostate cancer cell lines. Androgen?dependent LNCaP and androgen-independent LNCaP/AI cells, respectively, were cultured in fetal bovine and charcoal-stripped medium. Cell proliferation, androgen dependence, migration and invasion, respectively, were examined under the overexpression and knockdown of ANGPTL2 by transfection of ANGPTL2 cDNA and its small?interfering RNA (siRNA). The effects of exogenous ANGPTL2 and blocking of its receptor, integrin ?5?1, were also investigated. Human prostate cancer cell lines predominantly expressed ANGPTL2 among the members. Interrupting ANGPTL2 expression with siRNA suppressed the proliferation, migration and invasion of LNCaP cells. LNCaP/AI cells showed a higher ANGPTL2 expression than that of LNCaP cells. Furthermore, siRNA led to apoptosis of LNCaP/AI cells. The ANGPTL2-overexpressing LNCaP cells markedly increased proliferation, epithelial-to-mesenchymal transition (EMT) and malignant behavior in androgen?deprived medium. The migration rates were increased depending on the concentration of ANGPTL2 recombinant protein and were inhibited by anti-integrin ?5?1 antibodies. To the best of our knowledge, this is the first study to elucidate the expression of ANGPTL2 in human prostate cancer cells. ANGPTL2 may be important in the acquisition of androgen independency and tumor progression of prostate cancer in an autocrine and/or paracrine manner via the integrin ?5?1 receptor. Targeting ANGPTL2 may therefore be an efficacious therapeutic modality for prostate cancer. PMID:25370833

Sato, Ryuta; Yamasaki, Mutsushi; Hirai, Kenichi; Matsubara, Takanori; Nomura, Takeo; Sato, Fuminori; Mimata, Hiromitsu

2015-01-01

165

Repair of chromosome damage induced by X-irradiation during G2 phase in a line of normal human fibroblasts and its malignant derivative  

SciTech Connect

A line of normal human skin fibroblasts (KD) differed from its malignant derivative (HUT-14) in the extent of cytogenetic damage induced by X-irradiation during G2 phase. Malignant cells had significantly more chromatid breaks and gaps after exposure to 25, 50, or 100 rad. The gaps may represent single-strand breaks. Results from alkaline elution of cellular DNA immediately after irradiation showed that the normal and malignant cells in asynchronous population were equally sensitive to DNA single-strand breakage by X-irradiation. Caffeine or beta-cytosine arabinoside (ara-C), inhibitors of DNA repair, when added directly following G2 phase exposure, significantly increased the incidence of radiation-induced chromatid damage in the normal cells. In contrast, similar treatment of the malignant cells had little influence. Ara-C differed from caffeine in its effects; whereas both agents increased the frequency of chromatid breaks and gaps, only ara-C increased the frequency of gaps to the level observed in the irradiated malignant cells. Addition of catalase, a scavenger of the derivative free hydroxyl radical (.OH), to the cultures of malignant cells before, during, and following irradiation significantly reduced the chromatid damage; and catalase prevented formation of chromatid gaps. The DNA damage induced by X-ray during G2 phase in the normal KD cells was apparently repaired by a caffeine- and ara-C-sensitive mechanism(s) that was deficient or absent in their malignant derivatives.

Parshad, R.; Gantt, R.; Sanford, K.K.; Jones, G.M.; Tarone, R.E.

1982-08-01

166

Highly aneuploid zebrafish malignant peripheral nerve sheath tumors have genetic alterations similar to human cancers  

E-print Network

Aneuploidy is a hallmark of human cancers, but most mouse cancer models lack the extensive aneuploidy seen in many human tumors. The zebrafish is becoming an increasingly popular model for studying cancer. Here we report ...

Zhang, GuangJun

167

In vitro and in vivo radiosensitization induced by hydroxyapatite nanoparticles  

PubMed Central

Background Previous study showed that hydroxyapatite nanoparticles (nano-HAPs) inhibited glioma growth in vitro and in vivo; and in a drug combination, they could reduce adverse reactions. We investigated the possible enhancement of radiosensitivity induced by nano-HAPs. Methods In vitro radiosensitization of nano-HAPs was measured using a clonogenic survival assay in human glioblastoma U251 and breast tumor brain metastatic tumor MDA-MB-231BR cells. DNA damage and repair were measured using ?H2AX foci, and mitotic catastrophe was determined by immunostaining. The effect of nano-HAPs on in vivo tumor radiosensitivity was investigated in a subcutaneous and an orthotopic model. Results Nano-HAPs enhanced each cell line's radiosensitivity when the exposure was 1 h before irradiation, and they had no significant effect on irradiation-induced apoptosis or on the activation of the G2 cell cycle checkpoint. The number of ?H2AX foci per cell was significantly large at 24 h after the combination modality of nano-HAPs + irradiation compared with single treatments. Mitotic catastrophe was also significantly increased at an interval of 72 h in tumor cells receiving the combined modality compared with the individual treatments. In a subcutaneous model, nano-HAPs caused a larger than additive increase in tumor growth delay. In an orthotopic model, nano-HAPs significantly reduced tumor growth and extended the prolongation of survival induced by irradiation. Conclusions These results show that nano-HAPs can enhance the radiosensitivity of tumor cells in vitro and in vivo through the inhibition of DNA repair, resulting in an increase in mitotic catastrophe. PMID:23519742

Chu, Sheng-Hua; Karri, Surya; Ma, Yan-Bin; Feng, Dong-Fu; Li, Zhi-Qiang

2013-01-01

168

Activation of STAT3 is involved in malignancy mediated by CXCL12-CXCR4 signaling in human breast cancer.  

PubMed

The chemokine receptor CXCR4 and signal transducer and activator of transcription 3 (STAT3) play an important role in breast cancer malignancy and metastasis. However, it remains unknown whether STAT3 can be activated by CXCR4 in human breast cancer. The expression levels of CXCR4, STAT3 and p-STAT3 in 208 breast cancer tissues and 26 tumor-adjacent tissues were examined by immunohistochemistry. Flow cytometry, western blot analysis and immunoprecipitation were used to study activation of STAT3 by CXCL12-CXCR4 signaling in human breast cancer cell lines. The expression levels of CXCR4, STAT3 and p-STAT3 were higher in the breast cancer samples than these levels in the tumor-adjacent samples. The combined expression of CXCR4 and p-STAT3 was correlated with TNM stage, tumor size, lymph node metastasis and histological grade of breast cancer. In the breast cancer cells, CXCL12 treatment increased the expression of p-STAT3. The CXCR4 antagonist AMD3100 and the Janus kinase 2 (JAK2) antagonist AG490 inhibited the CXCL12-induced increase in the phosphorylation of STAT3. Furthermore, CXCL12 promoted direct binding of JAK2 to CXCR4. Our findings suggest that activation of the JAK2/STAT3 pathway via CXCL12-CXCR4 signaling plays an important role in breast cancer malignancy and metastasis. Targeting the CXCL12-CXCR4/JAK2/STAT3 signaling pathway may be a potential therapeutic strategy for the treatment of breast cancer. PMID:25310198

Liu, Xiaojian; Xiao, Qinghuan; Bai, Xuefeng; Yu, Zhaojin; Sun, Mingli; Zhao, Haishan; Mi, Xiaoyi; Wang, Enhua; Yao, Weifan; Jin, Feng; Zhao, Lin; Ren, Jie; Wei, Minjie

2014-12-01

169

Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors.  

PubMed

The brain is a specialized immune site representing a unique tumor microenvironment. The availability of fresh brain tumor material for ex vivo analysis is often limited because large parts of many brain tumors are resected using ultrasonic aspiration. We analyzed ultrasonic tumor aspirates as a biosource to study immune suppressive mechanisms in 83 human brain tumors. Lymphocyte infiltrates in brain tumor tissues and ultrasonic aspirates were comparable with respect to lymphocyte content and viability. Applying ultrasonic aspirates, we detected massive infiltration of CD4+FoxP3+CD25(high) CD127(low) regulatory T cells (Tregs) in glioblastomas (n = 29) and metastatic brain tumors (n = 20). No Treg accumulation was observed in benign tumors such as meningiomas (n = 10) and pituitary adenomas (n = 5). A significant Treg increase in blood was seen only in patients with metastatic brain tumors. Tregs in high-grade tumors exhibited an activated phenotype as indicated by decreased proliferation and elevated CTLA-4 and FoxP3 expression relative to blood Tregs. Functional analysis showed that the tumor-derived Tregs efficiently suppressed cytokine secretion and proliferation of autologous intratumoral lymphocytes. Most tumor-infiltrating Tregs were localized in close proximity to effector T cells, as visualized by immunohistochemistry. Furthermore, 61% of the malignant brain tumors expressed programmed death ligand-1 (PD-L1), while the inhibitory PD-1 receptor was expressed on CD4+ effector cells present in 26% of tumors. In conclusion, using ultrasonic tumor aspirates as a biosource we identified Tregs and the PD-L1/PD-1 pathway as immune suppressive mechanisms in malignant but not benign human brain tumors. PMID:19028999

Jacobs, Joannes F M; Idema, Albert J; Bol, Kalijn F; Nierkens, Stefan; Grauer, Oliver M; Wesseling, Pieter; Grotenhuis, J André; Hoogerbrugge, Peter M; de Vries, I Jolanda M; Adema, Gosse J

2009-08-01

170

L1CAM promotes enrichment of immunosuppressive T cells in human pancreatic cancer correlating with malignant progression.  

PubMed

Regulatory T cell (T-reg) enrichment in the tumor microenvironment is regarded as an important mechanism of tumor immune escape. Hence, the presence of T-regs in highly malignant pancreatic ductal adenocarcinoma (PDAC) is correlated with short survival. Likewise, the adhesion molecule L1CAM is upregulated during PDAC progression in the pancreatic ductal epithelium also being associated with poor prognosis. To investigate whether L1CAM contributes to enrichment of T-regs in PDAC, human CD4(+)CD25(+)CD127(-)CD49d(-) T-regs and CD4(+)CD25(-) T-effector cells (T-effs) were isolated by magnetic bead separation from blood of healthy donors. Their phenotype and functional behavior were analyzed in dependence on human premalignant (H6c7) or malignant (Panc1) pancreatic ductal epithelial cells, either exhibiting or lacking L1CAM expression. T cells derived from blood and tumors of PDAC patients were analyzed by flow cytometry and findings were correlated with clinical parameters. Predominantly T-regs but not T-effs showed an increased migration on L1CAM expressing H6c7 and Panc1 cells. Whereas proliferation of T-regs did not change in the presence of L1CAM, T-effs proliferated less, exhibited a decreased CD25 expression and an increased expression of CD69. Moreover, these T-effs exhibited a regulatory phenotype as they inhibited proliferation of autologous T cells. Accordingly, CD4(+)CD25(-)CD69(+) T cells were highly abundant in PDAC tissues compared to blood being associated with nodal invasion and higher grading in PDAC patients. Overall, these data point to an important role of L1CAM in the enrichment of immunosuppressive T cells in particular of a CD4(+)CD25(-)CD69(+)-phenotype in PDAC providing a novel mechanism of tumor immune escape which contributes to tumor progression. PMID:24746181

Grage-Griebenow, Evelin; Jerg, Elfi; Gorys, Artur; Wicklein, Daniel; Wesch, Daniela; Freitag-Wolf, Sandra; Goebel, Lisa; Vogel, Ilka; Becker, Thomas; Ebsen, Michael; Röcken, Christoph; Altevogt, Peter; Schumacher, Udo; Schäfer, Heiner; Sebens, Susanne

2014-07-01

171

Low-Dose Radiation Cataract and Genetic Determinants of Radiosensitivity  

SciTech Connect

The lens of the eye is one of the most radiosensitive tissues in the body. Ocular ionizing radiation exposure results in characteristic, dose related, progressive lens changes leading to cataract formation. While initial, early stages of lens opacification may not cause visual disability, the severity of such changes progressively increases with dose until vision is impaired and cataract extraction surgery may be required. Because of the transparency of the eye, radiation induced lens changes can easily be followed non-invasively over time. Thus, the lens provides a unique model system in which to study the effects of low dose ionizing radiation exposure in a complex, highly organized tissue. Despite this observation, considerable uncertainties remain surrounding the relationship between dose and risk of developing radiation cataract. For example, a growing number of human epidemiological findings suggest significant risk among various groups of occupationally and accidentally exposed individuals and confidence intervals that include zero dose. Nevertheless, questions remain concerning the relationship between lens opacities, visual disability, clinical cataract, threshold dose and/or the role of genetics in determining radiosensitivity. Experimentally, the response of the rodent eye to radiation is quite similar to that in humans and thus animal studies are well suited to examine the relationship between radiation exposure, genetic determinants of radiosensitivity and cataractogenesis. The current work has expanded our knowledge of the low-dose effects of X-irradiation or high-LET heavy ion exposure on timing and progression of radiation cataract and has provided new information on the genetic, molecular, biochemical and cell biological features which contribute to this pathology. Furthermore, findings have indicated that single and/or multiple haploinsufficiency for various genes involved in DNA repair and cell cycle checkpoint control, such as Atm, Brca1 or Rad9, influence cataract development and thus radiosensitivity. These observations have direct applicability to various human populations including accidentally exposed individuals, interventional medical workers, astronauts and nuclear plant workers.

Kleiman, Norman Jay [Columbia University] [Columbia University

2013-11-30

172

Monoclonal Antibody to HER2\\/neuReceptor Modulates Repair of Radiation induced DNA Damage and Enhances Radiosensitivity of Human Breast Cancer Cells Overexpressing This Oncogene1  

Microsoft Academic Search

The management of human breast cancer frequently includes radiation therapy as an important intervention, and improvement in the clinical efficacy of radiation is desirable. Overexpression of the HER-2 growth factor receptor occurs in 25-30% of human breast cancers and correlates with poor clinical outcome, including earlier local relapse following con- servative surgery accompanied by radiation therapy. In breast cancer cells

Richard J. Pietras; Joseph C. Poen; David Gallardo; P. Nancy Wongvipat; H. Julie Lee; Dennis J. Slamon

1999-01-01

173

Microwave-induced local hyperthermia in combination with radiotherapy of human malignant tumors  

SciTech Connect

Since 1976, two groups of patients have been treated with local microwave hyperthermia immediately following ionizing radiation. Group A patients had measurable multiple lesions assigned radiotherapy only, microwave hyperthermia only, or combined treatment. Ionizing radiation in 200 to 600 rad fractions was used 2 to 5 times per week to a total of 1800 to 4200 rad in 5 to 14 fractions. Group B patients had combination treatment only, with radiation fractions of 200 to 600 rad 2 to 5 times per week to a total of 200 to 4800 rad total in 6 to 20 fractions. Both groups received hyperthermia (42 to 44 C) 2 to 3 times per week, maximum ten sessions in four weeks. The 19 patients treated have had squamous cell carcinoma, adenocarcinoma, malignant melanoma, plasmacytoma, epithelioid sarcoma, and undifferentiated carcinoma. After more than 150 hyperthermia sessions, we find: (1) local hyperthermia with microwave alone or in combination with ionizing radiation can be used with excellent normal tissue tolerance provided local tissue temperatures are carefully monitored and controlled; (2) a higher level of heat induction in tumor tissue as compared to surrounding normal tissues; and (3) repeated hyperthermia at 42 to 43.5 C for 45 minutes per session immediately following photon irradiation yields a favorable therapeutic result, occasionally dramatic. Local microwave hyperthermia in combination withradiotherapy offers the possibility of substantial impact on clinical cancer therapy, whether of curative or palliative intent.

U, R.; Noell, K.T.; Woodward, K.T.; Worde, B.T.; Fishburn, R.I.; Miller, L.S.

1980-02-15

174

Antibody-based Therapeutics for the Treatment of Human B cell Malignancies  

PubMed Central

The dynamic expression of various phenotypic markers during B cell development not only defines the particular stage in ontogeny but also provides the necessary growth, differentiation, maturation and survival signals. When a B cell at any given stage becomes cancerous, these cell surface molecules, intracellular signaling molecules, and the over-expressed gene products become favorite targets for potential therapeutic intervention. Various adaptive and adoptive immunotherapeutic approaches induce T cell and antibody responses against cancer cells, and successful remission leading to minimal residual disease has been obtained. Nonetheless, subsequent relapse and development of resistant clones prompted further development and several novel strategies are evolving. Engineered monoclonal antibodies with high affinity and specificity to target antigens have been developed and used either alone or in combination with chemotherapeutic drugs. They are also used as vehicles to deliver cytotoxic drugs, toxins, or radio-nuclides that are either directly conjugated or encapsulated in liposomal vesicles. Likewise, genetically engineered T cells bearing chimeric antigen receptors are used to redirect cytotoxicity to antigen-positive target cells. This review describes recent advancements in some of these adoptive immunotherapeutic strategies targeting B cell malignancies. PMID:23229130

2013-01-01

175

Genetic and phenotypic heterogeneity of human malignancies: Finding order in chaos  

SciTech Connect

The presence of cellular heterogeneity within human tumors has been recognized for many years. Current concepts regarding the clonal origin of human neoplasms, and recent advances in the study of successive genetic changes that occur during tumor evolution may now make it possible to understand in greater depth the biological and clinical implications of intra-tumor heterogeneity at both the phenotypic and genotypic levels. In order to explore these concepts further, and to better identify the potential contributions that flow and image cytometry can make to our understanding of tumor heterogeneity, a session of the 1994 ISAC Congress was dedicated to plenary presentations on human cancer cell heterogeneity. Here, we provide a brief overview of the genetic evolutionary progression of human cancers, some considerations of clinically important phenotypic and genotypic markers, and an outline that might serve as a basis for framing relevant issues that are ammenable to further study. 21 refs., 1 fig.

Shackney, S.E. [Allegheny-Singer Research Institute, Pittsburgh, PA (United States); Shankey, T.V. [Loyola Univ. Medical Center, Maywood, IL (United States)]|[Edward J. Hines V.A. Hospital, Hines, IL (United States)

1995-09-01

176

Characterization of SWI/SNF protein expression in human breast cancer cell lines and other malignancies.  

PubMed

Organization of genomic DNA into chromatin aids in the regulation of gene expression by limiting access to transcriptional machinery. The SWI/SNF family of complexes, which are conserved from yeast to humans, are ATP-dependent chromatin-remodeling enzymes required for the transcription of a number of genes in yeast. In humans, the gene encoding the BAF47/hSNF5 subunit of the complex, located at 22q11.2, has been found to be mutated in a number of human tumors including rhabdoid, rhabdomyosarcoma, chronic myeloid leukemia, and CNS tumors such as medulloblastomas and choroid plexus carcinomas. In addition, loss of heterozygosity (LOH) has been reported for the BAF47 region in breast and liver cancer. LOH has also been reported in breast and ovarian cancer within 17q12-25, a gene-rich area including BRCA1, BAF60B, and BAF57. Interestingly, the gene encoding the BAF155/hSWI3 subunit of the complex maps to 3p21-p23, an area of chromosomal deletion seen in a number of human adenocarcinomas including breast, kidney, pancreas, and ovary. To look for abnormalities in these proteins as well as the SWI/SNF complex in general, we have determined the protein status of core human SWI/SNF components BAF170, BAF155, BAF57, BAF53a, and BAF47 in 21 breast cell lines. The complex status in other human tumor cell lines of various tissue types was also examined. We also determined the protein status of the human SWI2 homologues, hBRM/SWI2alpha and BRG1/SWI2beta as well as two other proteins found in human SWI/SNF complexes, BAF180 and BAF250. In this study, we identified the first cell line negative for the BAF57 protein as well as a pancreatic carcinoma cell line negative for both the BRG-1 and hBRM proteins. PMID:11147808

Decristofaro, M F; Betz, B L; Rorie, C J; Reisman, D N; Wang, W; Weissman, B E

2001-01-01

177

Deoxynucleotide-polymerizing Enzymes in Normal and Malignant Human Cells1  

Microsoft Academic Search

SUMMARY The cytoplasmic (175,000 x g supernatant) and the chromatin fractions from phytohemagglutinin-stimulated normal human lymphocytes, human thymus tissue, lympho cytes from chronic lymphocytic leukemia and acute lym- phoblastic leukemia patients and cultured cells of normal (RPMI 1788), multiple myeloma (RPMI 8226), Burkitt lymphoma (HR1K), and acute lymphoblastic leukemia (Molt-4) origin were examined for deoxynucleotide-polym- erizing enzymes by diethylaminoethyl cellulose

B. I. Sahai Srivastava

178

Differential expression of laminin 5 (alpha 3 beta 3 gamma 2) by human malignant and normal prostate.  

PubMed Central

Laminin 5 is an extracellular matrix protein integral to the formation of the hemidesmosomes that attach normal basal cells to the underlying basal lamina. We have shown that these hemidesmosomal complexes are lost in prostate carcinoma, possibly allowing malignant cells to detach from the anchoring structures and then to invade and migrate through the adjacent tissue. Our previous immunohistochemical studies of normal and malignant human prostate tissue demonstrated that the laminin subchains alpha 1, alpha 2, beta 1, beta 2, gamma 1, and gamma 2 were all expressed as normal components of the basal lamina surrounding prostate glands. Although most of these subchains were also expressed by the de novo basal lamina synthesized by prostate carcinoma, the gamma 2 subchain of laminin 5 was not detected. In an effort to investigate the role laminin 5 plays in the tumorigenesis of prostate carcinoma, the protein expression of the three subchains of laminin 5 (alpha 3, beta 3, and gamma 2) was compared in normal prostate, prostatic intraepithelial neoplasia, and invasive carcinoma using immunohistochemistry. The results showed that the protein for the alpha 3 subchain of laminin 5 is retained by both normal prostate epithelium and prostate carcinoma, but the beta 3 and the gamma 2 subchains were not detected in invasive carcinoma. Despite the absence of the gamma 2 protein, however, the carcinoma cells continued to express substantial amounts of the gamma 2 mRNA. Although it is unclear how the gene for the gamma 2 subchain of laminin 5 is regulated, results of this study suggest that there is a post-transcriptional defect in the expression of the gamma 2 subchain that occurs during the progression from a premalignant lesion to invasive carcinoma. As laminin 5 is a component of the anchoring filaments, the failure to express the gamma 2 subchain may contribute to the failure to form anchoring filaments and hemidesmosomes. This failure of hemidesmosome formation results in a less stable epithelial-stromal junction, which may allow malignant cells more potential to invade and spread through adjacent structures. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:8863681

Hao, J.; Yang, Y.; McDaniel, K. M.; Dalkin, B. L.; Cress, A. E.; Nagle, R. B.

1996-01-01

179

Role of androgen and vitamin D receptors in endothelial cells from benign and malignant human prostate  

PubMed Central

Forty years ago, Judah Folkman (Folkman. N Engl J Med 285: 1182–1186, 1971) proposed that tumor growth might be controlled by limiting formation of new blood vessels (angiogenesis) needed to supply a growing tumor with oxygen and nutrients. To this end, numerous “antiangiogenic” agents have been developed and tested for therapeutic efficacy in cancer patients, including prostate cancer (CaP) patients, with limited success. Despite the lack of clinical efficacy of lead anti-angiogenic therapeutics in CaP patients, recent published evidence continues to support the idea that prostate tumor vasculature provides a reasonable target for development of new therapeutics. Particularly relevant to antiangiogenic therapies targeted to the prostate is the observation that specific hormones can affect the survival and vascular function of prostate endothelial cells within normal and malignant prostate tissues. Here, we review the evidence demonstrating that both androgen(s) and vitamin D significantly impact the growth and survival of endothelial cells residing within prostate cancer and that systemic changes in circulating androgen or vitamin D drastically affect blood flow and vascularity of prostate tissue. Furthermore, recent evidence will be discussed about the expression of the receptors for both androgen and vitamin D in prostate endothelial cells that argues for direct effects of these hormone-activated receptors on the biology of endothelial cells. Based on this literature, we propose that prostate tumor vasculature represents an unexplored target for modulation of tumor growth. A better understanding of androgen and vitamin D effects on prostate endothelial cells will support development of more effective angiogenesis-targeting therapeutics for CaP patients. PMID:23548616

Chung, Ivy; Montecinos, Viviana P.; Buttyan, Ralph; Johnson, Candace S.; Smith, Gary J.

2013-01-01

180

Photoacoustic Tomography of Human Hepatic Malignancies Using Intraoperative Indocyanine Green Fluorescence Imaging  

PubMed Central

Recently, fluorescence imaging following the preoperative intravenous injection of indocyanine green has been used in clinical settings to identify hepatic malignancies during surgery. The aim of this study was to evaluate the ability of photoacoustic tomography using indocyanine green as a contrast agent to produce representative fluorescence images of hepatic tumors by visualizing the spatial distribution of indocyanine green on ultrasonographic images. Indocyanine green (0.5 mg/kg, intravenous) was preoperatively administered to 9 patients undergoing hepatectomy. Intraoperatively, photoacoustic tomography was performed on the surface of the resected hepatic specimens (n?=?10) under excitation with an 800 nm pulse laser. In 4 hepatocellular carcinoma nodules, photoacoustic imaging identified indocyanine green accumulation in the cancerous tissue. In contrast, in one hepatocellular carcinoma nodule and five adenocarcinoma foci (one intrahepatic cholangiocarcinoma and 4 colorectal liver metastases), photoacoustic imaging delineated indocyanine green accumulation not in the cancerous tissue but rather in the peri-cancerous hepatic parenchyma. Although photoacoustic tomography enabled to visualize spatial distribution of ICG on ultrasonographic images, which was consistent with fluorescence images on cut surfaces of the resected specimens, photoacoustic signals of ICG-containing tissues decreased approximately by 40% even at 4 mm depth from liver surfaces. Photoacoustic tomography using indocyanine green also failed to identify any hepatocellular carcinoma nodules from the body surface of model mice with non-alcoholic steatohepatitis. In conclusion, photoacoustic tomography has a potential to enhance cancer detectability and differential diagnosis by ultrasonographic examinations and intraoperative fluorescence imaging through visualization of stasis of bile-excreting imaging agents in and/or around hepatic tumors. However, further technical advances are needed to improve the visibility of photoacoustic signals emitted from deeply-located lesions. PMID:25379674

Miyata, Akinori; Ishizawa, Takeaki; Kamiya, Mako; Shimizu, Atsushi; Kaneko, Junichi; Ijichi, Hideaki; Shibahara, Junji; Fukayama, Masashi; Midorikawa, Yutaka; Urano, Yasuteru; Kokudo, Norihiro

2014-01-01

181

Study of immortalization and malignant transformation of human embryonic esophageal epithelial cells induced by HPV18 E6E7.  

PubMed

In order to study the effect of viruses and tumor promoters on the tumorigenicity of the esophagus, human embryonic esophageal epithelial cells were infected with human papilloma virus HPV18 E6E7-AAV in synergy with 12-O-tetradecanoylphorbol 13-acetate (TPA) to observe their malignant transformation. The cultured esophageal epithelial cells incubated with HPV18 E6E7-AAV were divided into two groups: the SHEEC1 group was exposed to TPA (5 ng/ml) for 4 weeks at the 5th passage of the cells; the SHEE group served as the control and was cultured in the same medium without TPA. The morphological phenotype, the DNA content during the cell cycle and the chromosomes were analyzed. The tumorigenicity was assessed by colony formation after cultivation in soft agar and transplanting the cells into nude mice. HPV18 E6E7 DNA was assayed by fluorescent in situ hybridization (FISH) and the polymerase chain reaction (PCR). The SHEE group, at its 20th passage, grew as a monolayer with the cells showing anchorage dependence and contact inhibition. The chromosome analysis showed diploidy, and soft-agar cultivation and injection into nude mice showed the cells to be non-tumorigenic. They were therefore immortalized cells. In contrast, the SHEEC1 group (TPA group) showed increased DNA synthesis and a proliferative index that was higher (45%) than that of the SHEE group (34%). The number of large colonies of dense multilayer cells (positively transformed foci) in soft agar was high in SHEEC1 group (4.0%) but low in the SHEE group (0.1%). Tumors resulting from transplantation were observed in all six nude mice injected subcutaneously with cells of the SHEEC1 group but no tumor developed in mice receiving cells of the SHEE group. In both groups of cells, HPV18 E6E7 DNA was positively detected by FISH and PCR. The malignant transformation of human embryonic epithelial cells was induced in vitro by HPV18 E6E7 in synergy with TPA. This is a good evidence for the close relationship between HPV and the etiology and pathogenicity of esophageal carcinoma. It is also a reliable model for studying the cellular and molecular mechanisms of carcinogenesis of esophageal carcinoma. PMID:11043396

Shen, Z; Cen, S; Shen, J; Cai, W; Xu, J; Teng, Z; Hu, Z; Zeng, Y

2000-10-01

182

The Tumor-Educated-Macrophage Increase of Malignancy of Human Pancreatic Cancer Is Prevented by Zoledronic Acid  

PubMed Central

We previously defined macrophages harvested from the peritoneal cavity of nude mice with subcutaneous human pancreatic tumors as “tumor-educated-macrophages” (Edu) and macrophages harvested from mice without tumors as “naïve-macrophages” (Naïve), and demonstrated that Edu-macrophages promoted tumor growth and metastasis. In this study, Edu- and Naïve-macrophages were compared for their ability to enhance pancreatic cancer malignancy at the cellular level in vitro and in vivo. The inhibitory efficacy of Zoledronic acid (ZA) on Edu-macrophage-enhanced metastasis was also determined. XPA1 human pancreatic cancer cells in Gelfoam co-cultured with Edu-macrophages proliferated to a greater extent compared to XPA1 cells cultured with Naïve-macrophages (P?=?0.014). XPA1 cells exposed to conditioned medium harvested from Edu culture significantly increased proliferation (P?=?0.016) and had more migration stimulation capability (P<0.001) compared to cultured cancer cells treated with the conditioned medium from Naïve. The mitotic index of the XPA1 cells, expressing GFP in the nucleus and RFP in the cytoplasm, significantly increased in vivo in the presence of Edu- compared to Naïve-macrophages (P?=?0.001). Zoledronic acid (ZA) killed both Edu and Naïve in vitro. Edu promoted tumor growth and metastasis in an orthotopic mouse model of the XPA1 human pancreatic cancer cell line. ZA reduced primary tumor growth (P?=?0.006) and prevented metastasis (P?=?0.025) promoted by Edu-macrophages. These results indicate that ZA inhibits enhanced primary tumor growth and metastasis of human pancreatic cancer induced by Edu-macrophages. PMID:25116261

Hiroshima, Yukihiko; Maawy, Ali; Hassanein, Mohamed K.; Menen, Rhiana; Momiyama, Masashi; Murakami, Takashi; Miwa, Shinji; Yamamoto, Mako; Uehara, Fuminari; Yano, Shuya; Mori, Ryutaro; Matsuyama, Ryusei; Chishima, Takashi; Tanaka, Kuniya; Ichikawa, Yasushi; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M.

2014-01-01

183

Loss of the malignant phenotype of human neuroblastoma cells by a catalytically inactive dominant-negative hTERT mutant.  

PubMed

Telomerase, a ribonucleoprotein complex mainly composed of the reverse transcriptase catalytic subunit (human telomerase reverse transcriptase, hTERT) and the RNA component (hTR), is a key enzyme of cancer progression. That aggressive stage 4-neuroblastoma expressed high levels of telomerase activity, whereas favorable tumors had no or little telomerase expression and activity, prompted us to investigate the role of this enzyme in this tumor model of altered proliferation, neuronal differentiation, and apoptosis. A human MYCN-amplified neuroblastoma cell line (IGR-N-91) was engineered to stably express either the normal hTERT protein (WT-hTERT) or a catalytically inactive dominant-negative mutant of this protein (DN-hTERT). We showed that DN-hTERT expression inhibited the endogenous hTERT in the malignant neuroblasts without telomere shortening nor loss of in vitro proliferative capacity. Importantly, DN-hTERT expression induced major changes in cell morphology of neuroblasts that switched them from a neuronal to a substrate adherent phenotype, which was more prone to apoptosis and lost their tumorigenic properties in nude mice. These biologic effects arose from modifications in the expression of genes involved in both apoptosis and neuroblastoma biology. Taken together these results highlighted the functional relevance of noncanonical functions of hTERT in the determination of neuroblast cell fate. Therefore, our results envision new therapeutic strategies for metastatic neuroblastoma therapeutic management. PMID:22933702

Samy, Mona; Gattolliat, Charles-Henry; Pendino, Frédéric; Hillion, Josette; Nguyen, Eric; Bombard, Sophie; Douc-Rasy, Sétha; Bénard, Jean; Ségal-Bendirdjian, Evelyne

2012-11-01

184

Do Epidermodysplasia Verruciformis Human Papillomaviruses Contribute to Malignant and Benign Epidermal Proliferations?  

Microsoft Academic Search

he aim of this review is to present new data on epidermodysplasia verruciformis (EV) and EV human papillomaviruses (HPVs), regarded previously as specific to the disease. Re- cently introduced highly sensitive molecular methods for virologic studies allow detec- tion of EV HPVs in non-EV populations. In this article, we present the most recent find- ings on EV and EV HPVs,

Slawomir Majewski; Stefania Jablonska

2002-01-01

185

Survivin 2?: a novel Survivin splice variant expressed in human malignancies  

Microsoft Academic Search

BACKGROUND: Survivin and its alternative splice forms are involved in critical cellular processes, including cell division and programmed cell death. Survivin is expressed in the majority of human cancers, but minimally in differentiated normal tissues. Expression levels correlate with tumor aggressiveness and resistance to therapy. RESULTS: In the present study, we identify and characterize a novel survivin isoform that we

Hugo Caldas; Laura E Honsey; Rachel A Altura

2005-01-01

186

Basic and clinical aspects of malignant melanoma  

SciTech Connect

This book contains the following 10 chapters: The role of oncogenes in the pathogenesis of malignant melanoma; Laminin and fibronectin modulate the metastatic activity of melanoma cells; Structure, function and biosynthesis of ganglioside antigens associated with human tumors derived from the neuroectoderm; Epidemiology of ocular melanoma; Malignant melanoma: Prognostic factors; Endocrine influences on the natural history of human malignant melanoma; Psychosocial factors associated with prognostic indicators, progression, psychophysiology, and tumor-host response in cutaneous malignant melanoma; Central nervous system metastases in malignant melanoma; Interferon trials in the management of malignant melanoma and other neoplasms: an overview; and The treatment of malignant melanoma by fast neutrons.

Nathanson, L. (Health Sciences Center, State Univ. of New York at Stony Brook, Stony Brook, NY (US))

1987-01-01

187

Anticancer Activity of ?-Elemene and its Synthetic Analogs in Human Malignant Brain Tumor Cells  

PubMed Central

Malignant brain tumors are aggressive in both children and adults. Despite recent improvements in diagnostic techniques, therapeutic approaches remain disappointing and unsuccessful. There is an urgent need for promising anticancer agents to improve overall survival of patients with brain cancer. ?-Elemene has been shown to have antiproliferative effects on many types of carcinomas. In this study, we compared the cytotoxic efficacy of ?-elemene and its synthetic analogs in the brain tumor cell lines A172, CCF-STTG1, and U-87MG. ?-Elemene exhibited cytotoxicity towards the tumor lines, effectively suppressing tumor cell survival. The inhibitory effect of ?-elemene was mediated by the induction of apoptosis, as demonstrated by three assays. The annexin V assay showed that ?-elemene increased the percentage of early- and late-apoptotic cells. Apoptotic nuclei were detected in cancer cells in situ by the terminal deoxynucleotidyltransferase-mediated deoxy-UTP-fluorescein nick end labeling (TUNEL) staining, and the number of TUNEL-positive cells was significantly increased at 24–72 h following drug treatment of the cell lines. Cell death enzyme-linked immunosorbent assay (ELISA) gave similar results. Furthermore, ?-elemene increased caspase-3/7/10 activity, up-regulated protein expression of BAX, and down-regulated the one of BCL-2, BCL-XL, and of X-linked inhibitor of apoptosis (XIAP) in the cells, suggesting that apoptotic signaling pathways are involved in the responses triggered by ?-elemene. Compared with ?-elemene, only three of the 10 synthetic ?-elemene analogs studied here, exerted comparable cytotoxic efficacy towards the three brain tumor lines: the analogs Lr-1 and Lr-2 had the same antitumor efficacy, while Lr-3 was less potent than ?-elemene. Thus, some synthetic analogs of ?-elemene may inhibit brain cancer cell growth and proliferation, and the synthetic analogs Lr-1 and Lr-2 may have great potential as alternatives to ?-elemene for anticancer therapy. Overall, this study provides, to our knowledge, the first evidence showing that synthetic analogs of ?-elemene hold promise for patients with brain tumors. PMID:23267129

LI, QINGDI QUENTIN; LEE, REBECCA X.; LIANG, HUASHENG; ZHONG, YUHUA

2013-01-01

188

Repair of chromosome damage induced by X-irradiation during G/sub 2/ phase in a line of normal human fibroblasts and its malignant derivative  

SciTech Connect

A line of normal human skin fibroblasts (KD) differed from its malignant derivative (HUT-14) in the extent of cytogenetic damage induced by X-irradiation during G/sub 2/ phase. Malignant cells had significantly more chromatid breaks and gaps after exposure to 25, 50, or 100 rad. Results from alkaline elution of cellular DNA immediately after irradiation showed that the normal and malignant cells in asynchronous population were equally sensitive to DNA single-strand breakage by X-irradiation. Caffeine or ..beta..-cytosine arabinoside (ara-C), inhibitors of DNA repair, when added directly following G/sub 2/ phase exposure, significantly increased the incidence of radiation-induced chromatid damage in the normal cells. In contrast, similar treatment of the malignant cells had little influence. Ara-C differed from caffeine in its effects; whereas both agents increased the frequency of chromatid breaks and gaps, only ara-C increased the frequency of gaps to the level observed in the irradiated malignant cells. Addition of catalase, which destroys H/sub 2/O/sub 2/, or mannitol, a scavenger of the derivative free hydroxyl radical (.OH), to the cultures of malignant cells before, during, and following irradiation significantly reduced the chromatid damage; and catalase prevented formation of chromatid gaps. The DNA damage induced by X-ray during G/sub 2/ phase in the normal KD cells was apparently repaired by a caffeine- and ara-C-sensitive mechanism(s) that was deficient or absent in their malignant derivatives.

Parshad, R. (Howard Univ. College of Medicine, Washington, DC); Gantt, R.; Sanford, K.K.; Jones, G.M.; Tarone, R.E.

1982-08-01

189

Alterations in expression of specific microRNAs by combination of 4-HPR and EGCG inhibited growth of human malignant neuroblastoma cells  

PubMed Central

Malignant neuroblastomas are childhood tumors that remain mostly incurable. We explored efficacy of N-(4-hydroxyphenyl) retinamide (4-HPR) and (?)-epigallocatechin-3-gallate (EGCG) in altering expression of oncogenic microRNAs (OGmiRs) and tumor suppressor miRs (TSmiRs) for controlling growth of human malignant neuroblastoma SK-N-BE2 and IMR-32 cells. Combination of 4-HPR and EGCG most significantly decreased expression of OGmiRs (miR-92, miR-93, and miR-106b) and increased expression of TSmiRs (miR-7-1, miR-34a, and miR-99a) in both cell lines. Overexpression of miR-93 and miR-7-1, respectively, decreased and increased efficacy of treatments. Thus, alterations in expression of specific OGmiRs and TSmiRs by 4-HPR and EGCG inhibited growth of malignant neuroblastomas. PMID:22498172

Chakrabarti, Mrinmay; Khandkar, Mehrab; Banik, Naren L.; Ray, Swapan K.

2012-01-01

190

E-Cadherin in human brain tumours: loss of immunoreactivity in malignant meningiomas  

Microsoft Academic Search

Cadherins are a family of glycoproteins that are associated with cell adhesion mechanisms. They are divided into subclasses.\\u000a The E- and P-cadherins are regarded as the epithelial subtype. Their expression has been demonstrated in many different carcinoma\\u000a types. Using immunomorphological techniques, we studied the expression of E-cadherin in a series of 145 human brain tumours\\u000a with the monoclonal antibody 5H9.

K. Schwechheimer; Lepu Zhou; Walter Birchmeier

1998-01-01

191

The Physical State of Human Papillomavirus Type 16 DNA in Benign and Malignant Genital Tumours  

Microsoft Academic Search

SUMMARY Cloned DNA from human papillomavirus (HPV) type 16 was subjected to restriction enzyme analysis. A genome size of 7.8 + 0.1 kb was determined and restriction maps were prepared. Fragments of HPV 16 DNA were nick-translated and hybridized with fragments of HPV 6b DNA. The two genomes appeared to be colinear. The physical state of HPV 16 DNA in

MATTHIAS DURST; ANDREAS KLEINHEINZ; MARLIES HOTZ; LUTZ GISSMANN

1985-01-01

192

Radiosensitization Effect of STI-571 on Pancreatic Cancer Cells In Vitro  

SciTech Connect

Purpose: To examine STI-571-induced radiosensitivity in human pancreatic cancer cells in vitro. Methods and Materials: Three human pancreatic cancer cell lines (Bxpc-3, Capan-1, and MiaPaCa-2) exhibiting different expression levels of c-Kit and platelet-derived growth factor receptor beta (PDGFRbeta) and showing different K-ras mutation types were used. For evaluation of the antitumor activity of STI-571 in combination with radiation, clonogenic survival assays, Western blot analysis, and the annexin V/propidium iodide assay with microscopic evaluation by 4',6-diamidino-2-phenylindole were conducted. Results: Dramatic phosphorylated (p)-c-Kit and p-PDGFRbeta attenuation, a modest dose- and time-dependent growth inhibition, and significant radiosensitization were observed after STI-571 treatment in view of apoptosis, although the levels of growth inhibition and increased radiosensitization were different according to cell lines. The grades of radiosensitivity corresponded to the attenuation levels of p-c-Kit and p-PDGFRbeta by STI-571, particularly to those of p-c-Kit, and the radiosensitivity was partially affected by K-ras mutation in pancreatic cancer cells. Among downstream pathways associated with c-Kit or PDGFRbeta, p-PLCgamma was more closely related to radiosensitivity compared with p-Akt1 or p-extracellular signal-regulated kinase 1. Conclusion: STI-571 enhances radiation response in pancreatic cancer cells. This effect is affected by the attenuation levels of p-c-Kit or p-PDGFRbeta, and K-ras mutation status. Among them, p-c-Kit plays more important roles in the radiosensitivity in pancreatic cancer compared with p-PDGFRbeta or K-ras mutation status.

Chung, Hye Won [Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Wen, Jing [Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul (Korea, Republic of); Lim, Jong-Baeck [Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Bang, Seung Min; Park, Seung Woo [Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Song, Si Young, E-mail: sysong@yuhs.a [Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul (Korea, Republic of); Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul (Korea, Republic of)

2009-11-01

193

Role of the human papilloma virus in the development of cervical intraepithelial neoplasia and malignancy  

PubMed Central

Human papilloma virus (HPV) is a public health problem as a sexually transmitted disease and as a critical factor in the pathogenesis of various cancers. The clinical manifestations, epidemiology, and virology that are critical to understanding the process of cervical dysplasia and neoplasia are reviewed. A discussion of the cervical transformation zone and the classification of cervical dysplasia and neoplasia leads into the importance of the Papanicolaou smear in prevention of potentially devastating sequelae of this virus. The role of the immune system in the progression of the disease and how it relates to vaccines, as well as treatment and prevention of HPV, are reviewed. PMID:11930025

Jastreboff, A; Cymet, T

2002-01-01

194

Transplantable malignant melanoma in LT.B6 congenic mice resembling pigmented epithelioid melanocytoma in humans  

PubMed Central

Genetically engineered mouse models have been generated to recapitulate major signaling pathways deregulated in melanoma. Although these models are invaluable to delineate the relationship between gene mutations and targeted therapeutics, no spontaneously occurring melanomas are available in laboratory mice, which might be used to discover novel disrupted pathways, other than the widely studied MAPK, PI3-AKT and CDK4-INK4A-RB1. We report multiple spontaneously occurring melanomas on the tail of LT.B6 congenic strain, commonly used to study spontaneous ovarian teratomas. We present the evidence of spontaneous mouse melanoma and successful transplantation into 2 out of 2 mice, thereby enabling a complete histopathologic and clinical characterization. The histopathology of LT.B6 melanomas remarkably resembled a human melanoma subtype, pigmented epithelioid melanocytoma (PEM); and their clinical behavior was similar in indolent growth, metastasis to local lymph nodes and lack of liver metastasis. Lung metastasis was unique in the mice. Using qRT-PCR, we detected the expression of two melanocyte specific genes, Tyrp1 and Mitf, in the transplanted primary tumors and nodal metastases but not liver, confirming the histopathology. This mouse model closely resembled a low-grade variant of human melanoma and could provide the opportunity to globally investigate the genetic and epigenetic alterations associated with metastasis. PMID:24476622

Dadras, Soheil S; Silva, Kathleen A.; King, Lloyd E.; Sundberg, John P.

2014-01-01

195

Radiosensitizing Effects of Ectopic miR-101 on Non-Small-Cell Lung Cancer Cells Depend on the Endogenous miR-101 Level  

SciTech Connect

Purpose: Previously, we showed that ectopic miR-101 could sensitize human tumor cells to radiation by targeting ATM and DNA-PK catalytic subunit (DNA-PKcs) to inhibit DNA repair, as the endogenous miR-101 levels are low in tumors in general. However, the heterogeneity of human cancers may result in an exception. The purpose of this study was to test the hypothesis that a few tumor cell lines with a high level of endogenous miR-101 would prove less response to ectopic miR-101. Methods and Materials: Fourteeen non-small-cell lung cancer (NSCLC) cell lines and one immortalized non-malignant lung epithelial cell line (NL20) were used for comparing endogenous miR-101 levels by real-time reverse transcription-polymerase chain reaction. Based on the different miR-101 levels, four cell lines with different miR-101 levels were chosen for transfection with a green fluorescent protein-lentiviral plasmid encoding miR-101. The target protein levels were measured by using Western blotting. The radiosensitizing effects of ectopic miR-101 on these NSCLC cell lines were determined by a clonogenic assay and xenograft mouse model. Results: The endogenous miR-101 level was similar or lower in 13 NSCLC cell lines but was 11-fold higher in one cell line (H157) than in NL20 cells. Although ectopic miR-101 efficiently decreased the ATM and DNA-PKcs levels and increased the radiosensitization level in H1299, H1975, and A549 cells, it did not change the levels of the miR-101 targets or radiosensitivity in H157 cells. Similar results were observed in xenograft mice. Conclusions: A small number of NSCLC cell lines could have a high level of endogenous miR-101. The ectopic miR-101 was able to radiosensitize most NSCLC cells, except for the NSCLC cell lines that had a much higher endogenous miR-101 level. These results suggest that when we choose one miRNA as a therapeutic tool, the endogenous level of the miRNA in each tumor should be considered.

Chen, Susie; Wang Hongyan; Ng, Wooi Loon; Curran, Walter J. [Department of Radiation Oncology, School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, GA (United States); Wang Ya, E-mail: ywang94@emory.edu [Department of Radiation Oncology, School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, GA (United States)

2011-12-01

196

Human papillomavirus type 16 DNA-induced malignant transformation of NIH 3T3 cells  

SciTech Connect

A biological function for human papillomavirus 16 (HPV 16) DNA was demonstrated by transformation of NIH 3T3 cells. HPV 16 DNA has been found frequently in genital cancer and has been classified as a papillomavirus on the basis of DNA homology. A recombinant HPV 16 DNA (pSHPV16d), which contains a head-to-tail dimer of the full-length HPV 16 genome, induced morphologic transformation; the transformed cells were tumorigenic in nude mice. Expression of transforming activity was unique because of the long latency period (more than 4 weeks) required for induction of morphologic transformation and because the transfected DNA existed primarily in a multimeric form with some rearrangement. Furthermore, virus-specific RNAs were expressed in the transformants. The transformation of NIH 3T3 cells provides a model for analyzing the functions of HPV 16, which is associated with cervical carcinomas.

Yasumoto, S.; Burkhardt, A.L.; Doniger, J.; DiPaolo, J.A.

1986-02-01

197

Estimation of the epidemiological burden of human papillomavirus-related cancers and non-malignant diseases in men in Europe: a review  

PubMed Central

Background The role of human papillomavirus (HPV) in malignant and non-malignant genital diseases in women is well known and the corresponding epidemiological burden has been widely described. However, less is known about the role of HPV in anal, penile and head and neck cancer, and the burden of malignant and non-malignant HPV-related diseases in men. The objective of this review is to estimate the epidemiological burden of HPV-related cancers and non-malignant diseases in men in Europe. Methods The annual number of new HPV-related cancers in men in Europe was estimated using Eurostat population data and applying cancer incidence rates published by the International Agency for Research on Cancer. The number of cancer cases attributable to HPV, and specifically to HPV16/18, was calculated based on the most relevant prevalence estimates. The annual number of new cases of genital warts was calculated from the most robust European studies; and latest HPV6/11 prevalence estimates were then applied. A literature review was also performed to retrieve exhaustive data on HPV infection at all anatomical sites under study, as well as incidence and prevalence of external genital warts, recurrent respiratory papillomatosis and HPV-related cancer trends in men in Europe. Results A total of 72, 694 new cancer cases at HPV-related anatomical sites were estimated to occur each year in men in Europe. 17,403 of these cancer cases could be attributable to HPV, with 15,497 of them specifically attributable to HPV16/18. In addition, between 286,682 and 325,722 new cases of genital warts attributable to HPV6/11were estimated to occur annually in men in Europe. Conclusions The overall estimated epidemiological burden of HPV-related cancers and non-malignant diseases is high in men in Europe. Approximately 30% of all new cancer cases attributable to HPV16/18 that occur yearly in Europe were estimated to occur in men. As in women, the vast majority of HPV-positive cancer in men is related to HPV16/18, while almost all HPV-related non-malignant diseases are due to HPV6/11. A substantial number of these malignant and non-malignant diseases may potentially be prevented by quadrivalent HPV vaccination. PMID:22260541

2012-01-01

198

Radiosensitization produced in vivo by once- vs. twice-weekly 2?2?-difluoro-2?-deoxycytidine (gemcitabine)  

Microsoft Academic Search

Purpose: Gemcitabine (2?2?-difluoro-2?-deoxycytidine, dFdCyd) is a potent radiosensitizer of rodent and human tumor cells. Our Phase I clinical trial using once-weekly dFdCyd as a radiosensitizer in the treatment of patients with Stage IV squamous cell head and neck cancer has produced a high rate of tumor response and significant normal mucosal toxicity. These findings raised the question of whether we

Marc T Fields; Avraham Eisbruch; Daniel Normolle; Anas Orfali; Mary A Davis; Anthony T Pu; Theodore S Lawrence

2000-01-01

199

Malignant transformation of an infinite life span human fibroblast cell strain by transfection with v-Ki-ras.  

PubMed

To determine if human fibroblasts can be transformed into malignant cells by transfection of a K-ras oncogene, we transfected the provirus of Kirsten murine sarcoma virus (v-Ki-ras) into an infinite life span human cell strain, MSU-1.1, which has a normal morphology, is not anchorage independent, and has a stable, near-diploid karyotype. The transfected populations gave rise to distinct foci composed of morphologically-altered cells. The cells from several independent foci were isolated, propagated, and assayed for anchorage independence and/or tumorigenicity. They formed large-sized colonies in soft agar at a high frequency. Cell strains derived from colonies isolated from agar as well as focus-derived cell strains were injected subcutaneously into athymic mice to test for tumorigenicity. One cell strain yielded myxoid fibromas, the rest produced well-differentiated, progressively-growing, invasive, myxoid or spindle cell sarcomas. The karyotype of each of the cell strains tested, including cell strains derived from tumors, was identical to that of non-transfected MSU-1.1 cells. Two focus-derived strains, and two cell strains derived from sarcomas produced from them, were tested and shown by DNA and RNA hybridization to contain and express the v-Ki-ras oncogene. Radioimmunoprecipitation analysis showed that these strains expressed ras-specific p21 products not found in non-transfected MSU.1.1 cells. When injected intraperitoneally, a cell strain derived from a myxoid tumor gave rise to invasive myxoid tumors at various sites in the body. The same cell strain gave rise to invasive spindle cell sarcomas when injected into the tail vein of the animals. PMID:2216465

Fry, D G; Milam, L D; Dillberger, J E; Maher, V M; McCormick, J J

1990-09-01

200

Argon laser phototherapy of human malignancies using rhodamine-123 as a new laser dye: The intracellular role of oxygen  

SciTech Connect

Recent studies demonstrated that the cationic, mitochondrial-specific dye Rhodamine-123 (Rh-123), is an efficient tumor photosensitizer for Argon laser treatment of human cancer cells both in vitro and in tumors grown as xenografts in athymic mice. To demonstrate the photodynamic mechanism of action of this reaction, the intracellular role of oxygen and temperature changes in treated cells have to be defined. In the current study, a large panel of human tumor cell lines of diverse histologic origin were tested for in vitro sensitivity to Rh-123 and the Argon laser (514.5 nm) in oxygen, deuterium oxide (D2O), and nitrogen (N2) environment. Tumor cells in suspension were first sensitized to Rh-123 (1 or 20 micrograms/ml for 1 hour), cooled on ice to 4 degrees C, and then exposed to the Argon laser (delta T = 14 +/- 1 degree C). Cell proliferation measured by (3H)-thymidine uptake 24 hours after sensitization with Rh-123 and laser treatment was significantly decreased in tumor cells kept in oxygen and D2O atmospheres. No decrease in DNA synthesis was seen in Rh-123 and laser treated cells kept in an N2 environment. Control tumor cells treated with Rh-123 or the Argon laser separately did not show any decreased (3H)-thymidine uptake in oxygen, D2O or N2 environment. These results provide evidence of a photodynamic process since Rh-123 sensitization and Argon laser activation occur at nonthermal levels of energy and are oxygen dependent. The high effectiveness of this technique of photodynamic therapy with the Argon laser, and low toxicity of Rh-123 could make its clinical use very attractive for the treatment of superficial malignancies.

Castro, D.J.; Saxton, R.E.; Markley, J.; Foote, C.S.; Fetterman, H.R.; Castro, D.J.; Ward, P.H. (Univ. of California, Los Angeles (USA))

1990-08-01

201

A pilot study of combination intraperitoneal recombinant human endostatin and chemotherapy for refractory malignant ascites secondary to ovarian cancer.  

PubMed

The management of refractory malignant ascites (MA) due to ovarian cancer (OC) remains a difficult clinical problem. A total of 23 eligible patients with refractory MA due to OC were treated with combined intraperitoneal therapy repeated 4 weeks, which consisted of paclitaxel 100 mg m(-2) (over 3 h) on day 1, 5-FU 600 mg m(-2) on day 1-3 followed by recombinant human endostatin 60 mg on day 4. The objective response rate was 60.9 % (14/23). The median time to progression and overall survival was 5.8 and 12.9 months, respectively. Treatment-related toxicities were uncommon and manageable without therapy-associated deaths. The mean Karnofsky performance status score was significantly improved from 60.0 ± 1.89 at enrollment to 70.0 ± 2.59 at 2 weeks after the first cycle of therapy (P = 0.000). Moreover, the mean score of overall ascites-associated symptoms was also increased significantly from 5.1 ± 0.32 to 4.0 ± 0.20 (P = 0.002). There were remarkable improvements in 7 out of 9 individual ascites-associated symptoms including well being, anxiety, abdominal distention, vomiting, anorexia, fatigue, and dyspnea as well (all P < 0.05). These results suggest that combination intraperitoneal recombinant human endostatin and chemotherapy is effective and safe in patients with refractory MA secondary to OC and significantly improves patients' quality of life with encouraging survival, which might highlight more effective treatment for this challenging disease and merits further investigation. PMID:24659268

Zhao, Jing; Chen, Xinxiao; Zhang, Aimu; Xu, Feng; Hu, Meilong; Xie, Congying; Xue, Shengliu

2014-04-01

202

BRCA1 modulates malignant cell behavior, the expression of survivin and chemosensitivity in human breast cancer cells.  

PubMed

BRCA1 is a multifunctional tumor-suppressive protein. Many functional aspects of BRCA1 are not fully understood. We used a shRNA approach to probe the function of BRCA1 in human breast cancer cells. Knocking down BRCA1 expression by shRNA in the wild-type BRCA1 human breast cancer MCF-7 and MDA-MB-231 cells resulted in an increase in cell proliferation, anchorage-independent growth, cell migration, invasion and a loss of p21/Waf1 and p27Kip1 expression. In BRCA1 knocked-down cells, the expression of survivin was significantly up regulated with a concurrent decrease in cellular sensitivity to paclitaxel. We also found that cells harboring endogenous mutant or defective BRCA1 (MDA-MB-436 and HCC1937) were highly proliferative and expressed a relatively low level of p21/Waf1 and p27Kip1 by comparison to wild-type BRCA1 cells. Cells harboring mutated BRCA1 also expressed a high level of survivin and were relatively resistant to paclitaxel by comparison to wild-type cells. Increase resistance to paclitaxel was due to an increase in the expression of survivin in both the BRCA1 knocked-down and mutant BRCA1 cells because knocking down survivin expression by siRNA restored sensitivity to paclitaxel. We conclude that BRCA1 down-modulates the malignant behavior of breast cancer cells, promotes the expression of p21/Waf1, p27Kip1 and inhibits the expression of survivin. Moreover, loss of BRCA1 expression or function leads to an increase in survivin expression and a reduction in chemosensitivity to paclitaxel. PMID:19551867

Promkan, Moltira; Liu, Guangming; Patmasiriwat, Pimpicha; Chakrabarty, Subhas

2009-12-15

203

Malignant mesothelioma  

Microsoft Academic Search

Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10–20 years. Pleural

Alastair J Moore; Robert J Parker; John Wiggins

2008-01-01

204

Wnt interaction and extracellular release of prominin-1/CD133 in human malignant melanoma cells.  

PubMed

Prominin-1 (CD133) is the first identified gene of a novel class of pentaspan membrane glycoproteins. It is expressed by various epithelial and non-epithelial cells, and notably by stem and cancer stem cells. In non-cancerous cells such as neuro-epithelial and hematopoietic stem cells, prominin-1 is selectively concentrated in plasma membrane protrusions, and released into the extracellular milieu in association with small vesicles. Previously, we demonstrated that prominin-1 contributes to melanoma cells pro-metastatic properties and suggested that it may constitute a molecular target to prevent prominin-1-expressing melanomas from colonizing and growing in lymph nodes and distant organs. Here, we report that three distinct pools of prominin-1 co-exist in cultures of human FEMX-I metastatic melanoma. Morphologically, in addition to the plasma membrane localization, prominin-1 is found within the intracellular compartments, (e.g., Golgi apparatus) and in association with extracellular membrane vesicles. The latter prominin-1-positive structures appeared in three sizes (small, ?40 nm; intermediates ~40-80 nm, and large, >80 nm). Functionally, the down-regulation of prominin-1 in FEMX-I cells resulted in a significant reduction of number of lipid droplets as observed by coherent anti-Stokes Raman scattering image analysis and Oil red O staining, and surprisingly in a decrease in the nuclear localization of beta-catenin, a surrogate marker of Wnt activation. Moreover, the T-cell factor/lymphoid enhancer factor (TCF/LEF) promoter activity was 2 to 4 times higher in parental than in prominin-1-knockdown cells. Collectively, our results point to Wnt signaling and/or release of prominin-1-containing membrane vesicles as mediators of the pro-metastatic activity of prominin-1 in FEMX-I melanoma. PMID:23318676

Rappa, Germana; Mercapide, Javier; Anzanello, Fabio; Le, Thuc T; Johlfs, Mary G; Fiscus, Ronald R; Wilsch-Bräuninger, Michaela; Corbeil, Denis; Lorico, Aurelio

2013-04-01

205

Uncovering the role of p53 splice variants in human malignancy: a clinical perspective  

PubMed Central

Thirty-five years of research on p53 gave rise to more than 68,000 articles and reviews, but did not allow the uncovering of all the mysteries that this major tumor suppressor holds. How p53 handles the different signals to decide the appropriate cell fate in response to a stress and its implication in tumorigenesis and cancer progression remains unclear. Nevertheless, the uncovering of p53 isoforms has opened new perspectives in the cancer research field. Indeed, the human TP53 gene encodes not only one but at least twelve p53 protein isoforms, which are produced in normal tissues through alternative initiation of translation, usage of alternative promoters, and alternative splicing. In recent years, it became obvious that the different p53 isoforms play an important role in regulating cell fate in response to different stresses in normal cells by differentially regulating gene expression. In cancer cells, abnormal expression of p53 isoforms contributes actively to cancer formation and progression, regardless of TP53 mutation status. They can also be associated with response to treatment, depending on the cell context. The determination of p53 isoform expression and p53 mutation status helps to define different subtypes within a particular cancer type, which would have different responses to treatment. Thus, the understanding of the regulation of p53 isoform expression and their biological activities in relation to the cellular context would constitute an important step toward the improvement of the diagnostic, prognostic, and predictive values of p53 in cancer treatment. This review aims to summarize the involvement of p53 isoforms in cancer and to highlight novel potential therapeutic targets. PMID:24379683

Surget, Sylvanie; Khoury, Marie P; Bourdon, Jean-Christophe

2014-01-01

206

Local interstitial delivery of z-butylidenephthalide by polymer wafers against malignant human gliomas  

PubMed Central

We have shown that the natural compound z-butylidenephthalide (Bdph), isolated from the chloroform extract of Angelica sinensis, has antitumor effects. Because of the limitation of the blood-brain barrier, the Bdph dosage required for treatment of glioma is relatively high. To solve this problem, we developed a local-release system with Bdph incorporated into a biodegradable polyanhydride material, p(CPP-SA; Bdph-Wafer), and investigated its antitumor effects. On the basis of in vitro release kinetics, we demonstrated that the Bdph-Wafer released 50% of the available Bdph by the sixth day, and the release reached a plateau phase (90% of Bdph) by the 30th day. To investigate the in situ antitumor effects of the Bdph-Wafer on glioblastoma multiforme (GBM), we used 2 xenograft animal models—F344 rats (for rat GBM) and nude mice (for human GBM)—which were injected with RG2 and DBTRG-05MG cells, respectively, for tumor formation and subsequently treated subcutaneously with Bdph-Wafers. We observed a significant inhibitory effect on tumor growth, with no significant adverse effects on the rodents. Moreover, we demonstrated that the antitumor effect of Bdph on RG2 cells was via the PKC pathway, which upregulated Nurr77 and promoted its translocation from the nucleus to the cytoplasm. Finally, to study the effect of the interstitial administration of Bdph in cranial brain tumor, Bdph-Wafers were surgically placed in FGF-SV40 transgenic mice. Our Bdph-Wafer significantly reduced tumor size in a dose-dependent manner. In summary, our study showed that p(CPP-SA) containing Bdph delivered a sufficient concentration of Bdph to the tumor site and effectively inhibited the tumor growth in the glioma. PMID:21565841

Harn, Horng-Jyh; Lin, Shinn-Zong; Lin, Po-Cheng; Liu, Cyong-Yue; Liu, Po-Yen; Chang, Li-Fu; Yen, Ssu-Yin; Hsieh, Dean-Kuo; Liu, Fu-Chen; Tai, Dar-Fu; Chiou, Tzyy-Wen

2011-01-01

207

Influence of the 100% w/v perfluorooctyl bromide (PFOB) emulsion dose on tumour radiosensitivity.  

PubMed

The radiosensitizing effect of a 100% w/v emulsion of a fluorocarbon, PFOB, which carries 4 times more oxygen than does Fluosol-DA 20% emulsion, was studied on two human tumour xenografts (HRT18 and HT29) and the murine tumour EMT6. This effect was compared with that obtained with carbogen alone. The fluorocrit (amount of fluorocarbon in the blood) and haematocrit remained unchanged from 7 to 65 min post-injection of the emulsion (8 ml/kg). Tumour-bearing mice were pretreated with 100% w/v PFOB emulsion doses ranging from 2 to 15 ml/kg in the presence of carbogen for 30 min prior to and during irradiation. The fluorocrit increased from 1.5% to 9.5% as the dose of 100% w/v PFOB emulsion increased from 2 to 15 ml/kg. The haematocrit remained the same for all the fluorocarbon emulsion doses used. Tumour radiosensitization varied with the fluorocarbon emulsion dose. Clinically relevant doses (2-4 ml/kg) of the 100% w/v PFOB emulsion plus carbogen produced significantly more radiosensitization than carbogen alone, with sensitizing enhancement ratios of 1.4 for EMT6 and 1.7 for HRT18. The radiosensitivity of HRT18 cells was thus very close to that obtained with normally oxygenated cells. For higher doses (8-15 ml/kg) the radiosensitizing effect of 100% w/v PFOB emulsion plus carbogen becomes comparable to that of carbogen alone. These experiments show that clinically useful doses of 100% w/v PFOB plus carbogen produced tumour radiosensitization only at relatively low fluorocrits. Thus the fluorocrit, and hence the fluorocarbon's oxygen-carrying capacity, is not the only factor involved in radiosensitizing tumour cells by oxygen-carrying fluorocarbon emulsions. PMID:1671693

Thomas, C; Riess, J; Guichard, M

1991-02-01

208

Radiosensitivity of hepatoma cell lines and human normal liver cell lines exposed in vitro to carbon ions and argon ions at the HIRFL  

NASA Astrophysics Data System (ADS)

Human hepatoma (SMMC-7721) and normal liver (L02) cells were irradiated with ?-rays, 12C 6+ and 36Ar 18+ ion beams at the Heavy Ion Research Facility in Lanzhou (HIRFL). By using the Calyculin-A induced premature chromosome condensation technique, chromatid-type breaks and isochromatid-type breaks were scored separately. Tumor cells irradiated with heavy ions produced a majority of isochromatid break, while chromatid breaks were dominant when cells were exposed to ?-rays. The relative biological effectiveness (RBE) for irradiation-induced chromatid breaks were 3.6 for L02 and 3.5 for SMMC-7721 cell lines at the LET peak of 96 keV?m -112C 6+ ions, and 2.9 for both of the two cell lines of 512 keV?m -136Ar 18+ ions. It suggested that the RBE of isochromatid-type breaks was pretty high when high-LET radiations were induced. Thus we concluded that the high production of isochromatid-type breaks, induced by the densely ionizing track structure, could be regarded as a signature of high-LET radiation exposure.

Jing, Xigang; Li, Wenjian; Wang, Zhuanzi; Wei, Wei; Guo, Chuanling; Lu, Dong; Yang, Jianshe

2009-05-01

209

Wnt interaction and extracellular release of prominin-1/CD133 in human malignant melanoma cells  

SciTech Connect

Prominin-1 (CD133) is the first identified gene of a novel class of pentaspan membrane glycoproteins. It is expressed by various epithelial and non-epithelial cells, and notably by stem and cancer stem cells. In non-cancerous cells such as neuro-epithelial and hematopoietic stem cells, prominin-1 is selectively concentrated in plasma membrane protrusions, and released into the extracellular milieu in association with small vesicles. Previously, we demonstrated that prominin-1 contributes to melanoma cells pro-metastatic properties and suggested that it may constitute a molecular target to prevent prominin-1-expressing melanomas from colonizing and growing in lymph nodes and distant organs. Here, we report that three distinct pools of prominin-1 co-exist in cultures of human FEMX-I metastatic melanoma. Morphologically, in addition to the plasma membrane localization, prominin-1 is found within the intracellular compartments, (e.g., Golgi apparatus) and in association with extracellular membrane vesicles. The latter prominin-1–positive structures appeared in three sizes (small, ?40 nm; intermediates ?40–80 nm, and large, >80 nm). Functionally, the down-regulation of prominin-1 in FEMX-I cells resulted in a significant reduction of number of lipid droplets as observed by coherent anti-Stokes Raman scattering image analysis and Oil red O staining, and surprisingly in a decrease in the nuclear localization of beta-catenin, a surrogate marker of Wnt activation. Moreover, the T-cell factor/lymphoid enhancer factor (TCF/LEF) promoter activity was 2 to 4 times higher in parental than in prominin-1-knockdown cells. Collectively, our results point to Wnt signaling and/or release of prominin-1–containing membrane vesicles as mediators of the pro-metastatic activity of prominin-1 in FEMX-I melanoma. - Highlights: ? First report of release of prominin-1–containing microvesicles from cancer cells. ? Pro-metastatic role of prominin-1–containing microvesicles in FEMX-I melanoma. ? Down-regulation of prominin-1 results in decreased nuclear localization of ?-catenin. ? Wnt signaling as mediator of the pro-metastatic activity of prominin-1.

Rappa, Germana [Cancer Research Program, Roseman University of Health Sciences, 10530 Discovery Drive. Las Vegas, NV 89135 (United States); College of Pharmacy, Roseman University of Health Sciences, Henderson, NV 89104 (United States); Mercapide, Javier; Anzanello, Fabio [Cancer Research Program, Roseman University of Health Sciences, 10530 Discovery Drive. Las Vegas, NV 89135 (United States); Le, Thuc T. [Nevada Cancer Institute, Las Vegas, NV 89135 (United States); Johlfs, Mary G. [Cancer Research Program, Roseman University of Health Sciences, 10530 Discovery Drive. Las Vegas, NV 89135 (United States); Center for Diabetes and Obesity Prevention, Treatment, Research and Education, Roseman University of Health Sciences, Henderson, NV 89104 (United States); Fiscus, Ronald R. [Cancer Research Program, Roseman University of Health Sciences, 10530 Discovery Drive. Las Vegas, NV 89135 (United States); College of Pharmacy, Roseman University of Health Sciences, Henderson, NV 89104 (United States); Center for Diabetes and Obesity Prevention, Treatment, Research and Education, Roseman University of Health Sciences, Henderson, NV 89104 (United States); Wilsch-Bräuninger, Michaela [Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307 Dresden (Germany); Corbeil, Denis [Tissue Engineering Laboratories (BIOTEC) and DFG Research Center and Cluster of Excellence for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Tatzberg 47–49, 01307 Dresden, Germany Technische Universitat Dresden, Dresden (Germany); Lorico, Aurelio, E-mail: alorico@roseman.edu [Cancer Research Program, Roseman University of Health Sciences, 10530 Discovery Drive. Las Vegas, NV 89135 (United States); College of Pharmacy, Roseman University of Health Sciences, Henderson, NV 89104 (United States)

2013-04-01

210

TPX2 in malignantly transformed human bronchial epithelial cells by anti-benzo[ a]pyrene-7,8-diol-9,10-epoxide  

Microsoft Academic Search

In order to elucidate the function of the targeting protein for Xenopus kinesin-like protein 2 (Xklp2) (TPX2) in the malignant transformation of human bronchial epithelial cells induced by anti-benzo[a]pyrene-trans-7, 8-dihydrodiol-9, 10-epoxide (anti-BPDE), TPX2 was characterized in cells at both the gene and the protein levels. TPX2 was present at higher levels in 16HBE-C cells than in 16HBE cells as demonstrated

Lijuan Zhang; He Huang; Luyao Deng; Ming Chu; Lan Xu; Juanling Fu; Yunlan Zhu; Xiuchun Zhang; Shulin Liu; Zongcan Zhou; Yuedan Wang

2008-01-01

211

Short Chain Fatty Acids Differentially Modulate Cellular Phenotype and c-myc Protein Levels in Primary Human Nonmalignant and Malignant Colonocytes  

Microsoft Academic Search

Short chain fatty acids may protect colonic mucosa against neoplastic transformation by modulating colonocyte phenotype, DNA synthesis, and c-myc levels. To test this hypothesis, nonmalignant and malignant human colonocytes were isolated from surgical specimens and treated with 10 mM acetate, propionate, or butyrate. Markers of cellular phenotype, DNA synthesis, and c-myc protein levels were assayed by alkaline phosphatase and dipeptidyl

Nancy J. Emenaker; Marc D. Basson

2001-01-01

212

Survivin knockdown increased anti-cancer effects of (-)-epigallocatechin-3-gallate in human malignant neuroblastoma SK-N-BE2 and SH-SY5Y cells  

SciTech Connect

Neuroblastoma is a solid tumor that mostly occurs in children. Malignant neuroblastomas have poor prognosis because conventional chemotherapeutic agents are hardly effective. Survivin, which is highly expressed in some malignant neuroblastomas, plays a significant role in inhibiting differentiation and apoptosis and promoting cell proliferation, invasion, and angiogenesis. We examined consequences of survivin knockdown by survivin short hairpin RNA (shRNA) plasmid and then treatment with (-)-epigallocatechin-3-gallate (EGCG), a green tea flavonoid, in malignant neuroblastoma cells. Our Western blotting and laser scanning confocal immunofluorescence microscopy showed that survivin was highly expressed in malignant neuroblastoma SK-N-BE2 and SH-SY5Y cell lines and slightly in SK-N-DZ cell line. Expression of survivin was very faint in malignant neuroblastoma IMR32 cell line. We transfected SK-N-BE2 and SH-SY-5Y cells with survivin shRNA, treated with EGCG, and confirmed knockdown of survivin at mRNA and protein levels. Survivin knockdown induced morphological features of neuronal differentiation, as we observed following in situ methylene blue staining. Combination of survivin shRNA and EGCG promoted neuronal differentiation biochemically by increases in the expression of NFP, NSE, and e-cadherin and also decreases in the expression of Notch-1, ID2, hTERT, and PCNA. Our in situ Wright staining and Annexin V-FITC/PI staining showed that combination therapy was highly effective in inducing, respectively, morphological and biochemical features of apoptosis. Apoptosis occurred with activation of caspase-8 and cleavage of Bid to tBid, increase in Bax:Bcl-2 ratio, mitochondrial release of cytochrome c, and increases in the expression and activity of calpain and caspase-3. Combination therapy decreased migration of cells through matrigel and inhibited proliferative (p-Akt and NF-{kappa}B), invasive (MMP-2 and MMP-9), and angiogenic (VEGF and b-FGF) factors. Also, in vitro network formation ability of cells was significantly inhibited by survivin silencing and completely by combination of survivin silencing and EGCG treatment. Collectively, survivin silencing potentiated anti-cancer effects of EGCG in human malignant neuroblastoma cells having survivin overexpression. -- Highlights: Black-Right-Pointing-Pointer Survivin shRNA + EGCG controlled growth of human malignant neuroblastoma cells. Black-Right-Pointing-Pointer Survivin knockdown induced neuronal differentiation in neuroblastoma cells. Black-Right-Pointing-Pointer Survivin shRNA + EGCG induced morphological and biochemical features of apoptosis. Black-Right-Pointing-Pointer Combination therapy inhibited invasion, proliferation, and angiogenesis as well. Black-Right-Pointing-Pointer So, combination therapy showed multiple anti-cancer mechanisms in neuroblastoma.

Hossain, Md. Motarab [Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC (United States)] [Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC (United States); Banik, Naren L. [Department of Neurosciences, Medical University of South Carolina, Charleston, SC (United States)] [Department of Neurosciences, Medical University of South Carolina, Charleston, SC (United States); Ray, Swapan K., E-mail: swapan.ray@uscmed.sc.edu [Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC (United States)

2012-08-01

213

In vitro and In vivo Growth Inhibition of Human Malignant Astrocytoma Cells by the Farnesyltransferase Inhibitor B1620  

Microsoft Academic Search

p21-Ras, the protein product of the proto-oncogene Ras is overactivated in malignant astrocytomas despite the absence of mutation. It is known that p21-Ras participates in signaling events from membrane tyrosine kinase receptors and a variety of intracellular biochemical pathways to downstream targets. Signal transduction inhibition by targeting against Ras is now thought to be a promising therapeutic strategy for malignant

Masanori Kurimoto; Yutaka Hirashima; Hideo Hamada; Hironaga Kamiyama; Shoichi Nagai; Nakamasa Hayashi; Shunro Endo

2003-01-01

214

Silencing SATB1 Inhibits the Malignant Phenotype and Increases Sensitivity of Human Osteosarcoma U2OS Cells to Arsenic Trioxide  

PubMed Central

In a previous study, we found that the global genome organizer Special AT-rich binding protein 1 (SATB1) is highly expressed in mesenchymal-derived human osteosarcoma U2OS cells and that the knock-down of SATB1 results in the inhibition of cell proliferation. The present study was aimed at investigating the effect of silencing SATB1 on cell migration, invasion, apoptosis and resistance to the chemotherapeutic drug arsenic trioxide. Cell migration and invasion were detected by wound-healing assays and trans-well invasion assays, respectively. Cell apoptosis was analyzed by an in situ Cell Death Detection POD Kit, based on terminal deoxynucleotydyl transferase mediated dUTP nick-end labeling (TUNEL) staining and mRNAs were analyzed by real time qRT-PCR. We found that cell migration and invasion were inhibited and that the proportion of apoptotic cells and sensitivities to the chemotherapeutic drug arsenic trioxide were enhanced by knockdown of SATB1 in U2OS cells. Furthermore, mRNA of ABCC1 and ABCG2 were decreased strikingly after SATB1 silencing. It was concluded that the elevated expression of SATB1 in U2OS cells contributes to maintenance of the malignant phenotype and resistance to chemotherapeutic drugs ATO, suggesting that silencing SATB1 in the cells might improve the effects of arsenic trioxides in the treatment of osteosarcoma in which SATB1 is over-expressed and that ABCC1 and ABCG2 were involved in SATB1 mediated resistance of U2OS cells to ATO. PMID:25317073

Zhang, Haiying; Su, Xuejin; Guo, Li; Zhong, Lingzhi; Li, Wenxue; Yue, Zhen; Wang, Xiaotong; Mu, Yan; Li, Xinna; Li, Ronggui; Wang, Zonggui

2014-01-01

215

Persistence of Human Papillomavirus DNA in Benign and (Pre)malignant Skin Lesions from Renal Transplant Recipients  

PubMed Central

An extremely diverse group of human papillomavirus (HPV) types consisting of epidermodysplasia verruciformis (EV)-associated HPV types and other cutaneous HPV types (e.g., HPV types 2 and 3) is associated with nonmelanoma cancers and benign lesions of the skin. The frequent presence of multiple HPV types in single skin biopsy specimens of renal transplant recipients prompted us to develop PCR techniques for the detection of distinct (sub)groups of genotypically related cutaneous HPV types, i.e., three subgroups of EV-associated HPV types and two groups (A2 and A4) of other cutaneous HPV types. This approach generally allowed a reliable identification of HPV genotypes by direct sequencing of the PCR products, despite the frequent occurrence of multiple infections. The targeted spectrum of HPV types comprises 66 cutaneous HPV types including 21 putative novel HPV types. We also detected 17 putative novel HPV subtypes. We demonstrated that the skin of nearly all renal transplant recipients who developed various benign and (pre)malignant skin lesions was persistently infected with one or more EV-associated HPV types and/or HPV types belonging to groups A2 and A4. The frequency and distribution of EV-associated HPV and HPV types belonging to groups A2 and A4 were similar in biopsy specimens from hyperkeratotic papillomas (77.5%), squamous cell carcinomas (77.8%), and actinic keratoses (67.9%) but appeared to be lower in specimens of basal cell carcinomas (35.7%), benign lesions (38.5%), and clinically normal skin (32.3%). These findings suggest that renal transplant recipients are prone to persistent cutaneous HPV infection. Our data do not support the existence of high-risk cutaneous HPV types. PMID:10834958

Berkhout, Ron J. M.; Bouwes Bavinck, Jan N.; ter Schegget, Jan

2000-01-01

216

Malignant hyperthermia.  

PubMed

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stresses such as vigorous exercise and heat. The incidence of MH reactions ranges from 1:5,000 to 1:50,000-100,000 anesthesias. However, the prevalence of the genetic abnormalities may be as great as one in 3,000 individuals. MH affects humans, certain pig breeds, dogs, horses, and probably other animals. The classic signs of MH include hyperthermia to marked degree, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. The syndrome is likely to be fatal if untreated. Early recognition of the signs of MH, specifically elevation of end-expired carbon dioxide, provides the clinical diagnostic clues. In humans the syndrome is inherited in autosomal dominant pattern, while in pigs in autosomal recessive. The pathophysiologic changes of MH are due to uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. Diagnostic testing relies on assessing the in vitro contracture response of biopsied muscle to halothane, caffeine, and other drugs. Elucidation of the genetic changes has led to the introduction, on a limited basis so far, of genetic testing for susceptibility to MH. As the sensitivity of genetic testing increases, molecular genetics will be used for identifying those at risk with greater frequency. Dantrolene sodium is a specific antagonist of the pathophysiologic changes of MH and should be available wherever general anesthesia is administered. Thanks to the dramatic progress in understanding the clinical manifestation and pathophysiology of the syndrome, the mortality from MH has dropped from over 80% thirty years ago to less than 5%. PMID:17456235

Rosenberg, Henry; Davis, Mark; James, Danielle; Pollock, Neil; Stowell, Kathryn

2007-01-01

217

Combined RAF1 protein expression and p53 mutational status provides a strong predictor of cellular radiosensitivity  

PubMed Central

The tumour suppressor gene, p53, and genes coding for positive signal transduction factors can influence transit through cell-cycle checkpoints and modulate radiosensitivity. Here we examine the effects of RAF1 protein on the rate of exit from a G2/M block induced by ?-irradiation in relation to intrinsic cellular radiosensitivity in human cell lines expressing wild-type p53 (wtp53) protein as compared to mutant p53 (mutp53) protein. Cell lines which expressed mutp53 protein were all relatively radioresistant and exhibited no relationship between RAF1 protein and cellular radiosensitivity. Cell lines expressing wtp53 protein, however, showed a strong relationship between RAF1 protein levels and the radiosensitivity parameter SF2. In addition, when post-irradiation perturbation of G2/M transit was compared using the parameter T50 (time after the peak of G2/M delay at which 50% of the cells had exited from a block induced by 2 Gy of irradiation), RAF1 was related to T50 in wtp53, but not mutp53, cell lines. Cell lines which expressed wtp53 protein and high levels of RAF1 had shorter T50s and were also more radiosensitive. These results suggest a cooperative role for wtp53 and RAF1 protein in determining cellular radiosensitivity in human cells, which involves control of the G2/M checkpoint. © 2000 Cancer Research Campaign PMID:10993658

Warenius, H M; Jones, M; Gorman, T; McLeish, R; Seabra, L; Barraclough, R; Rudland, P

2000-01-01

218

Prostate-Specific Natural Health Products (Dietary Supplements) Radiosensitize Normal Prostate Cells  

SciTech Connect

Purpose: Prostate-specific health products (dietary supplements) are taken by cancer patients to alleviate the symptoms linked with poor prostate health. However, the effect of these agents on evidence-based radiotherapy practice is poorly understood. The present study aimed to determine whether dietary supplements radiosensitized normal prostate or prostate cancer cell lines. Methods and Materials: Three well-known prostate-specific dietary supplements were purchased from commercial sources available to patients (Trinovin, Provelex, and Prostate Rx). The cells used in the study included normal prostate lines (RWPE-1 and PWR-1E), prostate tumor lines (PC3, DU145, and LNCaP), and a normal nonprostate line (HaCaT). Supplement toxicity was assessed using cell proliferation assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and cellular radiosensitivity using conventional clonogenic assays (0.5-4Gy). Cell cycle kinetics were assessed using the bromodeoxyuridine/propidium iodide pulse-labeling technique, apoptosis by scoring caspase-3 activation, and DNA repair by assessing gammaH2AX. Results: The cell growth and radiosensitivity of the malignant PC3, DU145, and LNcaP cells were not affected by any of the dietary prostate supplements (Provelex [2mug/mL], Trinovin [10mug/mL], and Prostate Rx [50 mug/mL]). However, both Trinovin (10mug/mL) and Prostate Rx (6mug/mL) inhibited the growth rate of the normal prostate cell lines. Prostate Rx increased cellular radiosensitivity of RWPE-1 cells through the inhibition of DNA repair. Conclusion: The use of prostate-specific dietary supplements should be discouraged during radiotherapy owing to the preferential radiosensitization of normal prostate cells.

Hasan, Yasmin; Schoenherr, Diane; Martinez, Alvaro A.; Wilson, George D. [William Beaumont Hospital, Royal Oak, MI (United States); Marples, Brian, E-mail: brian.marples@beaumont.ed [William Beaumont Hospital, Royal Oak, MI (United States)

2010-03-01

219

Long-term low-dose ?-particle enhanced the potential of malignant transformation in human bronchial epithelial cells through MAPK/Akt pathway.  

PubMed

Since the wide usage of ionizing radiation, the cancer risk of low dose radiation (LDR) (<0.1 Gy) has become attractive for a long time. However, most results are derived from epidemiologic studies on atomic-bomb survivors and nuclear accidents surrounding population, and the molecular mechanism of this risk is elusive. To explore the potential of a long-term LDR-induced malignant transformation, human bronchial epithelial cells Beas-2B were fractionally irradiated with 0.025 Gy ?-particles for 8 times in total and then further cultured for 1-2 months. It was found that the cell proliferation, the abilities of adhesion and invasion, and the protein expressions of p-ERK, p-Akt, especially p-P38 were not only increased in the multiply-irradiated cells but also in their offspring 1-2 months after the final exposure, indicating high potentiality of cell malignant transformation. On opposite, the expressions of p-JNK and p-P66 were diminished in the subcultures of irradiated cells and thus may play a role of negative regulation in canceration. When the cells were transferred with p38 siRNA, the LDR-induced enhancements of cell adhesion and invasion were significantly reduced. These findings suggest that long-term LDR of ?-particles could enhance the potential of malignant transformation incidence in human bronchial epithelial cells through MAPK/Akt pathway. PMID:24746471

Liu, Weili; Xiao, Linlin; Dong, Chen; He, Mingyuan; Pan, Yan; Xie, Yuexia; Tu, Wenzhi; Fu, Jiamei; Shao, Chunlin

2014-05-01

220

Aberrant Cytokeratin Expression During Arsenic-induced Acquired Malignant Phenotype in Human HaCaT Keratinocytes Consistent with Epidermal Carcinogenesis  

PubMed Central

Inorganic arsenic is a known human skin carcinogen. Chronic arsenic exposure results in various human skin lesions, including hyperkeratosis and squamous cell carcinoma (SCC), both characterized by distorted cytokeratin (CK) production. Prior work shows the human skin keratinocyte HaCaT cell line, when exposed chronically for >25 weeks to a low level of inorganic arsenite (100 nM) results in cells able to produce aggressive SCC upon inoculation into nude mice. In the present study, CK expression analysis was performed in arsenic-exposed HaCaT cells during the progressive acquisition of this malignant phenotype (0 to 20 weeks) to further validate this model as relevant to epidermal carcinogenesis induced by arsenic in humans. Indeed, we observed clear evidence of acquired cancer phenotype by 20 weeks of arsenite exposure including the formation of giant cells, a >4-fold increase in colony formation in soft agar and a ?2.5-fold increase in matrix metalloproteinase-9 secretion, an enzyme often secreted by cancer cells to help invade through the local extra-cellular matrix. During this acquired malignant phenotype, various CK genes showed markedly altered expression at the transcript and protein levels in a time-dependent manner. For example, CK1, a marker of hyperkeratosis, increased up to 34-fold during arsenic-induced transformation, while CK13, a marker for dermal cancer progression, increased up to 45-fold. The stem cell marker, CK15, increased up to 7-fold, particularly during the later stages of arsenic exposure, indicating a potential emergence of cancer stem-like cells with arsenic-induced acquired malignant phenotype. The expression of involucrin and loricrin, markers for keratinocyte differentiation, increased up to 9-fold. Thus, during arsenic-induced acquired cancer phenotype in human keratinocytes, dramatic and dynamic alterations in CK expression occur which are consistent with the process of epidermal carcinogenesis helping validate this as an appropriate model for the study of arsenic-induced skin cancer. PMID:19524636

Sun, Yang; Pi, Jingbo; Wang, Xueqian; Tokar, Erik J.; Liu, Jie; Waalkes, Michael P.

2009-01-01

221

AIM1, a novel non-lens member of the ??-crystallin superfamily, is associated with the control of tumorigenicity in human malignant melanoma  

PubMed Central

AIM1 is a novel gene whose expression is associated with the experimental reversal of tumorigenicity of human malignant melanoma. The predicted protein product of the major 4.1-kb transcript shows striking similarity to the ??-crystallin superfamily. All known members of this superfamily contain two or four characteristic motifs arranged as one or two symmetrical domains. AIM1, in contrast, contains 12 ?? motifs, suggesting a 6-domain structure resembling a trimer of ?- or ?-crystallin subunits. The structure of the AIM1 gene shows remarkable similarity to ?-crystallin genes, with homologous introns delineating equivalent protein structural units. AIM1 is the first mammalian member of the ?? superfamily with a primarily non-lens role. Other parts of the predicted AIM1 protein sequence have weak similarity with filament or actin-binding proteins. AIM1 is a good candidate for the putative suppressor of malignant melanoma on chromosome 6, possibly exerting its effects through interactions with the cytoskeleton. PMID:9096375

Ray, Michael E.; Wistow, Graeme; Su, Yan A.; Meltzer, Paul S.; Trent, Jeffrey M.

1997-01-01

222

Immunotherapy of Genitourinary Malignancies  

PubMed Central

Most cancer patients are treated with some combination of surgery, radiation, and chemotherapy. Despite recent advances in local therapy with curative intent, chemotherapeutic treatments for metastatic disease often remain unsatisfying due to severe side effects and incomplete long-term remission. Therefore, the evaluation of novel therapeutic options is of great interest. Conventional, along with newer treatment strategies target the immune system that suppresses genitourinary (GU) malignancies. Metastatic renal cell carcinoma and non-muscle-invasive bladder caner represent the most immune-responsive types of all human cancer. This review examines the rationale and emerging evidence supporting the anticancer activity of immunotherapy, against GU malignancies. PMID:22481927

Inamoto, Teruo; Azuma, Haruhito

2012-01-01

223

Radiosensitizers in cervical cancer. Cisplatin and beyond  

PubMed Central

Cervical cancer continues to be a significant health burden worldwide. Globally, the majority of cancers are locally advanced at diagnosis; hence, radiation remains the most frequently used therapeutical modality. Currently, the value of adding cisplatin or cisplatin-based chemotherapy to radiation for treatment of locally advanced cervical cancer is strongly supported by randomized studies and meta-analyses. Nevertheless, despite these significant achievements, therapeutic results are far from optimal; thus, novel therapies need to be assayed. A strategy currently being investigated is the use of newer radiosensitizers alone or in combination with platinum compounds. In the present work, we present preclinical information on known and newer cytotoxic agents as radiosensitizers on cervical cancer models, as well as the clinical information emanating from early phase trials that incorporate them to the cervical cancer management. In addition, we present the perspectives on the combined approach of radiation therapy and molecular target-based drugs with proven radiosensitizing capacity. PMID:16722549

Candelaria, Myrna; Garcia-Arias, Alicia; Cetina, Lucely; Duenas-Gonzalez, Alfonso

2006-01-01

224

An integrated approach for comparative proteomic analysis of human bile reveals overexpressed cancer-associated proteins in malignant biliary stenosis.  

PubMed

Proteomics is a key tool in the identification of new bile biomarkers for differentiating malignant and nonmalignant biliary stenoses. Unfortunately, the complexity of bile and the presence of molecules interfering with protein analysis represent an obstacle for quantitative proteomic studies in bile samples. The simultaneous need to introduce purification steps and minimize the use of pre-fractionation methods inevitably leads to protein loss and limited quantifications. This dramatically reduces the chance of identifying new potential biomarkers. In the present study, we included differential centrifugation as a preliminary step in a quantitative proteomic workflow involving iTRAQ labeling, peptide fractionation by OFFGEL electrophoresis and LC-MS/MS, to compare protein expression in bile samples collected from patients with malignant or nonmalignant biliary stenoses. A total of 1267 proteins were identified, including a set of 322 newly described bile proteins, mainly belonging to high-density cellular fractions. The subsequent comparative analysis led to a 5-fold increase in the number of quantified proteins over previously published studies and highlighted 104 proteins overexpressed in malignant samples. Finally, immunoblot verifications performed on a cohort of 8 malignant (pancreatic adenocarcinoma, n=4; cholangiocarcinoma, n=4) and 5 nonmalignant samples (chronic pancreatitis, n=3; biliary stones, n=2) confirmed the results of proteomic analysis for three proteins: olfactomedin-4, syntenin-2 and Ras-related C3 botulinum toxin substrate 1. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge. PMID:23872482

Lukic, Natalija; Visentin, Rémy; Delhaye, Myriam; Frossard, Jean-Louis; Lescuyer, Pierre; Dumonceau, Jean-Marc; Farina, Annarita

2014-05-01

225

Anticancer activity of extracts derived from the mature roots of Scutellaria baicalensis on human malignant brain tumor cells  

Microsoft Academic Search

BACKGROUND: Flavonoid-rich extracts from the mature roots of Scutellaria baicalensis have been shown to exhibit antiproliferative effects on various cancer cell lines. We assessed the ability of an ethanolic extract of S. baicalensis root to inhibit the proliferation of malignant glioma cells. METHODS: Cell lines derived from primary and recurrent brain tumors from the same patient and cells selected for

Adrienne C Scheck; Krya Perry; Nicole C Hank; W Dennis Clark

2006-01-01

226

Hemostasis and malignancy.  

PubMed

There is considerable evidence that the hemostatic system is involved in the growth and spread of malignant disease. There is an increased incidence of thromboembolic disease in patients with cancers and hemostatic abnormalities are extremely common in such patients. Antihemostatic agents have been successfully used to treat a variety of experimental tumors, and several clinical trials in humans have been initiated. Although metastasis is undoubtedly multifactorial, intravascular coagulation activation and peritumor fibrin deposition seem to be important. The mechanisms by which hemostatic activation facilitates the malignant process remain to be completely elucidated. Of central importance may be the presence on malignant cells of tissue factor and urokinase receptor. Recent studies have suggested that these proteins, and others, may be involved at several stages of metastasis, including the key event of neovascularization. Tissue factor, the principal initiator of coagulation, may have additional roles, outside of fibrin formation, that are central to the biology of some solid tumors. PMID:9579631

Francis, J L; Biggerstaff, J; Amirkhosravi, A

1998-01-01

227

Identification of proteins related to epigenetic regulation in the malignant transformation of aberrant karyotypic human embryonic stem cells by quantitative proteomics.  

PubMed

Previous reports have demonstrated that human embryonic stem cells (hESCs) tend to develop genomic alterations and progress to a malignant state during long-term in vitro culture. This raises concerns of the clinical safety in using cultured hESCs. However, transformed hESCs might serve as an excellent model to determine the process of embryonic stem cell transition. In this study, ITRAQ-based tandem mass spectrometry was used to quantify normal and aberrant karyotypic hESCs proteins from simple to more complex karyotypic abnormalities. We identified and quantified 2583 proteins, and found that the expression levels of 316 proteins that represented at least 23 functional molecular groups were significantly different in both normal and abnormal hESCs. Dysregulated protein expression in epigenetic regulation was further verified in six pairs of hESC lines in early and late passage. In summary, this study is the first large-scale quantitative proteomic analysis of the malignant transformation of aberrant karyotypic hESCs. The data generated should serve as a useful reference of stem cell-derived tumor progression. Increased expression of both HDAC2 and CTNNB1 are detected as early as the pre-neoplastic stage, and might serve as prognostic markers in the malignant transformation of hESCs. PMID:24465727

Sun, Yi; Yang, Yixuan; Zeng, Sicong; Tan, Yueqiu; Lu, Guangxiu; Lin, Ge

2014-01-01

228

Identification of Proteins Related to Epigenetic Regulation in the Malignant Transformation of Aberrant Karyotypic Human Embryonic Stem Cells by Quantitative Proteomics  

PubMed Central

Previous reports have demonstrated that human embryonic stem cells (hESCs) tend to develop genomic alterations and progress to a malignant state during long-term in vitro culture. This raises concerns of the clinical safety in using cultured hESCs. However, transformed hESCs might serve as an excellent model to determine the process of embryonic stem cell transition. In this study, ITRAQ-based tandem mass spectrometry was used to quantify normal and aberrant karyotypic hESCs proteins from simple to more complex karyotypic abnormalities. We identified and quantified 2583 proteins, and found that the expression levels of 316 proteins that represented at least 23 functional molecular groups were significantly different in both normal and abnormal hESCs. Dysregulated protein expression in epigenetic regulation was further verified in six pairs of hESC lines in early and late passage. In summary, this study is the first large-scale quantitative proteomic analysis of the malignant transformation of aberrant karyotypic hESCs. The data generated should serve as a useful reference of stem cell-derived tumor progression. Increased expression of both HDAC2 and CTNNB1 are detected as early as the pre-neoplastic stage, and might serve as prognostic markers in the malignant transformation of hESCs. PMID:24465727

Sun, Yi; Yang, Yixuan; Zeng, Sicong; Tan, Yueqiu; Lu, Guangxiu; Lin, Ge

2014-01-01

229

Phenethyl isothiocyanate triggers apoptosis in human malignant melanoma A375.S2 cells through reactive oxygen species and the mitochondria-dependent pathways.  

PubMed

We have reported previously that phenethyl isothiocyanate (PEITC) induces apoptosis in human osteosarcoma U-2 OS cells. Cytotoxic activity of PEITC towards other cancer cells such as human malignant melanoma and skin cancer cells has not been reported. In this study, the anticancer activity of PEITC towards human malignant melanoma cancer A375.S2 cells was investigated. To determine the mechanisms of PEITC inhibition of cell growth, the following end points were determined in A375.S2 cells: cell morphological changes, cell cycle arrest, DNA damage and fragmentation assays and morphological assessment of nuclear change, reactive oxygen species (ROS) and Ca(2+) generations, mitochondrial membrane potential disruption, and nitric oxide and 10-N-nonyl acridine orange productions, expression and activation of caspase-3 and -9, B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, poly (adenosine diphosphate-ribose) polymerase, and cytochrome c release, apoptosis-inducing factor and endonuclease G. PEITC induced morphological changes in time- and dose-dependent manner. PEITC induced G2/M phase arrest and induced apoptosis via endoplasmic reticulum stress-mediated mitochondria-dependent pathway. Western blot analysis showed that PEITC promoted Bax expression and inhibited Bcl-2 expression associated with the disintegration of the outer mitochondrial membrane causing cytochrome c release, and activation of caspase-9 and -3 cascade leading to apoptosis. We conclude that PEITC-triggered apoptotic death in A375.S2 cells occurs through ROS-mediated mitochondria-dependent pathways. PMID:23760257

Huang, S-H; Hsu, M-H; Hsu, S-C; Yang, J-S; Huang, W-W; Huang, A-C; Hsiao, Y-P; Yu, C-C; Chung, J-G

2014-03-01

230

A morphological study of 608 cases of canine malignant lymphoma in France with a focus on comparative similarities between canine and human lymphoma morphology.  

PubMed

This study reports cytomorphological, histomorphological, and immunological characterization of 608 biopsy cases of canine malignant lymphoma, with epidemiological and clinical data, collected from 7 French veterinary pathology laboratories. It compares morphological characteristics of malignant lymphoma in canines, per the updated Kiel classification system, with those reported in humans, per the World Health Organization (WHO) classification system. Of tumors described, 24.5% and 75.5% were classified as low- and high-grade malignant lymphomas, respectively. Presenting clinical signs included generalized or localized lymphadenopathy (82.4%) and extranodal diseases (17.6%) involving the skin (12.34%) and other sites (5.26%). Immunohistochemistry confirmed 63.8% B-cell (CD3-, CD79a+), 35.4% T-cell (CD3+, CD79a-), and 0.8% null-cell (CD3-, CD79a-) lymphomas. Most B-cell cases (38.49%) were of high-grade centroblastic polymorphic subtype; most T-cell cases (8.55%), high-grade pleomorphic mixed and large T-cell lymphoma subtypes. Some B-cell tumors showed morphologic characteristics consistent with follicular lymphomas and marginal zone lymphomas per the Revised European American Classification of Lymphoid Neoplasms and WHO canine classification systems and the WHO human classification system. Unusual high-grade B-cell subtypes included an atypical high-grade small B-cell lymphoma (0.66%), Burkitt-type B-cell lymphoma (1.64%), plasmacytoid lymphoma (0.99%), and mediastinal anaplastic large B-cell lymphoma (0.16%). Unusual T-cell subtypes included a previously undescribed high-grade canine immunoblastic T-cell type (1.15%), a rare low-grade prolymphocytic T-cell lymphoma (0.16%), and a recently described high-grade canine T-cell entity--aggressive granulocytic large-cell lymphoma (0.16%). Marginal zone lymphomas were common (10.86%); follicular lymphomas were rare (0.49%). Canine primary cutaneous malignant lymphoma subtypes were present (11.84%). There was no significant difference between B- and T-cell malignant lymphoma in regard to canine age and sex. A significant overrepresentation of Boxers (24.19%) was found for T-cell lymphomas. PMID:20472804

Ponce, F; Marchal, T; Magnol, J P; Turinelli, V; Ledieu, D; Bonnefont, C; Pastor, M; Delignette, M L; Fournel-Fleury, C

2010-05-01

231

ROS-dependent prostate apoptosis response-4 (Par-4) up-regulation and ceramide generation are the prime signaling events associated with curcumin-induced autophagic cell death in human malignant glioma  

PubMed Central

Malignant gliomas are extremely resistant to therapies that induce apoptosis, but are less resistant to therapies that induce autophagy. Therefore, drugs targeting autophagy are promising in the management of malignant gliomas. In this study, we investigated the anti-glioma potential of curcumin in vitro, and further examined the molecular mechanisms of curcumin-induced cell death in human malignant glioma. Here, we provide evidence that curcumin is cytotoxic against human malignant glioma cell lines, and the mechanism of cell death caused by curcumin is associated with features of autophagy. Curcumin suppresses the growth of human malignant glioma cells via ROS-dependent prostate apoptosis response-4 (Par-4) induction and ceramide generation. Extracellular supplementation of antioxidants such as glutathione and N-acetylcysteine to glioma cells abrogated the Par-4 induction, ceramide generation, and in turn, prevented curcumin-induced autophagic cell death. Moreover, tumor cells transfected with Par-4 gene sensitized the curcumin-induced autophagic cell death. Overall, this study describes a novel signaling pathway by which curcumin induces ROS-dependent Par-4 activation and ceramide generation, leading to autophagic cell death in human malignant glioma cells. PMID:25349781

Thayyullathil, Faisal; Rahman, Anees; Pallichankandy, Siraj; Patel, Mahendra; Galadari, Sehamuddin

2014-01-01

232

Uptake and retention of estramustine and the presence of estramustine binding protein in malignant brain tumours in humans.  

PubMed

Estraumustine phosphate (EMP), a cytotoxic drug used in the treatment of prostatic carcinoma, has been shown to exert cytotoxic effects on glioma cells in vitro. The drug uptake is assumed to depend on a specific estramustine binding protein (EMBP). One of the main difficulties in achieving cytotoxic effect in malignant brain tumours is believed to be due to the poor penetration of cytotoxic drugs into tumour tissue. In patients with malignant supratentorial brain tumours we have analysed the uptake of EMP metabolites in tumour tissue after oral administration and demonstrated EMBP in the same tissue specimens. Sixteen patients were given 280 mg EMP orally 14 h prior to surgery. Specimens from brain tumour tissue, cystic fluid, and serum were collected during surgery. Using gas chromatography the metabolites of EMP, estramustine (EaM) and estromustine (EoM), were quantified, EMBP was demonstrated by immunohistochemistry. The mean concentrations of EaM and EoM, expressed in ng g-1, were 60.3 and 38.4 in tumour tissue and 3.5 and 56.3 in serum, respectively. An accumulation of EaM in tumour tissue was found with a mean concentration gradient of 16.1 versus serum, while the gradient for EoM was 0.76. EMBP was demonstrated with a high degree of staining in all but one tumour. The high concentrations of EaM and EoM found in malignant brain tumour tissue correspond to potentially cytotoxic levels. The present results as well as the earlier in vitro demonstrated cytotoxic effects on glioma cells strengthen the possibility of a therapeutic effect of EMP in the treatment of malignant brain tumours. PMID:8431366

Bergenheim, A T; Gunnarsson, P O; Edman, K; von Schoultz, E; Hariz, M I; Henriksson, R

1993-02-01

233

Azidothymidine Enhances Fluorodeoxyuridine-Mediated Radiosensitization  

SciTech Connect

Purpose: To examine the role of DNA repair and altered thymidine analogues in altering the response to radiation during thymidine deprivation. Methods and Materials: Mismatch repair-deficient and -proficient cell lines HEC59 and HC-2.4 were treated with fluorodeoxyuridine (FUdR), azidothymidine (AZT), and irradiation either alone or in combination, and outcomes of clonogenic survival and cell-cycle distributions were determined. Results: Survival outcomes for all treatments were similar for both cell lines, suggesting that hMSH2 does not significantly influence thymidine deprivation toxicity or radiosensitization. The chain-terminating thymidine analogue AZT increased the toxicity of FUdR and increased DNA fragmentation. The combination of FUdR and AZT afforded greater radiosensitization than either drug alone. Drug enhancement ratios, the degree of excess radiation-induced cell death in drug-treated cultures compared with radiation alone for HEC59, were 1.2, 1.4, and 1.8 for AZT, FUdR, and the combination, respectively. Enhancement ratios for HC-2.4 were 1.3, 1.5, and 1.8 for AZT, FUdR, and the combination, respectively. Conclusion: Azidothymidine, a chain-terminating thymidine analogue, can enhance the radiosensitizing affects of thymidine deprivation. Deoxyribonucleic acid strand breaks may play an important role in the mechanism of thymidine deprivation-induced radiosensitization.

Chen, C.-M.; Johnson, Monika [Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA (United States); Smith, Brian J. [College of Public Health, University of Iowa, Iowa City, IA (United States); Dornfeld, Ken, E-mail: kdornfeld@smdc.or [Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA (United States)

2010-03-01

234

Complete Inhibition of Growth followed by Death of Human Malignant Melanoma Cells i\\/i Vitro and Regression of Human Melanoma Xenografts in Immunodeficient Mice Induced by Camptothecins1  

Microsoft Academic Search

The plant alkaloid camptothecin and three camptothecin derivatives were used to study responses of human malignant melanoma (BRO) cells xenografted in immunodeficient (nude) mice. Camptothecin and its derivatives 9-nitro-20(S')-camptothecin and 9-amino-20(S')-camptothe- cin inhibited growth of tumors and caused regression in all tumor- bearing mice. Tumor regression was accompanied by degenerative changes in the tumor cells, as assessed by microscopic observations

Panayotis Pantazis; Hellmuth R. Hinz; John T. Mendoza; A. J. Kozielski; Leo J. Williams; John S. Stehlin

1992-01-01

235

Laser-induced photodynamic therapy with aluminum phthalocyanine tetrasulfonate as the photosensitizer: Differential phototoxicity in normal and malignant human cells in vitro  

SciTech Connect

Photodynamic therapy (PDT) involves the use of laser or noncoherent light energy with photosensitizing dyes to induce a cytotoxic reaction in the target cells, resulting in cell injury and/or death. In this study, we have examined laser-induced phototoxicity in normal human skin fibroblasts and HT-1080 fibrosarcoma cells incubated with aluminum phthalocyanine tetrasulfonate (AlPcS) in vitro. The culture, laser, and photosensitizer parameters were varied in attempts to establish the conditions for differential cytotoxicity between normal and malignant human fibroblasts. Biochemical assays, as a measure of cytotoxicity, included (3H)thymidine incorporation (an index of DNA replication), (35S)methionine incorporation (a measure of protein synthetic activity), and the MTT assay (an indirect index of mitochondrial activity). In the absence of laser irradiation, AlPcS was non-toxic to both cell lines in concentrations up to 25 micrograms/ml. Laser light alone at 675 nm (the absorption maximum of AlPcS) had no effect on the cells at energy densities up to 16 J/cm2. In the presence of 3 or 10 micrograms/ml of AlPcS, both cell lines demonstrated marked energy-dependent toxicity. If an 8-h or a 24-h efflux period in AlPcS-free medium was allowed to take place prior to laser irradiation, normal fibroblasts were much less sensitive to PDT, whereas fibrosarcoma cells still exhibited a marked degree of toxicity. The results indicate that, under appropriate treatment conditions, AlPcS is capable of preferentially sensitizing a malignant mesenchymal cell line, while sparing its non-malignant normal cell counterpart.

Glassberg, E.; Lewandowski, L.; Lask, G.; Uitto, J. (Thomas Jefferson Univ., Philadelphia, PA (USA))

1990-05-01

236

Retinoids induce differentiation and downregulate telomerase activity and N-Myc to increase sensitivity to flavonoids for apoptosis in human malignant neuroblastoma SH-SY5Y cells  

PubMed Central

Human malignant neuroblastoma is characterized by poor differentiation and uncontrolled proliferation of immature neuroblasts. Retinoids such as all-trans-retinoic acid (ATRA), 13-cis-retinoic acid (13-CRA) and N-(4-hydroxyphenyl) retinamide (4-HPR) at low doses are capable of inducing differentiation, while flavonoids such as with (?)-epigallocatechin-3-gallate (EGCG) and genistein (GST) at relatively high dose can induce apoptosis. We used combination of retinoid and flavonoid for controlling growth of malignant neuroblastoma cells. SH-SY5Y cells were treated with a retinoid (1 ?M ATRA, 1 ?M 13-CRA, or 0.5 ?M 4-HPR) for 7 days and then with a flavonoid (25 ?M EGCG or 25 ?M GST) for 24 h. Treatment of cells with a low dose of a retinoid for 7 days induced neuronal differentiation with downregulation of telomerase activity and N-Myc but over-expression of neurofilament protein (NFP) and subsequent treatment with a relatively high dose of a flavonoid for 24 h increased apoptosis in the differentiated cells. Besides, retinoids reduced the levels of inflammatory and angiogenic factors. Apoptosis was associated with increases in intra-cellular-free [Ca2+], Bax expression, cytochrome c release from mitochondria and activities of calpain and caspases. Decreases in expression of calpastatin (endogenous calpain inhibitor) and baculovirus inhibitor-of-apoptosis repeat containing (BIRC) proteins (endogenous caspase inhibitors) favored apoptosis. Treatment of SH-SY5Y cells with EGCG activated caspase-8, indicating induction of the receptor-mediated pathway of apoptosis. Based on our observation, we conclude that combination of a retinoid and a flavonoid worked synergistically for controlling the malignant growth of human neuroblastoma cells. PMID:19212680

DAS, ARABINDA; BANIK, NAREN L.; RAY, SWAPAN K.

2009-01-01

237

Bcl-2 inhibitor and apigenin worked synergistically in human malignant neuroblastoma cell lines and increased apoptosis with activation of extrinsic and intrinsic pathways  

PubMed Central

Neuroblastoma is the most common extracranial solid tumor in infants and young children. Current treatments are not always effective and new therapies are needed. We examined efficacy of combination of the small molecule Bcl-2 inhibitor HA14-1 (HA) and the dietary isoflavonoid apigenin (APG) in human malignant neuroblastoma cells. Dose-response studies indicated that treatment with HA and APG for 24 h synergistically reduced cell viability in human malignant neuroblastoma SK-N-DZ, SH-SY5Y, and IMR32 cells. For further studies, we selected SK-N-DZ cells that showed the highest sensitivity following treatment with 2.5 ?M HA, 100 ?M APG, or combination (2.5 ?M HA + 100 ?M APG). Wright staining showed increase in morphological features of apoptosis. Cell cycle distribution and Annexin V assay showed that combination therapy caused more apoptosis than either treatment alone. Western blotting revealed that combination therapy down regulated angiogenic factors and also induced extrinsic pathway of apoptosis with activation of caspase-8 for Bid cleavage to tBid. Alterations in Bax and Bcl-2 levels resulted in an increase in Bax:Bcl-2 ratio to activate intrinsic pathway of apoptosis with mitochondrial release of cytochrome c into the cytosol and activation of proteases. Increases in calpain and caspase-3 activities generated 145 kD spectrin break down product (SBDP) and 120 kD SBDP, respectively. Results showed that combination of HA and APG could be used for down regulation of angiogenic factors and activation of extrinsic and intrinsic pathways of apoptosis in malignant neuroblastoma cells. PMID:19695221

Karmakar, Surajit; Davis, Kristin A.; Choudhury, Subhasree Roy; Deeconda, Anurag; Banik, Naren L.; Ray, Swapan K.

2009-01-01

238

Cadmium Induced Cell Apoptosis, DNA Damage, Decreased DNA Repair Capacity, and Genomic Instability during Malignant Transformation of Human Bronchial Epithelial Cells  

PubMed Central

Cadmium and its compounds are well-known human carcinogens, but the mechanisms underlying the carcinogenesis are not entirely understood. Our study was designed to elucidate the mechanisms of DNA damage in cadmium-induced malignant transformation of human bronchial epithelial cells. We analyzed cell cycle, apoptosis, DNA damage, gene expression, genomic instability, and the sequence of exons in DNA repair genes in several kinds of cells. These cells consisted of untreated control cells, cells in the fifth, 15th, and 35th passage of cadmium-treated cells, and tumorigenic cells from nude mice using flow cytometry, Hoechst 33258 staining, comet assay, quantitative real-time polymerase chain reaction (PCR), Western blot analysis, random amplified polymorphic DNA (RAPD)-PCR, and sequence analysis. We observed a progressive increase in cell population of the G0/G1 phase of the cell cycle and the rate of apoptosis, DNA damage, and cadmium-induced apoptotic morphological changes in cerebral cortical neurons during malignant transformation. Gene expression analysis revealed increased expression of cell proliferation (PCNA), cell cycle (CyclinD1), pro-apoptotic activity (Bax), and DNA damage of the checkpoint genes ATM, ATR, Chk1, Chk2, Cdc25A. Decreased expression of the anti-apoptotic gene Bcl-2 and the DNA repair genes hMSH2, hMLH1, ERCC1, ERCC2, and hOGG1 was observed. RAPD-PCR revealed genomic instability in cadmium-exposed cells, and sequence analysis showed mutation of exons in hMSH2, ERCC1, XRCC1, and hOGG1 in tumorigenic cells. This study suggests that Cadmium can increase cell apoptosis and DNA damage, decrease DNA repair capacity, and cause mutations, and genomic instability leading to malignant transformation. This process could be a viable mechanism for cadmium-induced cancers. PMID:24046522

Zhou, Zhiheng; Wang, Caixia; Liu, Haibai; Huang, Qinhai; Wang, Min; Lei, Yixiong

2013-01-01

239

Pediatric Malignancies  

Microsoft Academic Search

\\u000a Outcomes in many pediatric tumors have improved dramatically over the last few decades. Eighty percent of all children diagnosed\\u000a today with childhood malignancies are expected to be long-term survivors [1]. The number of long-term survivors in almost\\u000a every disease site and histology has increased with advancements in combined modality therapy such that a new era in cancer\\u000a therapy, treatment de-intensification

Nadia N. Issa Laack; Paula J. Schomberg; Suzanne Wolden; Jesus Vazquez

240

Enhancement of 5- Fluorouracil-induced In Vitro and In Vivo Radiosensitization with MEK Inhibition  

PubMed Central

Purpose Gastrointestinal cancers frequently exhibit mutational activation of the Ras/MAPK pathway, which is implicated in resistance to ionizing radiation (IR) and chemotherapy. Concurrent radiotherapy and 5-fluorouracil (5-FU) based chemotherapy is commonly used for treatment of gastrointestinal malignancies. We previously reported radiosensitization with selumetinib, an inhibitor of MEK1/2. The purpose of the current study was to evaluate if selumetinib could enhance radiosensitivity induced by 5-FU. Experimental Design Clonogenic survival assays were performed with the HT29 (colorectal), HCT116 (colorectal) and MiaPaca-2 (pancreatic) cell lines using pre-IR treatment with selumetinib, 5-FU and 5-FU+selumetinib. Cell proliferation was determined using a tetrazolium conversion assay. Mitotic catastrophe and DNA repair were analyzed using immunocytochemistry. Flow cytometry was used to analyze cell cycle and apoptosis. Growth delay was used to determine effects of 5-FU+selumetinib on in vivo tumor radiosensitivity. Results Pre-IR treatment with 5-FU+selumetinib significantly decreased clonogenic survival compared to either agent alone. Dose modifying factors at a surviving fraction of 0.1 for 5-FU+selumetinib was 1.78, 1.52, and 1.3 for HT29, HCT116, and MiaPaca-2, respectively. Cell proliferation was decreased by treatment with selumetinib+5-FU as compared to single agent treatment regardless of treatment sequencing. Enhancement of 5-FU cytotoxicity and 5-FU mediated radiosensitization with selumetinib treatment was accompanied by an increase in mitotic catastrophe and apoptosis, and reductions in Stat3 phosphorylation and survivin expression. In vivo, an additive growth delay was observed with 5-FU+selumetinib+5Gy versus 5-FU+5Gy and selumetinib alone. Conclusion These data suggest that selumetinib can be used with 5-FU to augment radiation response. PMID:21690569

Urick, Mary Ellen; Chung, Eun Joo; Shield, William P.; Gerber, Naamit; White, Ayla; Sowers, Anastasia; Thetford, Angela; Camphausen, Kevin; Mitchell, James; Citrin, Deborah E.

2011-01-01

241

Development of a Preclinical Orthotopic Xenograft Model of Ewing Sarcoma and Other Human Malignant Bone Disease Using Advanced In Vivo Imaging  

PubMed Central

Ewing sarcoma and osteosarcoma represent the two most common primary bone tumours in childhood and adolescence, with bone metastases being the most adverse prognostic factor. In prostate cancer, osseous metastasis poses a major clinical challenge. We developed a preclinical orthotopic model of Ewing sarcoma, reflecting the biology of the tumour-bone interactions in human disease and allowing in vivo monitoring of disease progression, and compared this with models of osteosarcoma and prostate carcinoma. Human tumour cell lines were transplanted into non-obese diabetic/severe combined immunodeficient (NSG) and Rag2?/?/?c?/? mice by intrafemoral injection. For Ewing sarcoma, minimal cell numbers (1000–5000) injected in small volumes were able to induce orthotopic tumour growth. Tumour progression was studied using positron emission tomography, computed tomography, magnetic resonance imaging and bioluminescent imaging. Tumours and their interactions with bones were examined by histology. Each tumour induced bone destruction and outgrowth of extramedullary tumour masses, together with characteristic changes in bone that were well visualised by computed tomography, which correlated with post-mortem histology. Ewing sarcoma and, to a lesser extent, osteosarcoma cells induced prominent reactive new bone formation. Osteosarcoma cells produced osteoid and mineralised “malignant” bone within the tumour mass itself. Injection of prostate carcinoma cells led to osteoclast-driven osteolytic lesions. Bioluminescent imaging of Ewing sarcoma xenografts allowed easy and rapid monitoring of tumour growth and detection of tumour dissemination to lungs, liver and bone. Magnetic resonance imaging proved useful for monitoring soft tissue tumour growth and volume. Positron emission tomography proved to be of limited use in this model. Overall, we have developed an orthotopic in vivo model for Ewing sarcoma and other primary and secondary human bone malignancies, which resemble the human disease. We have shown the utility of small animal bioimaging for tracking disease progression, making this model a useful assay for preclinical drug testing. PMID:24409320

Batey, Michael A.; Almeida, Gilberto S.; Wilson, Ian; Dildey, Petra; Sharma, Abhishek; Blair, Helen; Hide, I. Geoff; Heidenreich, Olaf; Vormoor, Josef; Maxwell, Ross J.; Bacon, Chris M.

2014-01-01

242

Sequence-Dependent Radiosensitization of Histone Deacetylase Inhibitors Trichostatin A and SK-7041  

PubMed Central

Purpose This preclinical study is to determine whether the capacity of histone deacetylase (HDAC) inhibitors to enhance radiation response depends on temporal sequences of HDAC inhibition and irradiation. Materials and Methods The effects of HDAC inhibitors trichostatin A (TSA) and SK-7041 on radiosensitivity in human lung cancer cells were examined using a clonogenic assay, exposing cells to HDAC inhibitors in various sequences of HDAC inhibition and radiation. We performed Western blot of acetylated histone H3 and flow cytometry to analyze cell cycle phase distribution. Results TSA and SK-7041 augmented radiation cell lethality in an exposure time-dependent manner when delivered before irradiation. The impact of TSA and SK-7041 on radiosensitivity rapidly diminished when HDAC inhibition was delayed after irradiation. Radiation induced the acetylation of histone H3 in cells exposed to TSA, while irradiation alone had no effect on the expression of acetylated histone H3 in TSA-naïve cells. Preirradiation exposure to TSA abrogated radiation-induced G2/M-phase arrest. When delivered after irradiation, TSA had no effect on the peak of radiation-induced G2/M-phase arrest. Conclusion TSA and SK-7041 enhances radiosensitivity only when delivered before irradiation. Unless proven otherwise, it seems prudent to apply scheduling including preirradiation HDAC inhibition so that maximal radiosensitization is obtained. PMID:24454006

Kim, Jin Ho; Shin, Jin Hee; Kim, Hak Jae; Kim, In Ah

2013-01-01

243

[Malignant peritoneal mesothelioma].  

PubMed

Mesothelioma is a neoplasm originating from the mesothelial surface lining cells of the serous human cavities. It may involve the pleura, less frequently the peritoneum rarely, the pericardium, the tunica vaginalis testis and ovarian epithelium. Asbestos has been widely used in industry. A causal relationship between asbestos exposure and pleural, peritoneal and pericardial malign mesothelioma was suggested, the risk of cancer being correlated to cumulate exposure. Studies from National Cancer Institute, USA, show that the malignant mesothelioma is a rare and aggressive asbestos related malignancy. The symptomatology is insidious and poses difficult problems in diagnosis and treatment. This paper presents the case of a 59 year old patient with malignant peritoneal mesothelioma who worked almost 40 years as an electrician, exposed to asbestos fibers. He was hospitalized for important weight loss, abdominal pain and tiredness being diagnosed after imaging tests with a giant tumor, localized at the abdominal upper level, which seems to originate from the spleen's superior pole. During surgery we discovered a tumor with cystic parts, intense vascularized, which turn to be adherent in the upper side to the lower face of the left midriff cupola, to the spleen superior pole and 1/3 middle level of the great gastric curve. It was performed surgical ablation of the tumor, splenectomy with favorable postoperative evolution, the patient being now under chemotherapy treatment. PMID:17283842

Scripcariu, V; Dajbog, Elena; Lefter, L; Ferariu, D; Pricop, Adriana; Grigora?, M; Dragomir, Cr

2006-01-01

244

Human leukocyte antigen-DO regulates surface presentation of human leukocyte antigen class II-restricted antigens on B cell malignancies.  

PubMed

Hematological malignancies often express surface HLA class II, making them attractive targets for CD4+ T cell therapy. We previously demonstrated that HLA class II ligands can be divided into DM-resistant and DM-sensitive antigens. In contrast to presentation of DM-resistant antigens, presentation of DM-sensitive antigens is suppressed by HLA-DM but can be rescued by HLA-DO. We also showed that HLA-DO expression remains low in nonhematopoietic cells under inflammatory conditions, suggesting that DM-sensitive antigens may be ideal T cell targets with a low risk for graft-versus-host disease. Here, we demonstrated that B cell malignancies often express HLA-DO and that levels are in particular high in chronic lymphocytic leukemia. Moreover, we showed that surface presentation of DM-sensitive antigens is regulated by HLA-DO, and that DM-sensitive antigens are relevant T cell targets for B cell malignancies and, especially, chronic lymphocytic leukemia. These data open the perspective to target HLA class II ligands with specific processing and presentation behavior for CD4+ T cell therapy of hematological malignancies. PMID:24530695

Kremer, Anita N; van der Meijden, Edith D; Honders, M Willy; Pont, Margot J; Goeman, Jelle J; Falkenburg, J H Frederik; Griffioen, Marieke

2014-05-01

245

Artemether Combined with shRNA Interference of Vascular Cell Adhesion Molecule-1 Significantly Inhibited the Malignant Biological Behavior of Human Glioma Cells  

PubMed Central

Artemether is the derivative extracted from Chinese traditional herb and originally used for malaria. Artemether also has potential therapeutic effects against tumors. Vascular cell adhesion molecule-1 (VCAM-1) is an important cell surface adhesion molecule associated with malignancy of gliomas. In this work, we investigated the role and mechanism of artemether combined with shRNA interference of VCAM-1 (shRNA-VCAM-1) on the migration, invasion and apoptosis of glioma cells. U87 human glioma cells were treated with artemether at various concentrations and shRNA interfering technology was employed to silence the expression of VCAM-1. Cell viability, migration, invasiveness and apoptosis were assessed with MTT, wound healing, Transwell and Annexin V-FITC/PI staining. The expression of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and phosphorylated Akt (p-Akt) was checked by Western blot assay. Results showed that artemether and shRNA-VCAM-1 not only significantly inhibited the migration, invasiveness and expression of MMP-2/9 and p-Akt, but also promoted the apoptosis of U87 cells. Combined treatment of both displayed the maximum inhibitory effects on the malignant biological behavior of glioma cells. Our work revealed the potential therapeutic effects of artemether and antiVCAM-1 in the treatments of gliomas. PMID:23593320

Wang, Ping; Xue, Yi-Xue; Yao, Yi-Long; Yu, Bo; Liu, Yun-Hui

2013-01-01

246

Nimotuzumab as a radiosensitizing agent in the treatment of high grade glioma: challenges and opportunities  

PubMed Central

Nimotuzumab is a humanized monoclonal antibody that binds specifically to human epidermal growth factor receptor, blocking receptor activation. Evidence of its radiosensitizing capacity has been widely evaluated. This article integrates published research findings regarding the role of nimotuzumab in the treatment of high grade glioma in combination with radiotherapy or radiochemotherapy in adult and pediatric populations. First, the mechanisms of action of nimotuzumab and its current applications in clinical trials containing both radiation and chemoradiation therapies are reviewed. Second, a comprehensive explanation of potential mechanisms driving radiosensitization by nimotuzumab in experimental settings is given. Finally, future directions of epidermal growth factor receptor targeting with nimotuzumab in combination with radiation containing regimens, based on its favorable toxicity profile, are proposed. It is hoped that this review may provide further insight into the rational design of new approaches employing nimotuzumab as a useful alternative for the therapeutic management of high grade glioma. PMID:23926436

Diaz-Miqueli, Arlhee; Martinez, Giselle Saurez

2013-01-01

247

Functional studies on B cells in human bone marrow: in vitro mitogen stimulation of normal and malignant B cells.  

PubMed Central

Using the protein A plaque assay, bone marrow cells from normal donors were shown to secrete spontaneously immunoglobulins mainly of the IgG and IgA class. After mitogenic activation, a marked increase in IgM production was observed with kinetics and cell density requirements similar to that of blood lymphocytes. In Morbus Waldenström patients, IgM was the predominant Ig class secreted spontaneously by bone marrow cells. The high in vitro background proliferation of these cells could be abolished by addition of the appropriate anti-idiotypic antiserum. After stimulation with mitogens, differentiation of cells within the malignant clone to immunoglobulin-secreting lymphocytes was evidenced, suggesting a retained responsive capacity of the transformed cells. PMID:6788412

Hammarstrom, L; Smith, C I; Pettersson, D; Mellstedt, H; Holm, G

1981-01-01

248

The effects of ponatinib, a multi-targeted tyrosine kinase inhibitor, against human U87 malignant glioblastoma cells  

PubMed Central

Glioblastoma is one of the most common malignant tumors in the nervous system in both adult and pediatric patients. Studies suggest that abnormal activation of receptor tyrosine kinases contributes to pathological development of glioblastoma. However, current therapies targeting tyrosine kinase receptors have poor therapeutic outcomes. Here, we examined anticancer effects of ponatinib, a multi-targeted tyrosine kinase inhibitor, on glioblastoma cells both in the U87MG cell line and in the mouse xenograft model. We showed that ponatinib treatment reduced cell viability and induced cell apoptosis in a dose-dependent manner in U87MG cells. In addition, ponatinib suppressed migration and invasion of U87MG cells effectively. Furthermore, ponatinib-treated tumors showed an obvious reduction of tumor volume and an increase of apoptosis as compared with vehicle-treated tumors in the mouse xenograft model. These findings support a potential application of ponatinib as a chemotherapeutic option against glioblastoma cells. PMID:25378936

Zhang, Junxia; Zhou, Qiang; Gao, Ge; Wang, Yanfen; Fang, Zhihui; Li, Guanlin; Yu, Mengfei; Kong, Lingfei; Xing, Ying; Gao, Xiaoqun

2014-01-01

249

Down-regulation of GnT-V enhances nasopharyngeal carcinoma cell CNE-2 radiosensitivity in vitro and in vivo  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer First investigated the role of GnT-V on the radiosensitivity of NPC cells in vitro and in vivo. Black-Right-Pointing-Pointer The mechanisms of the changing radiosensitivity were also investigated. Black-Right-Pointing-Pointer In this study, more than one experiment methods were used to investigate a problem. -- Abstract: The purpose of this study was to investigate the role of GnT-V on radiosensitivity in human nasopharyngeal carcinoma (NPC) both in vitro and in vivo, and the possible mechanism. The GnT-V stably suppressed cell line CNE-2 GnT-V/2224 was constructed from CNE-2 by transfection. The radiosensitivity of the cells was studied by CCK-8 assay, flow-cytometry, caspases-3 activity analysis and tumor xenografts model. The expression of Bcl-2, Bax and Bcl-xl was analyzed with or without radiation. The results showed that down-regulation of GnT-V enhanced CNE-2 radiosensitivity. The underlying mechanisms may be link to the cell cycle G2-M arrest and the reduction of Bcl-2/Bax ratio. The results suggest that GnT-V may be a potential target for predicting NPC response to radiotherapy.

Zhuo, Enqing; He, Jiao; Wei, Ting; Zhu, Weiliang; Meng, Hui; Li, Yan [Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou (China)] [Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou (China); Guo, Linlang, E-mail: linlangg@yahoo.com [Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou (China)] [Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou (China); Zhang, Jian, E-mail: 13925091863@139.com [Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou (China)] [Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou (China)

2012-08-03

250

Malignant melanoma of nose.  

PubMed

Malignant melanoma (MM) is one of the uncommon malignancies of the nose. We present an unusually big proliferative like MM in the vestibule of the nose. Malignancy of nose constitutes less than 1% of all malignancies (3% of head & neck tumour). MM however contributes only 2% of all malignant neoplasms of the nose (Moore & Martin. 1955). PMID:23119756

Kundu, I N; Haldar, B; Saha, A K

2001-01-01

251

C-erbB-2 or mutant Haras induced malignant transformation of immortalized human ovarian surface epithelial cells in vitro  

Microsoft Academic Search

Ovarian cancer is believed to develop from the ovarian surface epithelium through the accumulation of aberrations of oncogenes and\\/or tumor suppressor genes. However, it is unclear how the gene abnormalities are involved in ovarian carcinogenesis. To elucidate the process, we transfected genes reported to show their abnormalities in human ovarian cancers into human ovarian surface epithelial cells. Immortalization of the

T Kusakari; M Kariya; M Mandai; Y Tsuruta; A A Hamid; K Fukuhara; K Nanbu; K Takakura; S Fujii

2003-01-01

252

Lysophosphatidic acid receptor 4 signaling potentially modulates malignant behavior in human head and neck squamous cell carcinoma cells.  

PubMed

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common non-skin cancer worldwide. Despite improvement in therapeutic strategies, the prognosis of advanced HNSCC remains poor. The extacellular lipid mediators known as lysophosphatidic acids (LPAs) have been implicated in tumorigenesis of HNSCC. LPAs activate G-protein-coupled receptors not only in the endothelial differentiation gene (Edg) family (LPA1, LPA2, LPA3) but also in the phylogenetically distant non-Edg family (LPA4, LPA5, LPA6). The distinct roles of these receptor isoforms in HNSCC tumorigenesis have not been clarified. In the present study, we investigated the effect of ectopic expression of LPA4 in SQ-20B, an HNSCC cell line, expressing a trivial level of endogenous LPA4. LPA (18:1) stimulated proliferation of SQ-20B cells, but did not affect proliferation of HEp-2, an SCC cell line expressing higher levels of LPA4, comparable to those of with LPA1. LPA-stimulated proliferation of SQ-20B cells was attenuated by Ki16425 and Rac1 inhibitor, but not by Y-27632. Infection with doxycycline-regulatable adenovirus vector expressing green fluorescent protein-tagged LPA4 (AdvLPA4G) abolished LPA-stimulated proliferation in SQ-20B cells with the accumulation of G2/M-phasic cells. Ectopic LPA4 induction further downregulated proliferation of Ki16425-treated SQ-20B cells, of which downregulation was partially recovered by LPA. Ectopic LPA4 induction also downregulated proliferation of Rac1 inhibitor-treated SQ-20B cells, however, LPA no longer recovered it. Finally, LPA-induced cell motility was suppressed by ectopic LPA4 expression as well as by Ki16425, Rac1 inhibitor or Y-27632. Our data suggest that LPA4 signaling potentially modulates malignant behavior of SQ-20B cells. LPA signaling, which is mediated by both Edg and non-Edg receptors, may be a determinant of malignant behavior of HNSCC and could therefore be a promising therapeutic target. PMID:23467751

Matayoshi, Sen; Chiba, Shunmei; Lin, Yanfui; Arakaki, Kazunari; Matsumoto, Hirofumi; Nakanishi, Takaya; Suzuki, Mikio; Kato, Seiya

2013-05-01

253

Lysophosphatidic acid receptor 4 signaling potentially modulates malignant behavior in human head and neck squamous cell carcinoma cells  

PubMed Central

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common non-skin cancer worldwide. Despite improvement in therapeutic strategies, the prognosis of advanced HNSCC remains poor. The extacellular lipid mediators known as lysophosphatidic acids (LPAs) have been implicated in tumorigenesis of HNSCC. LPAs activate G-protein-coupled receptors not only in the endothelial differentiation gene (Edg) family (LPA1, LPA2, LPA3) but also in the phylogenetically distant non-Edg family (LPA4, LPA5, LPA6). The distinct roles of these receptor isoforms in HNSCC tumorigenesis have not been clarified. In the present study, we investigated the effect of ectopic expression of LPA4 in SQ-20B, an HNSCC cell line, expressing a trivial level of endogenous LPA4. LPA (18:1) stimulated proliferation of SQ-20B cells, but did not affect proliferation of HEp-2, an SCC cell line expressing higher levels of LPA4, comparable to those of with LPA1. LPA-stimulated proliferation of SQ-20B cells was attenuated by Ki16425 and Rac1 inhibitor, but not by Y-27632. Infection with doxycycline-regulatable adenovirus vector expressing green fluorescent protein-tagged LPA4 (AdvLPA4G) abolished LPA-stimulated proliferation in SQ-20B cells with the accumulation of G2/M-phasic cells. Ectopic LPA4 induction further downregulated proliferation of Ki16425-treated SQ-20B cells, of which downregulation was partially recovered by LPA. Ectopic LPA4 induction also downregulated proliferation of Rac1 inhibitor-treated SQ-20B cells, however, LPA no longer recovered it. Finally, LPA-induced cell motility was suppressed by ectopic LPA4 expression as well as by Ki16425, Rac1 inhibitor or Y-27632. Our data suggest that LPA4 signaling potentially modulates malignant behavior of SQ-20B cells. LPA signaling, which is mediated by both Edg and non-Edg receptors, may be a determinant of malignant behavior of HNSCC and could therefore be a promising therapeutic target. PMID:23467751

MATAYOSHI, SEN; CHIBA, SHUNMEI; LIN, YANFUI; ARAKAKI, KAZUNARI; MATSUMOTO, HIROFUMI; NAKANISHI, TAKAYA; SUZUKI, MIKIO; KATO, SEIYA

2013-01-01

254

C-Kit Expression, Angiogenesis, and Grading in Canine Mast Cell Tumour: A Unique Model to Study C-Kit Driven Human Malignancies  

PubMed Central

Canine cutaneous mast cell tumour (CMCT) is a c-Kit driven tumour sharing similar c-Kit aberrations found in human gastrointestinal stromal tumour. CMCT is classified into three forms: well- (G1), intermediately (G2) (more benign diseases), and poorly (G3) differentiated (malignant) forms. We assess a correlation between c-Kit status, grading, and angiogenesis in CMCTs to explore their potential significance in humans. C-Kit receptor (c-KitR) expression, microvascular density (MVD), and mast cell granulated and degranulated status density (MCGD and MCDD, resp.) were analyzed in 97 CMCTs, by means of histochemistry, immunohistochemistry double staining, and image analysis system. Data showed that predominantly diffuse cytoplasmic- and predominantly focal paranuclear- (Golgi-like) c-Kit protein (PDC-c-Kit and PFP-c-Kit, resp.) expression correlate with high MVD, G3 histopathological grade, and MCDD. Moreover, predominant cell membrane-c-KitR (PCM-c-KitR) expression status correlates with low MVD, G1-G2 histopathological grade, and MCGD. These findings underline the key role of c-Kit in the biopathology of canine MCTs, indicating a link between aberrant c-Kit expression, increased angiogenesis, and higher histopathological grade. CMCT seems to be a model to study contributions of c-Kit activated MCs in tumour angiogenesis and to evaluate the inhibition of MCs activation by means of c-Kit tyrosine kinase inhibitors, currently translated in humans. PMID:24900982

Patruno, Rosa; Marech, Ilaria; Zizzo, Nicola; Nardulli, Patrizia; Introna, Marcello; Capriuolo, Gennaro; Rubini, Rosa Angela; Ribatti, Domenico; Gadaleta, Cosmo Damiano

2014-01-01

255

c-Kit expression, angiogenesis, and grading in canine mast cell tumour: a unique model to study c-Kit driven human malignancies.  

PubMed

Canine cutaneous mast cell tumour (CMCT) is a c-Kit driven tumour sharing similar c-Kit aberrations found in human gastrointestinal stromal tumour. CMCT is classified into three forms: well- (G1), intermediately (G2) (more benign diseases), and poorly (G3) differentiated (malignant) forms. We assess a correlation between c-Kit status, grading, and angiogenesis in CMCTs to explore their potential significance in humans. C-Kit receptor (c-KitR) expression, microvascular density (MVD), and mast cell granulated and degranulated status density (MCGD and MCDD, resp.) were analyzed in 97 CMCTs, by means of histochemistry, immunohistochemistry double staining, and image analysis system. Data showed that predominantly diffuse cytoplasmic- and predominantly focal paranuclear- (Golgi-like) c-Kit protein (PDC-c-Kit and PFP-c-Kit, resp.) expression correlate with high MVD, G3 histopathological grade, and MCDD. Moreover, predominant cell membrane-c-KitR (PCM-c-KitR) expression status correlates with low MVD, G1-G2 histopathological grade, and MCGD. These findings underline the key role of c-Kit in the biopathology of canine MCTs, indicating a link between aberrant c-Kit expression, increased angiogenesis, and higher histopathological grade. CMCT seems to be a model to study contributions of c-Kit activated MCs in tumour angiogenesis and to evaluate the inhibition of MCs activation by means of c-Kit tyrosine kinase inhibitors, currently translated in humans. PMID:24900982

Patruno, Rosa; Marech, Ilaria; Zizzo, Nicola; Ammendola, Michele; Nardulli, Patrizia; Gadaleta, Claudia; Introna, Marcello; Capriuolo, Gennaro; Rubini, Rosa Angela; Ribatti, Domenico; Gadaleta, Cosmo Damiano; Ranieri, Girolamo

2014-01-01

256

Differential ?2-adrenergic receptor expression defines the phenotype of non-tumorigenic and malignant human breast cell lines.  

PubMed

Breast cancer is the most frequent malignancy in women. Several reports demonstrated that adrenergic receptors (ARs) are involved in breast cancer. Here we observed that epinephrine (Epi), an endogenous AR agonist, caused opposite effects in non-tumorigenic (MCF-10A and HBL-100) and tumor cells (MCF-7 and MDA-MB-231). Thus, Epi, in non-tumor breast cells, as well as isoproterenol (?-agonist), in all cell lines, maintained a benign phenotype, decreasing cell proliferation and migration, and stimulating cell adhesion. ?-AR expression and cAMP levels were higher in MCF-10A than in MCF-7 cells. ?2-AR knock-down caused a significant increase of cell proliferation and migration, and a decrease of cell adhesion both in basal and in Iso-stimulated conditions. Coincidently, ?2-AR over-expression induced a significant decrease of cell proliferation and migration, and an increase of cell adhesion. Therefore, ?2-AR is implied in cell phenotype and its agonists or antagonists could eventually complement cancer therapy. PMID:25375203

Gargiulo, Lucía; Copsel, Sabrina; Rivero, Ezequiel M; Galés, Céline; Sénard, Jean-Michel; Lüthy, Isabel A; Davio, Carlos; Bruzzone, Ariana

2014-10-30

257

Anticancer activity of extracts derived from the mature roots of Scutellaria baicalensis on human malignant brain tumor cells  

PubMed Central

Background Flavonoid-rich extracts from the mature roots of Scutellaria baicalensis have been shown to exhibit antiproliferative effects on various cancer cell lines. We assessed the ability of an ethanolic extract of S. baicalensis root to inhibit the proliferation of malignant glioma cells. Methods Cell lines derived from primary and recurrent brain tumors from the same patient and cells selected for resistance to the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) were used to identify antiproliferative effects of this extract when used alone and in conjunction with BCNU. Results and discussion Results indicated that Scutellaria baicalensis not only inhibits cellular growth in recurrent and drug resistant brain tumor cell lines, but also demonstrates an increased inhibitory effect when used in conjunction with BCNU. Conclusion The results of this study support the efficacy of S. baicalensis as an anticancer agent for glioblastomas multiforme and a potential adjuvant treatment to current chemotherapeutic agents used in the treatment of both primary and recurrent GBMs. Further studies of the effects of individual flavonoids alone and in combination with each other and with currently used therapies are needed. PMID:16914050

Scheck, Adrienne C; Perry, Krya; Hank, Nicole C; Clark, W Dennis

2006-01-01

258

Northwestern profiling of potential translation-regulatory proteins in human breast epithelial cells and malignant breast tissues: evidence for pathological activation of the IGF1R IRES  

PubMed Central

Genes involved in the control of cell proliferation and survival (those genes most important to cancer pathogenesis) are often specifically regulated at the translational level, through RNA-protein interactions involving the 5’-untranslated region of the mRNA. IGF1R is a proto-oncogene strongly implicated in human breast cancer, promoting survival and proliferation of tumor cells, as well as metastasis and chemoresistance. Our lab has focused on the molecular mechanisms regulating IGF1R expression at the translational level. We previously discovered an internal ribosome entry site (IRES) within the 5’-untranslated region of the human IGF1R mRNA, and identified and functionally characterized two individual RNA-binding proteins, HuR and hnRNP C, which bind the IGF1R 5’-UTR and differentially regulate IRES activity. Here we have developed and implemented a high resolution northwestern profiling strategy to characterize, as a group, the full spectrum of sequence-specific RNA-binding proteins potentially regulating IGF1R translational efficiency through interaction with the 5’-untranslated sequence. The putative IGF1R IRES trans-activating factors (ITAFs) are a heterogeneous group of RNA-binding proteins including hnRNPs originating in the nucleus as well as factors tightly associated with ribosomes in the cytoplasm. The IGF1R ITAFs can be categorized into three distinct groups: (a) high molecular weight external ITAFs, which likely modulate the overall conformation of the 5’-untranslated region of the IGF1R mRNA and thereby the accessibility of the core functional IRES; (b) low molecular weight external ITAFs, which may function as general chaperones to unwind the RNA, and (c) internal ITAFs which may directly facilitate or inhibit the fundamental process of ribosome recruitment to the IRES. We observe dramatic changes in the northwestern profile of non-malignant breast cells downregulating IGF1R expression in association with acinar differentiation in 3-D culture. Most importantly, we are able to assess the RNA-binding activities of these putative translation-regulatory proteins in primary human breast surgical specimens, and begin to discern positive correlations between individual ITAFs and the malignant phenotype. Together with our previous findings, these new data provide further evidence that pathological dysregulation of IGF1R translational control may contribute to development and progression of human breast cancer, and breast metastasis in particular. PMID:20233590

Blume, Scott W.; Jackson, Nateka L.; Frost, Andra R.; Grizzle, William E.; Shcherbakov, Oleg D.; Choi, Hyoungsoo; Meng, Zheng

2010-01-01

259

Human herpesvirus 8: Biology and role in the pathogenesis of Kaposi’s sarcoma and other AIDS-related malignancies  

Microsoft Academic Search

Human herpesvirus type 8, or Kaposi’s sarcoma-associated herpesvirus (KSHV), is the only known human 2 herpesvirus (rhadinovirus)\\u000a and the most recently discovered tumor virus. KSHV is associated with Kaposi’s sarcoma and two other lymphoproliferative disorders\\u000a in the AIDS setting: primary effusion lymphoma and the plasma cell variant of multicentric Castleman’s disease. This review\\u000a offers an update on the epidemiology and

Abel Viejo-Borbolla; Matthias Ottinger; Thomas F. Schulz

2003-01-01

260

Human herpesvirus 8: Biology and role in the pathogenesis of Kaposi’s sarcoma and other aids-related malignancies  

Microsoft Academic Search

Human herpesvirus type 8, or Kaposi’s sarcoma-associated herpesvirus (KSHV), is the only known human ? 2 herpesvirus (rhadinovirus) and the most recently discovered tumor virus. KSHV is associated with Kaposi’s sarcoma and two\\u000a other lymphoproliferative disorders in the AIDS setting: primary effusion lymphoma and the plasma cell variant of multicentric\\u000a Castleman’s disease. This review offers an update on the epidemiology

Abel Viejo-Borbolla; Matthias Ottinger; Thomas F. Schulz

2004-01-01

261

Expression of hPNAS-4 Radiosensitizes Lewis Lung Cancer  

SciTech Connect

Purpose: This study aimed to transfer the hPNAS-4 gene, a novel apoptosis-related human gene, into Lewis lung cancer (LL2) and observe its radiosensitive effect on radiation therapy in vitro and in vivo. Methods and Materials: The hPNAS-4 gene was transfected into LL2 cells, and its expression was detected via western blot. Colony formation assay and flow cytometry were used to detect the growth and apoptosis of cells treated with irradiation/PNAS-4 in vitro. The hPNAS-4 gene was transferred into LL2-bearing mice through tail vein injection of the liposome/gene complex. The tumor volumes were recorded after radiation therapy. Proliferating cell nuclear antigen (PCNA) immunohistochemistry staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed to detect the tumor cell growth and apoptosis in vivo. Results: The hPNAS-4 gene was successfully transferred into LL2 cells and tumor tissue, and its overexpressions were confirmed via western blot analysis. Compared with the control, empty plasmid, hPNAS-4, radiation, and empty plasmid plus radiation groups, the hPNAS-4 plus radiation group more significantly inhibited growth and enhanced apoptosis of LL2 cells in vitro and in vivo (P<.05). Conclusions: The hPNAS-4 gene was successfully transferred into LL2 cells and tumor tissue and was expressed in both LL2 cell and tumor tissue. The hPNAS-4 gene therapy significantly enhanced growth inhibition and apoptosis of LL2 tumor cells by radiation therapy in vitro and in vivo. Therefore, it may be a potential radiosensitive treatment of radiation therapy for lung cancer.

Zeng Hui [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)] [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Yuan Zhu [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)] [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Zhu Hong [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)] [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Li Lei; Shi Huashan [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)] [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Wang Zi; Fan Yu; Deng Qian; Zeng Jianshuang; He Yinbo [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)] [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Xiao Jianghong [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)] [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Li Zhiping, E-mail: lizhiping620312@yahoo.com.cn [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)

2012-11-15

262

Mechanisms of Disease: radiosensitization by epidermal growth factor receptor inhibitors  

Microsoft Academic Search

The epidermal growth factor receptor (EGFR) inhibitors are among the most intensely studied new molecular therapeutic agents. Although response rates have been somewhat disappointing when EGFR inhibitors are used as single-agent therapy for advanced disease, these inhibitors may be more effective as chemo- and radiosensitizers. The first phase III randomized trial evaluating EGFR inhibitors as radiosensitizers in patients with locally

Carolyn I Sartor

2004-01-01

263

Immunohistochemical expression of SFRP1 and SFRP3 proteins in normal and malignant reproductive tissues of rats and humans.  

PubMed

Secreted frizzled-related proteins 1 and 3 (SFRP1 and SFRP3) act as Wnt signaling pathway antagonists and play an important role in embryonic development and carcinogenesis. The aim of the present study was to analyze immunohistochemically the distribution of 2 SFRP family proteins, SFRP1 and SFRP3, in an experimental rat model, in normal and intrauterine growth-restricted (IUGR) human placentas, and in a subset of the corresponding human trophoblastic tumors (pure choriocarcinomas and mixed germ cell tumors with choriocarcinoma component). In rats, expression of both SFRP1 and SFRP3 was pronounced in the perimetrium and myometrium, whereas decidual cells showed only occasional positive cytoplasmic staining. The most prominent expression of both proteins was found in blood vessel endothelial cells. Stereological variable of volume density (Vv, mm) showed statistically higher expression of SFRP1 and SFRP3 in human IUGR placentas than in normal pregnancy placentas (P<0.0001). Compared with adjacent normal/benign tissues, reduced expression of SFRP1 and SFRP3 was observed in human trophoblastic tumors (58.5% and 31.25%, respectively), although none of the examined tumors exhibited complete loss of either protein. Our study indicates that increased expression of both SFRP1 and SFRP3 may contribute to the pathogenesis of IUGR placental dysfunction, whereas the loss of these proteins may be involved in the development of human trophoblastic tumors. PMID:25046226

Partl, Jasenka Z; Fabijanovic, Dora; Skrtic, Anita; Vranic, Semir; Martic, Tamara N; Serman, Ljiljana

2014-10-01

264

Advances in radiation biology: Relative radiation sensitivities of human organ systems. Volume 12  

SciTech Connect

This volume is a thematically focused issue of Advances in Radiation Biology. The topic surveyed is relative radiosensitivity of human organ systems. Topics considered include relative radiosensitivities of the thymus, spleen, and lymphohemopoietic systems; relative radiosensitivities of the small and large intestine; relative rediosensitivities of the oral cavity, larynx, pharynx, and esophagus; relative radiation sensitivity of the integumentary system; dose response of the epidermal; microvascular, and dermal populations; relative radiosensitivity of the human lung; relative radiosensitivity of fetal tissues; and tolerance of the central and peripheral nervous system to therapeutic irradiation.

Lett, J.T.; Altman, K.I.; Ehmann, U.K.; Cox, A.B.

1987-01-01

265

A new treatment for human malignant melanoma targeting L-type amino acid transporter 1 (LAT1): A pilot study in a canine model  

SciTech Connect

Highlights: •LAT1 is highly expressed in tumors but at low levels in normal tissues. •We examine LAT1 expression and function in malignant melanoma (MM). •LAT1 expression in MM tissues and cell lines is higher than those in normal tissues. •LAT1 selective inhibitors inhibit amino acid uptake and cell growth in MM cells. •New chemotherapeutic protocols including LAT1 inhibitors are effective for treatment. -- Abstract: L-type amino acid transporter 1 (LAT1), an isoform of amino acid transport system L, transports branched or aromatic amino acids essential for fundamental cellular activities such as cellular growth, proliferation and maintenance. This amino acid transporter recently has received attention because of its preferential and up-regulated expression in a variety of human tumors in contrast to its limited distribution and low-level expression in normal tissues. In this study, we explored the feasibility of using LAT1 inhibitor as a new therapeutic agent for human malignant melanomas (MM) using canine spontaneous MM as a model for human MM. A comparative study of LAT expression was performed in 48 normal tissues, 25 MM tissues and five cell lines established from MM. The study observed LAT1 mRNA levels from MM tissues and cell lines that were significantly (P < 0.01) higher than in normal tissues. Additionally, MM with distant metastasis showed a higher expression than those without distant metastasis. Functional analysis of LAT1 was performed on one of the five cell lines, CMeC-1. [{sup 3}H]L-Leucine uptake and cellular growth activities in CMeC-1 were inhibited in a dose-dependent manner by selective LAT1 inhibitors (2-amino-2-norbornane-carboxylic acid, BCH and melphalan, LPM). Inhibitory growth activities of various conventional anti-cancer drugs, including carboplatin, cyclophosphamide, dacarbazine, doxorubicin, mitoxantrone, nimustine, vinblastine and vincristine, were significantly (P < 0.05) enhanced by combination use with BCH or LPM. These findings suggest that LAT1 could be a new therapeutic target for MM.

Fukumoto, Shinya; Hanazono, Kiwamu [Veterinary Internal Medicine, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan)] [Veterinary Internal Medicine, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan); Fu, Dah-Renn; Endo, Yoshifumi; Kadosawa, Tsuyoshi [Veterinary Oncology, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan)] [Veterinary Oncology, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan); Iwano, Hidetomo [Veterinary Biochemistry, Department of Basic Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan)] [Veterinary Biochemistry, Department of Basic Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan); Uchide, Tsuyoshi, E-mail: uchide@rakuno.ac.jp [Veterinary Internal Medicine, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan)] [Veterinary Internal Medicine, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan)

2013-09-13

266

Taxonomic and developmental aspects of radiosensitivity  

SciTech Connect

Considerable information is available on the effects of radioactivity on adult and early life stages of organisms. The preponderance of data is on mortality after a single irradiation with relatively high doses. Unfortunately, because experiments were carried out under different conditions and for different time periods, the validity of comparing the results from different laxonomic groups is questionable. In general, the conclusions are that there is a relationship (1) between radioresistance to high doses of acute radiation and taxonomy of the organism, primitive forms being more radioresistant than complex vertebrates and (2) between radiosensitivity and developmental stage, early life stages being more sensitive than later stages. The first conclusion may be related to the capability of the organism to repopulate cells and to differentiate and redifferentiate them; the second to the rate of cellular division and to the degree of differentiation. In question, however, is the relevance of the responses from high levels of acute radiation to that of the responses to long-term exposure to low levels of radiation, which are ecologically of more interest. Data from studies of the effects of acute and chronic exposure on development of gametes and zygotes indicate that, for some fishes and invertebrates, responses at the cellular and molecular levels show effect levels comparable to those observed in some mammals. Acute doses between 0,05 and 0.5Cy and dose rates between 0.02 to 0.2mCy/h appear to define critical ranges in which detrimental effects on fertility are first observed in a variety of radiosensitive organisms. To better understand inherent radiosensitivity, we need more information on the ability of cells to repopulate and differentiate and to prevent or repair damage to biological critical molecules, such as DNA, because these factors may alter significantly organisms` responses to radiation.

Harrison, F.L. [Lawrence Livermore National Lab., CA (United States); Anderson, S.L. [Lawrence Berkeley National Lab., CA (United States)

1996-11-01

267

On the mechanism of salivary gland radiosensitivity  

SciTech Connect

Purpose: To contribute to the understanding of the enigmatic radiosensitivity of the salivary glands by analysis of appropriate literature, especially with respect to mechanisms of action of early radiation damage, and to supply information on the possibilities of amelioration of radiation damage to the salivary glands after radiotherapy of head-and-neck cancer. Methods and Materials: Selected published data on the mechanism of salivary gland radiosensitivity and radioprotection were studied and analyzed. Results: From a classical point of view, the salivary glands should not respond as rapidly to radiation as they appear to do. Next to the suggestion of massive apoptosis, the leakage of granules and subsequent lysis of acinar cells was suggested to be responsible for the acute radiation-induced function loss of the salivary glands. The main problem with these hypotheses is that recently performed assays show no cell loss during the first days after irradiation, while saliva flow is dramatically diminished. The water secretion is selectively hampered during the first days after single-dose irradiation. Literature is discussed that shows that the compromised cells suffer selective radiation damage to the plasma membrane, disturbing signal transduction primarily affecting watery secretion. Although the cellular composition of the submandibular gland and the parotid gland are different, the damage response is very alike. The acute radiation-induced function loss in both salivary glands can be ameliorated by prophylactic treatment with specific receptor agonists. Conclusions: The most probable mechanism of action, explaining the enigmatic high radiosensitivity for early effects, is selective radiation damage to the plasma membrane of the secretory cells, disturbing muscarinic receptor stimulated watery secretion. Later damage is mainly due to classical mitotic cell death of progenitor cells, leading to a hampered replacement capacity of the gland for secretory cells, but is also caused by damage to the extracellular environment, preventing proper cell functioning.

Konings, Antonius W.T. [Department of Radiation and Stress Cell Biology, University of Groningen, Groningen (Netherlands)]. E-mail: a.w.t.konings@med.rug.nl; Coppes, Rob P. [Department of Radiation and Stress Cell Biology, University of Groningen, Groningen (Netherlands); Department of Radiation Oncology, University Hospital Groningen, Groningen (Netherlands); Vissink, Arjan [Department of Oral and Maxillofacial Surgery, University Hospital, Groningen (Netherlands)

2005-07-15

268

Expression of pro-opiomelanocortin gene and quantification of adrenocorticotropic hormone-like immunoreactivity in human normal peripheral mononuclear cells and lymphoid and myeloid malignancies.  

PubMed Central

Using Northern blotting with a human genomic DNA probe for the pro-opiomelanocortin (POMC) gene, we have shown specific mRNA in normal human peripheral mononuclear cells (PBMC); the presence of specific mRNA was also observed in a T lymphocyte cell line derived from a patient with lymphoma. We then demonstrated that PBMC translate the message into protein. Thus, using a radioimmunoassay with an antibody for ACTH, a median of 29 pg of ACTH-like immunoreactivity (ACTH-LIR) was found in 10(7) PBMC. ACTH-LIR was also detected in seven different cell lines derived from patients with lymphoid and myeloid malignancies, two of them JM and U937 showing the highest values 135 and 108 pg/10(7) cells, respectively. The chromatographic characterization of this ACTH-LIR showed, at least, three molecular forms of immunoreactive ACTH with molecular weights of the order of 31,000 POMC, 22,000 ACTH, and 4,500 ACTH, in addition to high-molecular-weight material (greater than 43,000). We conclude that PBMC produce ACTH-LIR which may act as a paracrine immunomodulator in a similar way to lymphokines and/or may signal the adrenal gland to secrete glucocorticoids. Images PMID:2536407

Buzzetti, R; McLoughlin, L; Lavender, P M; Clark, A J; Rees, L H

1989-01-01

269

Enhancement of radiosensitivity by dual inhibition of the HER family with ZD1839 ('Iressa') and trastuzumab ('Herceptin')  

SciTech Connect

Purpose: The aims of this study were twofold: (1) to examine the effects of dual inhibition of 2 members of the HER family, the epidermoid growth factor receptor (EGFR) and HER2/neu, by gefitinib (ZD1839) and trastuzumab on radiosensitivity; and (2) to explore the molecular mechanism of radiosensitization especially focusing on the survival signal transduction pathways by using A431 human vulvar squamous carcinoma cells expressing EGFR and HER2/neu. Methods and Materials: The effects of inhibitors on Radiation-induced activation of EGFR and/or HER2/neu, and the intracellular proteins that are involved in their downstream signaling, were quantified by the Western blot. Radiosensitizing effects by the blockage of EGFR and/or HER2/neu were determined by a clonogenic assay. Results: Radiation-induced activation of the EGFR and HER2/neu was inhibited with ZD1839 and/or trastuzumab. ZD1839 also inhibited Radiation-induced phosphorylation of HER2/neu. Radiation in combination with the HER family inhibitors inhibited the activation of Akt and MEK1/2, the downstream survival signaling of the HER family. ZD1839 enhanced radiosensitivity with a dose-modifying factor (DMF) (SF3) of 1.45 and trastuzumab did so with a DMF (SF3) of 1.11. Simultaneous blockade of EGFR and HER2/neu induced a synergistic radiosensitizing effect with a DMF (SF3) of 2.29. Conclusions: The present data suggest that a dual EGFR and HER2/neu targeting may have potential for radiosensitization in tumors in which both of these pathways are active.

Fukutome, Mika [Department of Radiology, Tokyo Women's Medical University, School of Medicine, Tokyo (Japan)]. E-mail: fukutome@rad.twmu.ac.jp; Maebayashi, Katsuya [Department of Radiology, Tokyo Women's Medical University, School of Medicine, Tokyo (Japan); Nasu, Sachiko [Department of Radiology, Tokyo Women's Medical University, School of Medicine, Tokyo (Japan); Seki, Kaori [Department of Radiology, Tokyo Women's Medical University, School of Medicine, Tokyo (Japan); Mitsuhashi, Norio [Department of Radiology, Tokyo Women's Medical University, School of Medicine, Tokyo (Japan)

2006-10-01

270

Differential Radiosensitizing Potential of Temozolomide in MGMT Promoter Methylated Glioblastoma Multiforme Cell Lines  

SciTech Connect

Purpose: To investigate the radiosensitizing potential of temozolomide (TMZ) for human glioblastoma multiforme (GBM) cell lines using single-dose and fractionated {gamma}-irradiation. Methods and Materials: Three genetically characterized human GBM cell lines (AMC-3046, VU-109, and VU-122) were exposed to various single (0-6 Gy) and daily fractionated doses (2 Gy per fraction) of {gamma}-irradiation. Repeated TMZ doses were given before and concurrent with irradiation treatment. Immediately plated clonogenic cell-survival curves were determined for both the single-dose and the fractionated irradiation experiments. To establish the net effect of clonogenic cell survival and cell proliferation, growth curves were determined, expressed as the number of surviving cells. Results: All three cell lines showed MGMT promoter methylation, lacked MGMT protein expression, and were sensitive to TMZ. The isotoxic TMZ concentrations used were in a clinically feasible range of 10 {mu}mol/L (AMC-3046), 3 {mu}mol/L (VU-109), and 2.5 {mu}mol/L (VU-122). Temozolomide was able to radiosensitize two cell lines (AMC 3046 and VU-122) using single-dose irradiation. A reduction in the number of surviving cells after treatment with the combination of TMZ and fractionated irradiation was seen in all three cell lines, but only AMC 3046 showed a radiosensitizing effect. Conclusions: This study on TMZ-sensitive GBM cell lines shows that TMZ can act as a radiosensitizer and is at least additive to {gamma}-irradiation. Enhancement of the radiation response by TMZ seems to be independent of the epigenetically silenced MGMT gen000.

Nifterik, Krista A. van [Department of Radiation Oncology, VU University Medical Center, Amsterdam (Netherlands); Department of Neurogenetics, Academic Medical Center, Amsterdam (Netherlands); Berg, Jaap van den [Department of Radiation Oncology, VU University Medical Center, Amsterdam (Netherlands); Stalpers, Lukas J.A. [Department of Radiotherapy, Academic Medical Center, Amsterdam (Netherlands); Lafleur, M. Vincent M. [Department of Radiation Oncology, VU University Medical Center, Amsterdam (Netherlands); Leenstra, Sieger [Department of Neurosurgery, Academic Medical Center, Amsterdam (Netherlands); Slotman, Ben J. [Department of Radiation Oncology, VU University Medical Center, Amsterdam (Netherlands); Hulsebos, Theo J.M. [Department of Neurogenetics, Academic Medical Center, Amsterdam (Netherlands); Sminia, Peter [Department of Radiation Oncology, VU University Medical Center, Amsterdam (Netherlands)], E-mail: p.sminia@vumc.nl

2007-11-15

271

The meaning of the anti-cancer antibody CLN-IgG (Pritumumab) generated by human × human hybridoma technology against the cyto-skeletal protein, vimentin, in the course of the treatment of malignancy.  

PubMed

Cancer stem cells in a tumor mass form a very small subpopulation ranging from below 0.1% in a brain tumor but they have the crucial ability to become malignant. The goal of cancer therapy has been the total killing of tumor cells. However we should clarify that most of all tumor cells are differentiated cancer cells. Thus the elimination of 99.9% of tumor cells under histological criteria cannot ensure the cancer will be cured. Rather cancer cell biologists should turn their attention to reprogramming cancer stem cells to normal stem cells by which malignancy recuperates normal organogenesis from the aspect of the dichotomy of cancer stem cell. The cue points underlying the reverse cancer stem cell at blastogenesis in inflammation site is depending upon cell-to-cell recognition of the tumor-niche cells. Normalization of tumor-niche promises to lead cancer stem cell into normal stem cell owing to autonomous healing mechanisms that reside in the self-defense mechanisms in immunity and the cell competition mechanisms in the wound healing of the tissue cells. Among the cyto-skeletal proteins, vimentin becomes a target of self-restoration of cancer stem cell by means of immune surveillance. A human monoclonal antibody, CLN-IgG recognizes vimentin expressing on the cell surface of the malignant tumor. Since vimentin network resides in the cytoplasm connecting the plasma membrane with chromatin assembly in the nucleus, it is highly likely vimentin plays an important role in up-regulation and down-regulation through signal transduction between certain membrane receptors and gene expression with respect to the transformation of the cell. Aberrant arrangement of vimentin undergoes malignancy accompanied by epithelial-mesenchymal-transition relating to the aberrant apoptotic cellular behavior in the tumor-niche. Restraint of the aberrant expression of vimentin on the plasma membrane of the malignant cell evokes a pertinent signal transduction pathway for healing that is an indication there must be a reverse path that reprograms cancer stem cells to normal organogenesis. PMID:23856243

Hugwil, Albert V

2013-09-01

272

Mutant EGFRs, p16 Bypass, Telomerase) Are Not Sufficient to Confer a Full Malignant Phenotype on Human Bronchial Epithelial Cells  

Microsoft Academic Search

We evaluated the contribution of three genetic alterations (p53 knockdown, K-RASV12 ,a ndmutant EGFR )t o lung tumorigenesis using human bronchial epithelial cells (HBEC) immortalized with telomerase and Cdk4-mediated p16 bypass. RNA interference p53 knockdown or oncogenic K-RASV12 resulted in enhanced anchorage-independent growth and increased saturation density of HBECs. The combination of p53 knockdown and K-RASV12 further enhanced the tumori-

Mitsuo Sato; Melville B. Vaughan; Luc Girard; Michael Peyton; Woochang Lee; David S. Shames; Ruben D. Ramirez; Noriaki Sunaga; Adi F. Gazdar; Jerry W. Shay

2006-01-01

273

The human anti-CD30 antibody 5F11 shows in vitro and in vivo activity against malignant lymphoma  

Microsoft Academic Search

CD30 is a promising target for antibody- based immunotherapy of Hodgkin lym- phoma (HL) and anaplastic large cell lym- phoma. To overcome the limitations from currently available murine anti-CD30 monoclonal antibodies (mAbs), a new fully human anti-CD30 antibody was gener- ated. Binding properties were evaluated by recombinant CD30 capture enzyme- linked immunosorbent assay (ELISA) and fluorescence-activated cell-sorter (FACS) flow cytometry.

Peter Borchmann; John F. Treml; Hinrich Hansen; Claudia Gottstein; Roland Schnell; Oliver Staak; Hui-fen Zhang; Thomas Davis; Tibor Keler; Volker Diehl; Robert F. Graziano; Andreas Engert

2003-01-01

274

Light and electron microscopical demonstration of c- erbB -2 gene product-like immunoreactivity in human malignant tumors  

Microsoft Academic Search

Summary  \\u000a C-erbB- 2 is a human protooncogene homologous with the well-knownc-erbB. Genes and gene products of the EGF receptor andc-erbB are known to be closely related and to be closely homologous in their intracellular domain. Inspection of the deduced amino\\u000a acid sequence suggested that thec-erbB- 2 gene encodes a receptor for a yet unidentified growth factor. An immunohistological study was

Shigeo Mori; Tetsu Akiyama; Yasuyuki Morishita; Sho-ichi Shimizu; Keisuke Sakai; Katsuko Sudoh; Kumao Toyoshima; Tadashi Yamamoto

1987-01-01

275

Radiosensitization Effect of Nedaplatin on Nasopharyngeal Carcinoma Cells in Different Status of Epstein-Barr Virus Infection  

PubMed Central

This study aims to evaluate the radiosensitization effect of nedaplatin on nasopharyngeal carcinoma (NPC) cell lines with different Epstein-Barr virus (EBV) status. Human NPC cell lines CNE-2 (EBV-negative) and C666 (EBV-positive) were treated with 0–100??g/mL nedaplatin, and inhibitory effects on cell viability and IC50 were calculated by MTS assay. We assessed changes in radiosensitivity of cells by MTS and colony formation assays, and detected the apoptosis index and changes in cell cycle by flow cytometry. MTS assay showed that nedaplatin caused significant cytotoxicity in CNE-2 and C666 cells in a time- and dose-dependent manner. After 24?h, nedaplatin inhibited growth of CNE-2 and C666 cells with IC50 values of 34.32 and 63.69??g/mL, respectively. Compared with radiation alone, nedaplatin enhanced the radiation effect on both cell lines. Nedaplatin markedly increased apoptosis and cell cycle arrest in G2/M phase. Nedaplatin radiosensitized human NPC cells CNE-2 and C666, with a significantly greater effect on the former. The mechanisms of radiosensitization include induction of apoptosis and enhancement of cell cycle arrest in G2/M phase. PMID:24900979

Wu, Jing; Wu, Jianfeng; Ye, Jinjun; Jiang, Xuesong; Chen, Meng; Wang, Dejun; Wang, Xue; Zong, Dan; Gu, Jiajia; Zhang, Junying; Wu, Jianzhong; Xu, Lin; Guo, Wenjie

2014-01-01

276

Prolactin-immunoglobulin G complexes from human serum act as costimulatory ligands causing proliferation of malignant B lymphocytes.  

PubMed Central

Several lines of evidence indicate that immunoglobulin-bound prolactin found in human serum is not a conventional complex between an anti-prolactin antibody and prolactin but a different type of association of prolactin with the Fab portion of IgG heavy chains. The complex of prolactin with IgG was purified from serum by anti-human prolactin affinity chromatography and was shown to contain close to 1 mole of N epsilon-(gamma-glutamyl)lysine crosslinks per mole of complex, a characteristic feature in structures crosslinked by transglutaminase. Interestingly, the complex caused a proliferation of cells from a subset of patients with chronic lymphocytic leukemia, while it was inactive in a cell proliferation prolactin bioassay. By contrast, human prolactin stimulated the proliferation of cells in the bioassay but had no effect on the complex-responsive cells from the patients. Competition studies with prolactin and free Fc fragment of IgG demonstrated a necessity for engaging both the prolactin and the immunoglobulin receptors for proliferation. More importantly, competition for the growth response by free prolactin and IgG suggests both possible reasons for the slow growth of this neoplasm as well as avenues for control of the disease. Images Fig. 1 Fig. 2 Fig. 4 PMID:7724552

Walker, A M; Montgomery, D W; Saraiya, S; Ho, T W; Garewal, H S; Wilson, J; Lorand, L

1995-01-01

277

Malignant transformation of human colon epithelial cells by benzo[c]phenanthrene dihydrodiolepoxides as well as 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine  

SciTech Connect

Polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HCAs) ingested with food have repeatedly been suggested to be involved in the malignant transformation of colon epithelial cells. In order to test this hypothesis, HCEC cells (SV40 large T antigen-immortalized human colon epithelial cells) were incubated with a racemic mixture of benzo[c]phenanthrene dihydrodiol epoxides (B[c]PhDE), extremely potent carcinogenic PAH metabolites in vivo, or with 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP), the N-hydroxylated metabolite of the most abundant HCA in cooked meat. First, it was shown that HCEC cells express sulfotransferase 1A1, which is needed to metabolize N-OH-PhIP to the corresponding N-sulfonyloxy derivative, the direct precursor molecule of genotoxic nitrenium ions. Thereafter, exponentially growing HCEC cells were exposed five times to 0.1 {mu}g (0.37 nmol) B[c]PhDE/ml for 30 min or 0.72 {mu}g (3 nmol) N-OH-PhIP/ml for 24 h. Chemically treated HCEC cells showed an enhanced saturation density and grew faster than the corresponding solvent-treated cell cultures. After five treatment cycles, HCEC{sup B[c]PhDE} as well as HCEC {sup N-OH-PhIP} cells lost cell-cell contact inhibition and started piling up and forming foci in the culture flasks. Furthermore, HCEC{sup B[c]PhDE} and HCEC {sup N-OH-PhIP} cells were injected i.m. into SCID mice. Within 6 weeks after injection, eight animals out of eight injected with HCEC{sup B[c]PhDE} or HCEC {sup N-OH-PhIP} cells developed tumors at the site of injection, thus demonstrating the high tumorigenic potential of the HCEC{sup B[c]PhDE} and HCEC {sup N-OH-PhIP} cell cultures. Taken together, we show for the first time that the abovementioned active PAH metabolites as well as N-OH-PhIP are indeed able to malignantly transform human colon epithelial cells in vitro.

Herbst, Uta [Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal (Germany); Fuchs, Judith Iris [Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal (Germany); Teubner, Wera [Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal (Germany); Steinberg, Pablo [Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal (Germany)]. E-mail: steinber@rz.uni-potsdam.de

2006-04-15

278

Evaluation of nitrobenzimidazoles as hypoxic cell radiosensitizers  

SciTech Connect

Radiobiological and pharmacokinetic assays were performed to determine the potential of 2-nitrobenzimidazole (NBI) as a hypoxic cell radiosensitizing agent. As judged by comparing survival curve slopes of Serratia marcescens irradiated under aerated and hypoxic conditions, the NBI enhancement ratio (ER) at 2 mM concentration was 2.4 +- 0.2, compared with an oxygen enhancement ratio of 3.3 +- 0.3. 2,5-Dinitrobenzimidazole (DNBI) was investigated in vitro; its ER was 3.0 +- 0.3 at 4 mM concentration. Very poor tissue penetration of DNBI precluded further testing in vivo. Acute toxic signs appeared in C3H/HeJ mice following ip injection of NBI at 100 mg/kg. These would be partly attributable to the stress caused by the high pH of the injection vehicle. The LD/sub 50/ was estimated to be 125 to 150 mg/kg. Mammary adenocarcinoma tumors grown in the flanks of these mice exhibited maximum NBI levels at 5 min postinjection (ip). Peak tumor radiosensitization occurred in the interval between 5 and 10 min postinjection. The ER for tumor regrowth delay was 2.1 +- 0.3 following 50 mg/kg injected into mice 5 min before irradiation. Functional evaluation up to 40 days after treatment revealed no evidence of neurological deficit.

Wright, J.; Frank, L.R.; Bush, D.; Harrison, G.H.

1983-07-01

279

Evaluation of nitrobenzimidazoles as hypoxic cell radiosensitizers  

SciTech Connect

Radiobiological and pharmacokinetic assays were performed to determine the potential of 2-nitrobenzimidazole (NBI) as a hypoxic cell radiosensitizing agent. As judged by comparing survival curve slopes of Serratia marcescens irradiated under aerated and hypoxic conditions, the NBI enhancement ratio (ER) at 2 mM concentration was 2.4 +/- 0.2, compared with an oxygen enhancement ratio of 3.3 +/- 0.3. 2,5-Dinitrobenzimidazole (DNBI) was investigated in vitro; its ER was 3.0 +/- 0.3 at 4 mM concentration. Very poor tissue penetration of DNBI precluded further testing in vivo. Acute toxic signs appeared in C3H/HeJ mice following ip injection of NBI at 100 mg/kg. These would be partly attributable to the stress caused by the high pH of the injection vehicle. The LD50 was estimated to be 125-150 mg/kg. Mammary adenocarcinoma tumors grown in the flanks of these mice exhibited maximum NBI levels at 5 min postinjection (ip). Peak tumor radiosensitization occurred in the interval between 5 and 10 min postinjection. The ER for tumor regrowth delay was 2.1 +/- 0.3 following 50 mg/kg injected into mice 5 min before irradiation. Functional evaluation up to 40 days after treatment revealed no evidence of neurological deficit.

Wright, J.; Frank, L.R.; Bush, D.; Harrison, G.H.

1983-07-01

280

Increased expression of annexin A1 predicts poor prognosis in human hepatocellular carcinoma and enhances cell malignant phenotype.  

PubMed

Annexin A1 (ANXA1) belongs to the annexin superfamily of proteins, which contribute to the pathological consequence and sequelae of most serious human diseases. Recent studies have reported diverse roles of ANXA1 in various human cancers; however, its involvement in human hepatocellular carcinoma (HCC) still remains controversial. To investigate the expression pattern of ANXA1 in HCC tissues and evaluate its associations with tumor progression and patients' prognosis, immunohistochemistry was performed using 160 pairs of formalin-fixed and paraffin-embedded cancerous and adjacent non-cancerous tissues from patients with HCC. Then, the associations between ANXA1 expression, clinicopathological characteristics, and prognosis of HCC patients were statistically evaluated. In vitro migration and invasion assays of siRNA-targeted ANXA1-transfected cells were further performed. As a result, the expression levels of ANXA1 protein in HCC tissues were significantly higher than those in adjacent non-cancerous tissues (P < 0.001). High ANXA1 expression was closely correlated with advanced TNM stage (P = 0.001) and high Edmondson grade (P = 0.02). Then, univariate and multivariate analyses showed that the status of ANXA1 expression was an independent predictor for overall survival of HCC patients. Furthermore, knockdown of ANXA1 by transfection of siRNA-ANXA1 could suppress the migration and invasion abilities of HCC cells in vitro. Collectively, these findings offer the convincing evidence that ANXA1 may play an important role in HCC progression and can be used as a molecular marker to predict prognosis and a potential target for therapeutic intervention of HCC. PMID:25412936

Lin, Ya; Lin, Guoqing; Fang, Wenzheng; Zhu, Hongwei; Chu, Kedan

2014-12-01

281

Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells  

PubMed Central

The family of ubiquitin (Ub)-specific proteases (USP) removes Ub from Ub conjugates and regulates a variety of cellular processes. The human genome contains many putative USP-encoding genes, but little is known about USP tissue distribution, pattern of expression, activity, and substrate specificity. We have used a chemistry-based functional proteomics approach to identify active USPs in normal, virus-infected, and tumor-derived human cells. Depending on tissue origin and stage of activation/differentiation, different USP activity profiles were revealed. The activity of specific USPs, including USP5, -7, -9, -13, -15, and -22, was up-regulated by mitogen activation or virus infection in normal T and B lymphocytes. UCH-L1 was highly expressed in tumor cell lines of epithelial and hematopoietic cell origin but was not detected in freshly isolated and mitogen-activated cells. Up-regulation of this USP was a late event in the establishment of Epstein–Barr virus-immortalized lymphoblastoid cell lines and correlated with enhanced proliferation, suggesting a possible role in growth transformation. PMID:14982996

Ovaa, Huib; Kessler, Benedikt M.; Rolén, Ulrika; Galardy, Paul J.; Ploegh, Hidde L.; Masucci, Maria G.

2004-01-01

282

Molecularly Targeted Agents as Radiosensitizers in Cancer Therapy--Focus on Prostate Cancer  

PubMed Central

As our understanding of the molecular pathways driving tumorigenesis improves and more druggable targets are identified, we have witnessed a concomitant increase in the development and production of novel molecularly targeted agents. Radiotherapy is commonly used in the treatment of various malignancies with a prominent role in the care of prostate cancer patients, and efforts to improve the therapeutic ratio of radiation by technologic and pharmacologic means have led to important advances in cancer care. One promising approach is to combine molecularly targeted systemic agents with radiotherapy to improve tumor response rates and likelihood of durable control. This review first explores the limitations of preclinical studies as well as barriers to successful implementation of clinical trials with radiosensitizers. Special considerations related to and recommendations for the design of preclinical studies and clinical trials involving molecularly targeted agents combined with radiotherapy are provided. We then apply these concepts by reviewing a representative set of targeted therapies that show promise as radiosensitizers in the treatment of prostate cancer. PMID:23863691

Alcorn, Sara; Walker, Amanda J.; Gandhi, Nishant; Narang, Amol; Wild, Aaron T.; Hales, Russell K.; Herman, Joseph M.; Song, Danny Y.; DeWeese, Theodore L.; Antonarakis, Emmanuel S.; Tran, Phuoc T.

2013-01-01

283

Melittin enhances radiosensitivity of hypoxic head and neck squamous cell carcinoma by suppressing HIF-1?.  

PubMed

Hypoxia is a widespread phenomenon present in many human solid tumors and is associated with a poor prognosis and therapy resistance. Here, we tested the feasibility of melittin, a major component of bee venom, on radiosensitization of hypoxic head and neck squamous cell carcinoma (HNSCC). CNE-2 and KB cells were treated with melittin and radiation response was determined. Cell viability, cytotoxicity and apoptosis induction were examined by CCK-8 assay, colony formation assay, and flow cytometry. Expression of hypoxia-inducible factor 1-alpha (HIF-1?) and vascular endothelial growth factor (VEGF) proteins were assessed using western blotting. Additionally, we also examined the effect of melittin on tumor growth and radiosensitivity in vivo using a xenograft model of HNSCC. Treatment with melittin resulted in cell growth inhibition, induction of cell apoptosis, and reduction of HIF-1? and VEGF expression, which has been linked to hypoxia cell radioresistance. In addition, intraperitoneal injection of melittin significantly reduced the growth of HNSCC tumors in CNE-2 tumor-bearing mice. These data suggest that melittin enhances radiosensitivity of HNSCC under hypoxia condition, and this is associated with the suppression of HIF-1? expression. Melittin appears to be a potential radiotherapy sensitization agent due to its significant antihypoxia activity. PMID:25053591

Yang, Xi; Zhu, Hongcheng; Ge, Yangyang; Liu, Jia; Cai, Jing; Qin, Qin; Zhan, Liangliang; Zhang, Chi; Xu, Liping; Liu, Zheming; Yang, Yan; Yang, Yuehua; Ma, Jianxin; Cheng, Hongyan; Sun, Xinchen

2014-10-01

284

Inhibition of Hsp27 Radiosensitizes Head-and-Neck Cancer by Modulating Deoxyribonucleic Acid Repair  

SciTech Connect

Purpose: To present a novel method of tumor radiosensitization through Hsp27 knockdown using locked nucleic acid (LNA) and to investigate the role of Hsp27 in DNA double strand break (DSB) repair. Methods and Materials: Clonogenic survival assays, immunoblotting, the proximity ligation assay, and ?H2AX foci analysis were conducted in SQ20B and FaDu human head-and-neck cancer cell lines treated with Hsp27 LNA and Hsp27 short hairpin RNA (shRNA). Additionally, nude mice with FaDu flank tumors were treated with fractionated radiation therapy after pretreatment with Hsp27 LNA and monitored for tumor growth. Results: Hsp27 LNA and Hsp27 shRNA radiosensitized head-and-neck cancer cell lines in an Hsp27-dependent manner. Ataxia-Telangectasia Mutated-mediated DNA repair signaling was impaired in irradiated cells with Hsp27 knockdown. ATM kinase inhibition abrogated the radiosensitizing effect of Hsp27. Furthermore, Hsp27 LNA and shRNA both attenuated DNA repair kinetics after radiation, and Hsp27 was found to colocalize with ATM in both untreated and irradiated cells. Last, combined radiation and Hsp27 LNA treatment in tumor xenografts in nude mice suppressed tumor growth compared with either treatment alone. Conclusions: These results support a radiosensitizing property of Hsp27 LNA in vitro and in vivo, implicate Hsp27 in double strand break repair, and suggest that Hsp27 LNA might eventually serve as an effective clinical agent in the radiotherapy of head-and-neck cancer.

Guttmann, David M.; Hart, Lori [Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Du, Kevin [Department of Radiation Oncology, New York University School of Medicine, New York, New York (United States); Seletsky, Andrew [Department of Biology, Drexel University, Philadelphia, Pennsylvania (United States); Koumenis, Constantinos, E-mail: koumenis@xrt.upenn.edu [Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States)

2013-09-01

285

Phenethyl isothiocyanate inhibits in vivo growth of subcutaneous xenograft tumors of human malignant melanoma A375.S2 cells.  

PubMed

Numerous studies have shown that phenethyl isothiocyanate (PEITC) induces apoptosis of different types of human cancer cell lines, however, there are no reports showing that PEITC inhibits tumor growth in a xenograft model of melanoma in nude mice. We investigated effects of PEITC on the growth of xenografted A375.S2 cell tumors in nude BALB/c mice. A375.S2 cancer cells were inoculated subcutaneously into the lower flanks of mice. Seven days post-inoculation, mice having one palpable tumor were randomly divided into three groups and injected intraperitoneally with PEITC (0, 20 and 40 mg/kg). PEITC reduced tumor weight but total body weight was unaffected. These in vivo results provide support for further investigations to determine the potential use of PEITC as an anticancer drug. PMID:25189905

Ni, Wei-Ya; Lu, Hsu-Feng; Hsu, Shu-Chun; Hsiao, Yu-Ping; Liu, Kuo-Ching; Liu, Jia-You; Ji, Bin-Chuan; Hsueh, Shu-Ching; Hung, Fang-Ming; Shang, Hung-Sheng; Chung, Jing-Gung

2014-01-01

286

Photodynamic Therapy Alone Or In Conjunction With Near-Infrared Light-Induced Hyperthermia In Human Malignant Tumors. A Methodological Case Study  

NASA Astrophysics Data System (ADS)

Several relevant physical parameters, such as superficial blood perfusion, temperature rise and tumor fluorescence characteristics, were monitored in an attempt to perform well-controlled photodynamic thera-py (PDT) on several human malignant tumors. DHE (Photofrin TT) was used as a photosensitizer at a concentration of 2 mg/kg b.w. administered i.v. 48-120 hours before treatment. 630 nm radiation from a CW dye laser, normally at an energy dose of 60 J/c10, at a dose rate well below the hyper-thermal region was delivered to seven 1-4 mm thick basal cell carcinoma lesions. PDT and near-infrared light-induced hyperthermia were performed simultaneously on six 5- 10 mm thick lesions of recurrent breast cancer in another patient. A filtered slide projector running at a power of about 200 mW/c1.0 with radiation above 665 nm was used for the light-induced hyperthermia. All the tumors were eradicated. PDT parameters and tissue temperature recordings were used as input data for an analytical PDT/hyperthermia model. The measured parameters have to be supplemented with assumed values for several other parameters. Although highly qualitative the model provides some interesting insight into the relative importance of PDT and hyperthermia.

Andersson-Engels, S.; Johansson, J.; Killander, D.; Kjellen, E.; Oliva, M.; Svaasand, L. O.; Svanberg, K.; Svanberg, S.

1988-06-01

287

TGF-beta signaling engages an ATM-CHK2-p53-independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells.  

PubMed

Oncogene-induced senescence (OIS), the proliferative arrest engaged in response to persistent oncogene activation, serves as an important tumor-suppressive barrier. We show here that finite lifespan human mammary epithelial cells (HMEC) undergo a p16/RB- and p53-independent OIS in response to oncogenic RAS that requires TGF-? signaling. Suppression of TGF-? signaling by expression of a dominant-negative TGF-? type II receptor, use of a TGF-? type I receptor inhibitor, or ectopic expression of MYC permitted continued proliferation upon RAS expression. Surprisingly, unlike fibroblasts, shRNA-mediated knockdown of ATM or CHK2 was unable to prevent RAS-mediated OIS, arguing that the DNA damage response is not required for OIS in HMEC. Abrogation of TGF-? signaling not only allowed HMEC lacking p53 to tolerate oncogenic RAS but also conferred the capacity for anchorage-independent growth. Thus, the OIS engaged after dysregulated RAS expression provides an early barrier to malignant progression and is mediated by TGF-? receptor activation in HMEC. Understanding the mechanisms that initiate and maintain OIS in epithelial cells may provide a foundation for future therapies aimed at reengaging this proliferative barrier as a cancer therapy. PMID:21555587

Cipriano, Rocky; Kan, Charlene E; Graham, James; Danielpour, David; Stampfer, Martha; Jackson, Mark W

2011-05-24

288

Down-regulation of HPV18 E6, E7, or VEGF expression attenuates malignant biological behavior of human cervical cancer cells.  

PubMed

To investigate the effect of down-regulation of VEGF (vascular endothelial growth factor) and HPV18 E6/E7 by hairpin RNA (shRNA) on cell proliferation, apoptosis, migration, invasion, and adhesion abilities of cervical carcinoma cells, recombinant plasmids including pS-E6 shRNA, pS-E7 shRNA, and pS-VEGF shRNA were constructed and transfected into HeLa cells. The levels of E6 mRNA, E7 mRNA, or VEGF mRNA were significantly reduced after transfection of pS-E6 shRNA (76.0%), pS-E7 shRNA (74.4%), and pS-VEGF shRNA (46.7%). VEGF expression was down-regulated by pS-E6 shRNA (55.1%) and pS-E7 shRNA (46.6%). The apoptosis of HeLa cells was increased, and the proliferation, invasion, and adhesion abilities were decreased significantly. For in vivo study, cancer cells that stably expressed the plasmids were cultured. Cells were transplanted subcutaneously into nude mice to establish xenograft tumor model. Finally, expression of E6 shRNA, E7 shRNA, and VEGF shRNA in cancer cells led to inhibition of the growth of xenograft. Hence, RNA interference could effectively suppress the expression of HPV18 E6/E7 and VEGF in human cervical cancer cells. This suppression attenuates malignant biological behavior of human cervical cancer cells. RNA interference of HPV E6/E7 or VEGF expression implies an effective anti-cervical cancer strategy. PMID:21222176

Chen, Li; Wu, Yuan-Yuan; Liu, Peigen; Wang, Jianli; Wang, Guilan; Qin, Jin; Zhou, Jiaming; Zhu, Jianwei

2011-12-01

289

Human Umbilical Cord-Derived Mesenchymal Stem Cells Do Not Undergo Malignant Transformation during Long-Term Culturing in Serum-Free Medium  

PubMed Central

Background Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are in the foreground as a preferable application for treating diseases. However, the safety of hUC-MSCs after long-term culturing in vitro in serum-free medium remains unclear. Methods hUC-MSCs were separated by adherent tissue culture. hUC-MSCs were cultured in serum-free MesenCult-XF medium and FBS-bases DMEM complete medium. At the 1st, 3rd, 5th, 8th, 10th, and 15th passage, the differentiation of MSCs into osteogenic, chondrogenic, and adipogenic cells was detected, and MTT, surface antigens were measured. Tumorigenicity was analyzed at the 15th passage. Conventional karyotyping was performed at passage 0, 8, and 15. The telomerase activity of hUC-MSCs at passage 1–15 was analyzed. Results Flow cytometry analysis showed that very high expression was detected for CD105, CD73, and CD90 and very low expression for CD45, CD34, CD14, CD79a, and HLA-DR. MSCs could differentiate into osteocytes, chondrocytes, and adipocytes in vitro. There was no obvious chromosome elimination, displacement, or chromosomal imbalance as determined from the guidelines of the International System for Human Cytogenetic Nomenclature. Telomerase activity was down-regulated significantly when the culture time was prolonged. Further, no tumors formed in rats injected with hUC-MSCs (P15) cultured in serum-free and in serum-containing conditions. Conclusion Our data showed that hUC-MSCs met the International Society for Cellular Therapy standards for conditions of long-term in vitro culturing at P15. Since hUC-MSCs can be safely expanded in vitro and are not susceptible to malignant transformation in serum-free medium, these cells are suitable for cell therapy. PMID:24887492

Chen, Gecai; Yue, Aihuan; Ruan, Zhongbao; Yin, Yigang; Wang, RuZhu; Ren, Yin; Zhu, Li

2014-01-01

290

Can Drugs Enhance Hypofractionated Radiotherapy? A Novel Method of Modeling Radiosensitization Using In Vitro Data  

SciTech Connect

Purpose: Hypofractionated radiotherapy (hRT) is being explored for a number of malignancies. The potential benefit of giving concurrent chemotherapy with hRT is not known. We sought to predict the effects of combined modality treatments by using mathematical models derived from laboratory data. Methods and Materials: Data from 26 published clonogenic survival assays for cancer cell lines with and without the use of radiosensitizing chemotherapy were collected. The first three data points of the RT arm of each assay were used to derive parameters for the linear quadratic (LQ) model, the multitarget (MT) model, and the generalized linear quadratic (gLQ) model. For each assay and model, the difference between the predicted and observed surviving fractions at the highest tested RT dose was calculated. The gLQ model was fitted to all the data from each RT cell survival assay, and the biologically equivalent doses in 2-Gy fractions (EQD2s) of clinically relevant hRT regimens were calculated. The increase in cell kill conferred by the addition of chemotherapy was used to estimate the EQD2 of hRT along with a radiosensitizing agent. For comparison, this was repeated using conventionally fractionated RT regimens. Results: At a mean RT dose of 8.0 Gy, the average errors for the LQ, MT, and gLQ models were 1.63, 0.83, and 0.56 log units, respectively, favoring the gLQ model (p < 0.05). Radiosensitizing chemotherapy increased the EQD2 of hRT schedules by an average of 28% to 82%, depending on disease site. This increase was similar to the gains predicted for the addition of chemotherapy to conventionally fractionated RT. Conclusions: Based on published in vitro assays, the gLQ equation is superior to the LQ and MT models in predicting cell kill at high doses of RT. Modeling exercises demonstrate that significant increases in biologically equivalent dose may be achieved with the addition of radiosensitizing agents to hRT. Clinical study of this approach is warranted.

Ohri, Nitin; Dicker, Adam P. [Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Lawrence, Yaacov Richard, E-mail: yaacovla@gmail.com [Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Center for Translational Research in Radiation Oncology, Sheba Medical Center, Tel Hashomer (Israel)

2012-05-01

291

Effects of Radiation on a Model of Malignant Glioma Invasion  

Microsoft Academic Search

We sought to characterize the effects of radiation alone and in combination with BCNU and dexamethasone on malignant glioma invasion. A model of malignant glioma invasion into a gel matrix of collagen type I was used to characterize response to radiation treatment for four malignant glioma cell lines (C6, U251, U373, A172) and nine primary human glioblastoma explants. A radiation

Glenn S. Bauman; Warren MacDonald; Emi Moore; David A. Ramsey; Barbara J. Fisher; Verena R. Amberger; Rolando M. Del Maestro

1999-01-01

292

Optical control of DNA radio-sensitivity  

NASA Astrophysics Data System (ADS)

We explore the manipulation of the radio-sensitivity of the DNA molecules driven by the spin blockade mechanism of diffusive free radicals. We propose a mechanism which uses the simultaneous application of circularly polarized light and an external magnetic field to control the polarization of the free radicals and create an S=1 electron-hole spin excitation (exciton) on DNA molecules. It allows us to manipulate and partially suppress the damage induced by ionizing radiation. We deploy an ab-initio molecular dynamics model to calculate the characteristic parameters of the light needed for optical transitions and investigate the effect of spin-injection on the formation of a free energy barrier in diffusion controlled chemical reaction pathways that controls radiation-induced DNA damage. As a specific example, we present the numerical results calculated for a nucleotide-base, e.g., Guanine, in the presence of an OH free radical.

Abolfath, Ramin

2009-03-01

293

Celecoxib Induced Tumor Cell Radiosensitization by Inhibiting Radiation Induced Nuclear EGFR Transport and DNA-Repair: A COX-2 Independent Mechanism  

SciTech Connect

Purpose: The purpose of the study was to elucidate the molecular mechanisms mediating radiosensitization of human tumor cells by the selective cyclooxygenase (COX)-2 inhibitor celecoxib. Methods and Materials: Experiments were performed using bronchial carcinoma cells A549, transformed fibroblasts HH4dd, the FaDu head-and-neck tumor cells, the colon carcinoma cells HCT116, and normal fibroblasts HSF7. Effects of celecoxib treatment were assessed by clonogenic cell survival, Western analysis, and quantification of residual DNA damage by {gamma}H{sub 2}AX foci assay. Results: Celecoxib treatment resulted in a pronounced radiosensitization of A549, HCT116, and HSF7 cells, whereas FaDu and HH4dd cells were not radiosensitized. The observed radiosensitization could neither be correlated with basal COX-2 expression pattern nor with basal production of prostaglandin E2, but was depended on the ability of celecoxib to inhibit basal and radiation-induced nuclear transport of epidermal growth factor receptor (EGFR). The nuclear EGFR transport was strongly inhibited in A549-, HSF7-, and COX-2-deficient HCT116 cells, which were radiosensitized, but not in FaDu and HH4dd cells, which resisted celecoxib-induced radiosensitization. Celecoxib inhibited radiation-induced DNA-PK activation in A549, HSF7, and HCT116 cells, but not in FaDu and HH4dd cells. Consequentially, celecoxib increased residual {gamma}H2AX foci after irradiation, demonstrating that inhibition of DNA repair has occurred in responsive A549, HCT116, and HSF7 cells only. Conclusions: Celecoxib enhanced radiosensitivity by inhibition of EGFR-mediated mechanisms of radioresistance, a signaling that was independent of COX-2 activity. This novel observation may have therapeutic implications such that COX-2 inhibitors may improve therapeutic efficacy of radiation even in patients whose tumor radioresistance is not dependent on COX-2.

Dittmann, Klaus H. [Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen (Germany)], E-mail: klaus.dittmann@uni-tuebingen.de; Mayer, Claus; Ohneseit, Petra A. [Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen (Germany); Raju, Uma [Department of Experimental Radiation Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX (United States); Andratschke, Nickolaus H. [Klinik und Poliklinik fuer Strahlentherapie und Radiologische Onkologie, Klinikum Rechts Der Isar, Technische Universitaet Muenchen, Munich (Germany); Milas, Luka [Department of Experimental Radiation Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX (United States); Rodemann, H. Peter [Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen (Germany)

2008-01-01

294

Oxidized silicon nanoparticles for radiosensitization of cancer and tissue cells.  

PubMed

The applicability of ultrasmall uncapped and aminosilanized oxidized silicon nanoparticles (SiNPs and NH2-SiNPs) as radiosensitizer was studied by internalizing these nanoparticles into human breast cancer (MCF-7) and mouse fibroblast cells (3T3) that were exposed to X-rays at a single dose of 3 Gy. While SiNPs did not increase the production of reactive oxygen species (ROS) in X-ray treated cells, the NH2-SiNPs significantly enhanced the ROS formation. This is due to the amino functionality as providing positive surface charges in aqueous environment. The NH2-SiNPs were observed to penetrate into the mitochondrial membrane, wherein these nanoparticles provoked oxidative stress. The NH2-SiNPs induced mitochondrial ROS production was confirmed by the determination of an increased malondialdehyde level as representing a gauge for the extent of membrane lipid peroxidation. X-ray exposure of NH2-SiNPs incubated MCF-7 and 3T3 cells increased the ROS concentration for 180%, and 120%, respectively. Complementary cytotoxicity studies demonstrate that these silicon nanoparticles are more cytotoxic for MCF-7 than for 3T3 cells. PMID:23535374

Klein, Stefanie; Dell'Arciprete, Maria L; Wegmann, Marc; Distel, Luitpold V R; Neuhuber, Winfried; Gonzalez, Mónica C; Kryschi, Carola

2013-05-01

295

Contact inhibition and malignancy  

Microsoft Academic Search

The role of contact inhibition in influencing the behaviour of malignant cells is discussed in a review. Although tissue culture cannot simulate the immense complexity of the conditions in vivo, some of the distinctive features of malignant invasion can be conveniently observed with this technique. The evidence derived from this technique indicates that defective contact inhibition of movement of malignant

M. Abercrombie

1979-01-01

296

Stages of Malignant Mesothelioma  

MedlinePLUS

... cells. The disease is metastatic malignant mesothelioma, not brain cancer. The following stages are used for malignant mesothelioma: ... distant parts of the body such as the brain, spine, thyroid , or prostate . Recurrent Malignant ... mesothelioma is cancer that has recurred (come back) after it has ...

297

Development and Evaluation of a Real-Time PCR Assay for Detection and Quantification of Blastocystis Parasites in Human Stool Samples: Prospective Study of Patients with Hematological Malignancies?  

PubMed Central

Blastocystis anaerobic parasites are widespread worldwide in the digestive tract of many animal species, including humans. Epidemiological Blastocystis studies are often limited by the poor sensitivity of standard parasitological assays for its detection. This report presents a highly sensitive real-time quantitative PCR (qPCR) assay developed to detect Blastocystis parasites in stool samples. The assay targets a partial sequence of the Blastocystis small ribosomal subunit (SSU) rRNA gene, allowing subtyping (ST) of Blastocystis isolates by direct sequencing of qPCR products. This qPCR method was assessed in a prospective study of 186 patients belonging to two cohorts—a group of 94 immunocompromised patients presenting hematological malignancies and a control group of 92 nonimmunocompromised patients. Direct-light microscopy and xenic in vitro stool culture analysis showed only 29% and 52% sensitivity, respectively, compared to our qPCR assay. Of the 27 (14.5%) Blastocystis-positive patients, 8 (4%) experienced digestive symptoms. No correlation was found between symptomatic patients and immune status, parasite load, or parasite subtypes, although subtyping of all isolates revealed a high (63.0%) prevalence of ST4. Two unexpected avian subtypes were found, i.e., ST6 and ST7, which are frequently isolated in Asia but rarely present in Western countries. In conclusion, this qPCR proved by far the most sensitive of the tested methods and allowed subtype determination by direct sequencing of qPCR products. New diagnostic tools such as the qPCR are essential for evaluating the clinical relevance of Blastocystis subtypes and their role in acute or chronic digestive disorders. PMID:21177897

Poirier, Philippe; Wawrzyniak, Ivan; Albert, Aurelie; El Alaoui, Hicham; Delbac, Frederic; Livrelli, Valerie

2011-01-01

298

Overexpression of Cyclooxygenase-2 in Malignant Peripheral Nerve Sheath Tumor and Selective Cyclooxygenase-2 Inhibitor-Induced Apoptosis by Activating Caspases in Human Malignant Peripheral Nerve Sheath Tumor Cells  

PubMed Central

Background Cyclooxygenase-2 (COX-2) is a key enzyme in the conversion of arachidonic acid to prostanoids, and its activation is associated with carcinogenesis as well as inflammation. The antitumor effect of selective COX-2 inhibitors has been noted in various malignancies. Malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive soft tissue sarcoma for which effective treatments have not yet been established. The purpose of this study was to investigate a potential therapeutic role of COX-2 in MPNST. Methods We evaluated the expression of COX-2 in 44 cases of high-grade MPNST using immunohistochemical staining and compared the staining results with the characteristics and outcome of the patients. We also investigated the antitumor effect of etodolac, a selective COX-2 inhibitor, on MPNST cells in vitro using the MPNST cell line, FMS-1. Results Overexpression of COX-2 (?50% positive cells) was observed in 29 cases (65.9%), was significantly associated with a poor overall survival (P?=?0.0495), and was considered an independent risk factor for a poor outcome by the results of both univariate and multivariate analysis. Etodolac induced apoptosis of FMS-1 cells through the activation of caspase-8, -9, and -3. Moreover, several caspase inhibitors significantly inhibited etodolac-induced apoptosis. Conclusions Selective COX-2 inhibitors including etodolac had an antitumor effect on MPNST cells, and their use holds promise as a novel therapeutic strategy for patients with MPNST to improve their prognoses. PMID:24516579

Hakozaki, Michiyuki; Tajino, Takahiro; Konno, Shinichi; Kikuchi, Shinichi; Yamada, Hitoshi; Yanagisawa, Michiro; Nishida, Jun; Nagasawa, Hiroyuki; Tsuchiya, Takashi; Ogose, Akira; Abe, Masafumi; Hojo, Hiroshi

2014-01-01

299

[Utility of hyperbaric oxygenation in radiotherapy for malignant brain tumors--a literature review].  

PubMed

Over the past 50 years, hyperbaric oxygenation (HBO) therapy has been used in a wide variety of medical conditions; this theraphy causes an increase in oxygen tension in blood and tissues. In the treatment of malignant gliomas, HBO therapy is used for the radiosensitization of cells in combination with radiotherapy (RT). Further, HBO therapy is applied for the treatment and prevention of radiation-induced brain necrosis that is the most serious complication observed after radiosurgery. We reviewed the literature to evaluate the manner in which HBO therapy contributes to clinical fields in cases of RT administration for malignant brain tumors. PMID:19526835

Beppu, Takaaki; Tanaka, Katsuyuki; Kohshi, Kiyotaka

2009-06-01

300

From Melanocyte to Metastatic Malignant Melanoma  

PubMed Central

Malignant melanoma is one of the most aggressive malignancies in human and is responsible for almost 60% of lethal skin tumors. Its incidence has been increasing in white population in the past two decades. There is a complex interaction of environmental (exogenous) and endogenous, including genetic, risk factors in developing malignant melanoma. 8–12% of familial melanomas occur in a familial setting related to mutation of the CDKN2A gene that encodes p16. The aim of this is to briefly review the microanatomy and physiology of the melanocytes, epidemiology, risk factors, clinical presentation, historical classification and histopathology and, more in details, the most recent discoveries in biology and genetics of malignant melanoma. At the end, the final version of 2009 AJCC malignant melanoma staging and classification is presented. PMID:20936153

Bandarchi, Bizhan; Ma, Linglei; Navab, Roya; Seth, Arun; Rasty, Golnar

2010-01-01

301

Immunological evaluation of patients with hematological malignancies receiving ambulatory cytokine-mediated immunotherapy with recombinant human interferon-alpha 2a and interleukin-2.  

PubMed

Immunological parameters were evaluated in patients treated with cytokine-mediated immunotherapy (CMI) consisting of low doses of recombinant human interferon alpha 2a (rIFN alpha) and recombinant human interleukin-2 (rIL-2) administered either concomitantly or sequentially by subcutaneous self-injections in an outpatient setting. Twenty-six patients with hematological malignancies and 2 metastatic melanoma patients in a progressive stage were enrolled in this clinical trial. Of the 26 patients, 24 were at a stage of minimal residual disease, including 14 patients who had received autologous bone marrow transplantation (ABMT) 2-5 months previously, 7 chronic myelogenous leukemia (CML) and 3 acute myeloid leukemia (AML) patients. Two patients (1 CML and 1 mult. myeloma) were treated at a stage of progressive disease. Non-MHC-restricted cytotoxicity directed against natural-killer(NK)-resistant (Daudi) and NK-sensitive (K562) target cells was assessed before, during and after CMI, either in fresh peripheral blood samples (spontaneous activity) or after in vitro rIL-2 activation (induced activity). Spontaneous killing activity was low prior to treatment, but increased upon termination of treatment in 10/15 evaluated cycels. rIL-2-activated cytotoxicity in vitro was markedly elevated in 8/12 and 6/8 patients after one and two cycles, respectively, of sequential treatment, as well as in 3/8 CML and 5/6 patients after one and two cycles, respectively, of concomitant treatment. Activation of the T cell mitogenic response was demonstrated in 6/9 patients after concomitant CMI, while no such effect was observed throughout a sequential treatment in lymphoma and leukemia patients after ABMT. Although a direct correlation between immune stimulation and the in vivo antitumor response cannot yet be determined, our clinical observations support a beneficial therapeutic effect in a substantial number of patients. These results indicated that the ambulatory CMI protocol of rIL-2 and rIFN alpha could stimulate the host defense immune system and may be helpful in mediating the in vivo antitumor response in patients with minimal residual disease. PMID:1394343

Morecki, S; Revel-Vilk, S; Nabet, C; Pick, M; Ackerstein, A; Nagler, A; Naparstek, E; Ben Shahar, M; Slavin, S

1992-01-01

302

HER1-Targeted 86Y-Panitumumab Possesses Superior Targeting Characteristics than 86Y-Cetuximab for PET Imaging of Human Malignant Mesothelioma Tumors Xenografts  

PubMed Central

Malignant mesothelioma (MM), a rare form of cancer is often associated with previous exposure to fibrous minerals, such as asbestos. Asbestos exposure increases HER1-activity and expression in pre-clinical models. Additionally, HER1 over-expression is observed in the majority of MM cases. In this study, the utility of HER1-targeted chimeric IgG1, cetuximab, and a human IgG2, panitumumab, radiolabeled with 86Y, were evaluated for PET imaging to detect MM non-invasively in vivo, and to select an antibody candidate for radioimmunotherapy (RIT). Methods Radioimmunoconjugates (RICs) of cetuximab and panitumumab were prepared by conjugation with CHX-A’’-DTPA followed by radiolabeling with 86Y. The HER1 expression of NCI-H226, NCI-H2052, NCI-H2452 and MSTO-211H human mesothelioma cells was characterized by flow cytometry. In vivo biodistribution, pharmacokinetic analysis, and PET imaging were performed in tumor bearing athymic mice. Results In vivo studies demonstrated high HER1 tumor uptake of both RICs. Significant reduction in tumor uptake was observed in mice co-injected with excess mAb (0.1 mg), demonstrating that uptake in the tumor was receptor specific. Significant differences were observed in the in vivo characteristics of the RICs. The blood clearance T½? of 86Y-cetuximab (0.9–1.1 h) was faster than 86Y-panitumumab (2.6–3.1 h). Also, the tumor area under the curve (AUC) to liver AUC ratios of 86Y-panitumumab were 1.5 to 2.5 times greater than 86Y-cetuximab as observed by the differences in PET tumor to background ratios, which could be critical when imaging orthotopic tumors and concerns regarding radiation doses to normal organs such as the liver. Conclusion This study demonstrates the more favorable HER1-targeting characteristics of 86Y-panitumumab than 86Y-cetuximab for non-invasive assessment of the HER1 status of MM by PET imaging. Due to lower liver uptake, panitumumab based immunoconjugates may fare better in therapy than corresponding cetuximab based immunoconjugates. PMID:21464917

Nayak, Tapan K.; Garmestani, Kayhan; Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.

2011-01-01

303

Induction of stem-like cells with malignant properties by chronic exposure of human lung epithelial cells to single-walled carbon nanotubes  

PubMed Central

Background Carbon nanotubes (CNT) hold great promise to create new and better products for commercial and biomedical applications, but their long-term adverse health effects are a major concern. The objective of this study was to address human lung cancer risks associated with chronic pulmonary exposure to single-walled (SW) CNT through the fundamental understanding of cellular and molecular processes leading to carcinogenesis. We hypothesized that the acquisition of cancer stem cells (CSC), a subpopulation that drive tumor initiation and progression, may contribute to CNT carcinogenesis. Methods Non-tumorigenic human lung epithelial cells were chronically exposed to well-dispersed SWCNT for a period of 6 months at the physiologically relevant concentration of 0.02 ?g/cm2 surface area dose. Chronic SWCNT-exposed cells were evaluated for the presence of CSC-like cells under CSC-selective conditions of tumor spheres and side population (SP). CSC-like cells were isolated using fluorescence-activated cell sorting and were assessed for aggressive behaviors, including acquired apoptosis resistance and increased cell migration and invasion in vitro, and tumor-initiating capability in vivo. Non-small cell lung cancer cells served as a positive control. Results We demonstrated for the first time the existence of CSC-like cells in all clones of chronic SWCNT-exposed lung epithelial cells. These CSC-like cells, in contrary to their non-CSC counterpart, possessed all biological features of lung CSC that are central to irreversible malignant transformation, self-renewal, aggressive cancer behaviors, and in vivo tumorigenesis. These cells also displayed aberrant stem cell markers, notably Nanog, SOX-2, SOX-17 and E-cadherin. Restored expression of tumor suppressor p53 abrogated CSC properties of CSC-like cells. Furthermore, we identified specific stem cell surface markers CD24low and CD133high that are associated with SWCNT-induced CSC formation and tumorigenesis. Conclusions Our findings provide new and compelling evidence for the acquisition of CSC-like cells induced by chronic SWCNT exposure, which are likely to be a major driving force for SWCNT tumorigenesis. Thus, our study supports prudent adoption of prevention strategies and implementation of exposure control for SWCNT. We also suggest that the detection of CSC and associated surface markers may provide an effective screening tool for prediction of the carcinogenic potential of SWCNT and related nanoparticles. PMID:24885671

2014-01-01

304

Precursors to Lymphoproliferative Malignancies  

PubMed Central

We review monoclonal B-cell lymphocytosis (MBL) as a precursor to chronic lymphocytic leukemia and monoclonal gammopathy of undetermined significance (MGUS) as a precursor to plasma cell disorders. These conditions are present in the general population and increase with age. These precursors aggregate with lymphoproliferative malignancies in families suggesting shared inheritance. MBL and MGUS may share some of the same risk factors as their related malignancies but data are limited. While these conditions are characterized by enhanced risk for the associated malignancy, the majority of individuals with these conditions do not progress to malignancy. A key focus for current work is to identify markers that predict progression to malignancy. PMID:23549397

Goldin, Lynn R.; McMaster, Mary L.; Caporaso, Neil E.

2013-01-01

305

Down-regulation of Wilms’ tumor 1 expression in glioblastoma cells increases radiosensitivity independently of p53  

Microsoft Academic Search

The Wilms’ tumor 1 (WT1) gene is overexpressed in human glioblastoma and correlates with wild-type p53 status. In other cell\\u000a types, WT1 inhibits p53-mediated apoptosis in response to DNA damaging agents. However, neither this interaction nor the relationship\\u000a between WT1 and radiosensitivity has been studied in glioblastoma. To study this interaction, we generated LN-229 glioma cell\\u000a lines (p53 mutant) stably

Aaron J. Clark; Dana C. Chan; Mike Y. Chen; Helen Fillmore; Wagner G. Dos Santos; Timothy E. Van Meter; Martin R. Graf; William C. Broaddus

2007-01-01

306

Phase I Study of GC1008 (Fresolimumab): A Human Anti-Transforming Growth Factor-Beta (TGF?) Monoclonal Antibody in Patients with Advanced Malignant Melanoma or Renal Cell Carcinoma  

PubMed Central

Background In advanced cancers, transforming growth factor-beta (TGF?) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGF? monoclonal antibody that neutralizes all isoforms of TGF?. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma. Methods In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed. Results Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4–44.4 weeks). Conclusions GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments. Trial Registration Clinicaltrials.gov NCT00356460 PMID:24618589

Morris, John C.; Tan, Antoinette R.; Olencki, Thomas E.; Shapiro, Geoffrey I.; Dezube, Bruce J.; Reiss, Michael; Hsu, Frank J.; Berzofsky, Jay A.; Lawrence, Donald P.

2014-01-01

307

Angiogenesis in Malignant Fibrous Histiocytoma  

Microsoft Academic Search

The significance of neovascularization for tumor growth and metastasis has recently been postulated for human cancers; increased microvessel density correlates with increased frequency of metastasis. In the present study, micro-vessel density was examined in 42 cases of malignant fibrous histiocytoma (MFH). Microvessels were defined as lumens surrounded by anti-factor-VIII-related antigen (FVIII-RA)-antibody-stained endothelium, and counted in a × 400 field. The

Masahiko Ohsawa; Yasuhiko Tomita; Shigeyuki Kuratsu; Hiroyuki Kanno; Katsuyuki Aozasa

1995-01-01

308

Inhibition of protein phosphatase 2A radiosensitizes pancreatic cancers by modulating CDC25C/CDK1 and homologous recombination repair  

PubMed Central

Purpose To identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer and thus improve survival, we performed an siRNA library screen in pancreatic cancer cells. We investigated PPP2R1A, a scaffolding subunit of protein phosphatase 2A (PP2A) as a lead radiosensitizing target. Experimental Design We determined the effect of PP2A inhibition by genetic (PPP2R1A siRNA) and pharmacological (LB100, a small molecule entering Phase I clinical trials) approaches on radiosensitization of Panc-1 and MiaPaCa-2 pancreatic cancer cells both in vitro and in vivo. Results PPP2R1A depletion by siRNA radiosensitized Panc-1 and MiaPaCa-2 cells, with radiation enhancement ratios of 1.4 (P<0.05). Likewise, LB100 produced similar radiosensitization in pancreatic cancer cells, but minimal radiosensitization in normal small intestinal cells. Mechanistically, PPP2R1A siRNA or LB100 caused aberrant CDK1 activation, likely resulting from accumulation of the active forms of PLK1 (pPLK1 T210) and CDC25C (pCDC25C T130). Furthermore, LB100 inhibited radiation-induced Rad51 focus formation and homologous recombination repair (HRR), ultimately leading to persistent radiation-induced DNA damage, as reflected by ?H2AX expression. Finally, we identified CDC25C as a key PP2A substrate involved in LB100-mediated radiosensitization as depletion of CDC25C partially reversed LB100-mediated radiosensitization. In a mouse xenograft model of human pancreatic cancer, LB100 produced significant radiosensitization with minimal weight loss. Conclusions Collectively, our data demonstrate that PP2A inhibition radiosensitizes pancreatic cancer both in vitro and in vivo via activation of CDC25C/CDK1 and inhibition of HRR, and provide proof-of-concept evidence that PP2A is a promising target for the improvement of local therapy in pancreatic cancer. PMID:23780887

Wei, Dongping; Parsels, Leslie A.; Karnak, David; Davis, Mary A.; Parsels, Joshua D.; Zhao, Lili; Maybaum, Jonathan; Lawrence, Theodore S.; Sun, Yi; Morgan, Meredith A.

2013-01-01

309

Enhanced radiosensitization of p53 mutant cells by oleamide  

SciTech Connect

Purpose: Effect of oleamide, an endogenous fatty-acid primary amide, on tumor cells exposed to ionizing radiation (IR) has never before been explored. Methods and Materials: NCI H460, human lung cancer cells, and human astrocytoma cell lines, U87 and U251, were used. The cytotoxicity of oleamide alone or in combination with IR was determined by clonogenic survival assay, and induction of apoptosis was estimated by FACS analysis. Protein expressions were confirmed by Western blotting, and immunofluorescence analysis of Bax by use of confocal microscopy was also performed. The combined effect of IR and oleamide to suppress tumor growth was studied by use of xenografts in the thighs of nude mice. Results: Oleamide in combination with IR had a synergistic effect that decreased clonogenic survival of lung-carcinoma cell lines and also sensitized xenografts in nude mice. Enhanced induction of apoptosis of the cells by the combined treatment was mediated by loss of mitochondrial membrane potential, which resulted in the activation of caspase-8, caspase-9, and caspase-3 accompanied by cytochrome c release and Bid cleavage. The synergistic effects of the combined treatment were more enhanced in p53 mutant cells than in p53 wild-type cells. In p53 wild-type cells, both oleamide and radiation induced Bax translocation to mitochondria. On the other hand, in p53 mutant cells, radiation alone slightly induced Bax translocation to mitochondria, whereas oleamide induced a larger translocation. Conclusions: Oleamide may exhibit synergistic radiosensitization in p53 mutant cells through p53-independent Bax translocation to mitochondria.

Lee, Yoon-Jin [Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Chung, Da Yeon [Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Lee, Su-Jae [Laboratory of Experimental Radiation Therapeutics, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Ja Jhon, Gil [Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Laboratory of Experimental Radiation Therapeutics, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Division of Molecular Life Science, Ewha Woman's University, Seoul (Korea, Republic of); Lee, Yun-Sil [Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)]. E-mail: yslee@kcch.re.kr

2006-04-01

310

Canine olfactory detection of malignant melanoma.  

PubMed

Our patient is a 75-year-old man who presented after his pet dog licked persistently at an asymptomatic lesion behind his right ear. Examination revealed a nodular lesion in the postauricular sulcus. Histology confirmed malignant melanoma, which was subsequently excised. Canine olfactory detection of human malignancy is a well-documented phenomenon. Advanced olfaction is hypothesised to explain canine detection of bladder, breast, colorectal, lung, ovarian, prostate and skin cancers. Further research in this area may facilitate the development of a highly accurate aid to diagnosis for many malignancies, including melanoma. PMID:24127369

Campbell, Leon Frederick; Farmery, Luke; George, Susannah Mary Creighton; Farrant, Paul B J

2013-01-01

311

Mannose Phosphate Isomerase Regulates Fibroblast Growth Factor Receptor Family Signaling and Glioma Radiosensitivity  

PubMed Central

Asparagine-linked glycosylation is an endoplasmic reticulum co- and post- translational modification that enables the transit and function of receptor tyrosine kinase (RTK) glycoproteins. To gain insight into the regulatory role of glycosylation enzymes on RTK function, we investigated shRNA and siRNA knockdown of mannose phosphate isomerase (MPI), an enzyme required for mature glycan precursor biosynthesis. Loss of MPI activity reduced phosphorylation of FGFR family receptors in U-251 and SKMG-3 malignant glioma cell lines and also resulted in significant decreases in FRS2, Akt, and MAPK signaling. However, MPI knockdown did not affect ligand-induced activation or signaling of EGFR or MET RTKs, suggesting that FGFRs are more susceptible to MPI inhibition. The reductions in FGFR signaling were not caused by loss of FGF ligands or receptors, but instead were caused by interference with receptor dimerization. Investigations into the cellular consequences of MPI knockdown showed that cellular programs driven by FGFR signaling, and integral to the clinical progression of malignant glioma, were impaired. In addition to a blockade of cellular migration, MPI knockdown also significantly reduced glioma cell clonogenic survival following ionizing radiation. Therefore our results suggest that targeted inhibition of enzymes required for cell surface receptor glycosylation can be manipulated to produce discrete and limited consequences for critical client glycoproteins expressed by tumor cells. Furthermore, this work identifies MPI as a potential enzymatic target for disrupting cell surface receptor-dependent survival signaling and as a novel approach for therapeutic radiosensitization. PMID:25314669

Cazet, Aurelie; Charest, Jonathan; Bennett, Daniel C.; Sambrooks, Cecilia Lopez; Contessa, Joseph N.

2014-01-01

312

Clonal cell populations unresponsive to radiosensitization induced by telomerase inhibition  

SciTech Connect

Research highlights: {yields} In our present manuscript, we have clearly showed an interesting but problematic obstacle of a radiosensitization strategy based on telomerase inhibition by showing that: Clonal population unresponsive to this radiosensitization occasionally arise. {yields} The telomere length of unsensitized clones was reduced, as was that of most sensitized clones. {yields} The unsensitized clones did not show chromosome end fusion which was noted in all sensitized clones. {yields} P53 status is not associated with the occurrence of unsensitized clone. {yields} Telomere end capping in unsensitized clone is operative even under telomerase deficiency. -- Abstract: A combination of a radiotherapeutic regimen with telomerase inhibition is valuable when tumor cells are to be sensitized to radiation. Here, we describe cell clones unresponsive to radiosensitization after telomere shortening. After extensive division of individual transformed clones of mTERC{sup -/-} cells, about 22% of clones were unresponsive to radiosensitization even though telomerase action was inhibited. The telomere lengths of unsensitized mTERC{sup -/-} clones were reduced, as were those of most sensitized clones. However, the unsensitized clones did not exhibit chromosomal end-to-end fusion to the extent noted in all sensitized clones. Thus, a defense mechanism preventing telomere erosion is operative even when telomeres become shorter under conditions of telomerase deficiency, and results in unresponsiveness to the radiosensitization generally mediated by telomere shortening.

Ju, Yeun-Jin; Shin, Hyun-Jin; Park, Jeong-Eun; Juhn, Kyoung-Mi; Woo, Seon Rang; Kim, Hee-Young; Han, Young-Hoon; Hwang, Sang-Gu; Hong, Sung-Hee; Kang, Chang-Mo [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)] [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Yoo, Young-Do [Laboratory of Molecular Cell Biology, Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of)] [Laboratory of Molecular Cell Biology, Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Park, Won-Bong [Division of Natural Science, Seoul Women's University, Seoul 139-774 (Korea, Republic of)] [Division of Natural Science, Seoul Women's University, Seoul 139-774 (Korea, Republic of); Cho, Myung-Haing [Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul (Korea, Republic of)] [Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul (Korea, Republic of); Park, Gil Hong, E-mail: ghpark@korea.ac.kr [Department of Biochemistry, College of Medicine, Korea University, Seoul (Korea, Republic of); Lee, Kee-Ho, E-mail: khlee@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)] [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)

2010-11-12

313

Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants  

NASA Technical Reports Server (NTRS)

The radiosensitizing effect of caffeine has been associated with the disruption of multiple DNA damage-responsive cell cycle checkpoints, but several lines of evidence also implicate inhibition of DNA repair. The role of DNA repair inhibition in caffeine radiosensitization remains uncharacterized, and it is unknown which repair process, or lesion, is affected. We show that a radiosensitive cell line, mutant for the RAD51 homolog XRCC2 and defective in homologous recombination repair (HRR), displays significantly diminished caffeine radiosensitization that can be restored by expression of XRCC2. Despite the reduced radiosensitization, caffeine effectively abrogates checkpoints in S and G2 phases in XRCC2 mutant cells indicating that checkpoint abrogation is not sufficient for radiosensitization. Another radiosensitive line, mutant for XRCC3 and defective in HRR, similarly shows reduced caffeine radiosensitization. On the other hand, a radiosensitive mutant (irs-20) of DNA-PKcs with a defect in non-homologous end-joining (NHEJ) is radiosensitized by caffeine to an extent comparable to wild-type cells. In addition, rejoining of radiation-induced DNA DSBs, that mainly reflects NHEJ, remains unaffected by caffeine in XRCC2 and XRCC3 mutants, or their wild-type counterparts. These observations suggest that caffeine targets steps in HRR but not in NHEJ and that abrogation of checkpoint response is not sufficient to explain radiosensitization. Indeed, immortalized fibroblasts from AT patients show caffeine radiosensitization despite the checkpoint defects associated with ATM mutation. We propose that caffeine radiosensitization is mediated by inhibition of stages in DNA DSB repair requiring HRR and that checkpoint disruption contributes by allowing these DSBs to transit into irreparable states. Thus, checkpoints may contribute to genomic stability by promoting error-free HRR.

Asaad, N. A.; Zeng, Z. C.; Guan, J.; Thacker, J.; Iliakis, G.

2000-01-01

314

Malignant melanoma in children  

Microsoft Academic Search

Background: Cutaneous melanoma is an uncommon malignancy in children and for this reason, there is little information available regarding\\u000a the timing and patterns of recurrence in children with this disease. This study reviews the experience at a single institution\\u000a (Duke University Melanoma Clinic) in treating children with malignant melanoma.\\u000a \\u000a \\u000a \\u000a Methods: Eighty-five patients ?18 years of age with malignant melanoma have

Andrew M. Davidoff; Constance Cirrincione; Hilliard F. Seigler

1994-01-01

315

Activation of the neuregulin-1\\/ErbB signaling pathway promotes the proliferation of neoplastic Schwann cells in human malignant peripheral nerve sheath tumors  

Microsoft Academic Search

Patients with neurofibromatosis type 1 develop aggressive Schwann cell neoplasms known as malignant peripheral nerve sheath tumors (MPNSTs). Although tumor suppressor gene mutations play an important role in MPNST pathogenesis, it is likely that dysregulated signaling by as yet unidentified growth factors also contributes to the formation of these sarcomas. To test the hypothesis that neuregulin-1 (NRG-1) growth factors promote

Mark S Stonecypher; Stephanie J Byer; William E Grizzle; Steven L Carroll

2005-01-01

316

Radiosensitization by derivatives of isoindole-4,7-dione.  

PubMed

New derivatives of isoindole -4,7-dione have been synthesized and their radiation sensitization and chemical behavior have been studied. One-electron reduction potentials have been determined by pulse radiolysis and found to be in the range of -0.45 to -0.36 V vs NHE . Radiosensitization effects were tested in vivo using soft tissue sarcoma transplanted in mice. All the isoindole -4,7-diones tested were found to exert considerable radiosensitization, approaching that of misonidazole tested under comparable conditions. The derivatives which contain a carbethoxy group on the pyrrolic ring were found to have more positive reduction potentials and to act as more efficient sensitizers. Further development of this class of radiosensitizers is underway. PMID:6729035

Infante, G A; Guzman, P; Alvarez, R; Figueroa, A; Correa, J N; Myers, J A; Lanier, L J; Williams, T M; Burgos, S; Vera, J

1984-05-01

317

Inhibition of autophagy enhances the radiosensitivity of nasopharyngeal carcinoma by reducing Rad51 expression.  

PubMed

Radiotherapy has long been considered as the mainstay of treatment for nasopharyngeal carcinoma (NPC). However, locoregional recurrence or distant metastasis may occur in some patients due to the radiation resistance of cancer cells. Autophagy plays a vital role in protecting cells against radiation. However, the mechanism of autophagy in radiation therapy remains obscure. In the present study, we demonstrated that suppression of autophagy related 5 (Atg5) aggravated ionizing radiation (IR)-induced DNA damage and apoptosis in human NPC cells without accelerating the cell cycle, whereas regulation of the cell cycle has been widely regarded as the most important determinant of IR sensitivity. Further study showed that inhibition of autophagy suppressed the mRNA expression of Rad51, a key protein of homologous recombination that has been demonstrated to play a critical role in the repair of DNA double-strand breaks induced by radiation. Moreover, suppression of Atg5 had no impact on the radiosensitivity when cells were pre-treated by the Rad51 inhibitor, and the enhanced radiosensitivity by Atg5 suppression was reversed by overexpression of Rad51 in human NPC cells. Our results suggest that inhibition of autophagy enhances the susceptibility of NPC cells to radiation by reducing Rad51 expression. Therefore, Rad51 targeted therapy may be investigated as a potential novel agent for the adjuvant treatment of traditional radiation of NPC. PMID:25175062

Mo, Ning; Lu, Yong-Kui; Xie, Wei-Min; Liu, Yan; Zhou, Wen-Xian; Wang, Hong-Xue; Nong, Li; Jia, Yu-Xian; Tan, Ai-Hua; Chen, Ying; Li, Shan-Shan; Luo, Bao-Hua

2014-11-01

318

Rheumatic Diseases and Malignancies  

PubMed Central

ABSTRACT There are many studies which demonstrate a higher risk for malignancy in patients with rheumatic diseases. There have been a number of possible explanations for the differences in the risk of certain malignancies in patients with rheumatic disease, compared with general population, but a clear mechanism is difficult to identify. Rheumatoid syndromes may be associated with malignancy as paraneoplastic conditions, which can antedate the neoplasm diagnosis. On the other hand, autoimmune rheumatic diseases have a higher risk of malignancy by themselves or because of the immunosuppressant treatments. PMID:23482881

BOJINCA, Violeta; JANTA, Iustina

2012-01-01

319

The Myb-p300-CREB axis modulates intestine homeostasis, radiosensitivity and tumorigenesis  

PubMed Central

The gastrointestinal (GI) epithelium is constantly renewing, depending upon the intestinal stem cells (ISC) regulated by a spectrum of transcription factors (TFs), including Myb. We noted previously in mice with a p300 mutation (plt6) within the Myb-interaction-domain phenocopied Myb hypomorphic mutant mice with regard to thrombopoiesis, and here, changes in GI homeostasis. p300 is a transcriptional coactivator for many TFs, most prominently cyclic-AMP response element-binding protein (CREB), and also Myb. Studies have highlighted the importance of CREB in proliferation and radiosensitivity, but not in the GI. This prompted us to directly investigate the p300–Myb–CREB axis in the GI. Here, the role of CREB has been defined by generating GI-specific inducible creb knockout (KO) mice. KO mice show efficient and specific deletion of CREB, with no evident compensation by CREM and ATF1. Despite complete KO, only modest effects on proliferation, radiosensitivity and differentiation in the GI under homeostatic or stress conditions were evident, even though CREB target gene pcna (proliferating cell nuclear antigen) was downregulated. creb and p300 mutant lines show increased goblet cells, whereas a reduction in enteroendocrine cells was apparent only in the p300 line, further resembling the Myb hypomorphs. When propagated in vitro, crebKO ISC were defective in organoid formation, suggesting that the GI stroma compensates for CREB loss in vivo, unlike in MybKO studies. Thus, it appears that p300 regulates GI differentiation primarily through Myb, rather than CREB. Finally, active pCREB is elevated in colorectal cancer (CRC) cells and adenomas, and is required for the expression of drug transporter, MRP2, associated with resistance to Oxaliplatin as well as several chromatin cohesion protein that are relevant to CRC therapy. These data raise the prospect that CREB may have a role in GI malignancy as it does in other cancer types, but unlike Myb, is not critical for GI homeostasis. PMID:23618903

Sampurno, S; Bijenhof, A; Cheasley, D; Xu, H; Robine, S; Hilton, D; Alexander, W S; Pereira, L; Mantamadiotis, T; Malaterre, J; Ramsay, R G

2013-01-01

320

The HSP90 Inhibitor NVP-AUY922 Radiosensitizes by Abrogation of Homologous Recombination Resulting in Mitotic Entry with Unresolved DNA Damage  

PubMed Central

Background Heat shock protein 90 (HSP90) is a molecular chaperone responsible for the conformational maintenance of a number of client proteins that play key roles in cell cycle arrest, DNA damage repair and apoptosis following radiation. HSP90 inhibitors exhibit antitumor activity by modulating the stabilisation and activation of HSP90 client proteins. We sought to evaluate NVP-AUY922, the most potent HSP90 inhibitor yet reported, in preclinical radiosensitization studies. Principal Findings NVP-AUY922 potently radiosensitized cells in vitro at low nanomolar concentrations with a concurrent depletion of radioresistance-linked client proteins. Radiosensitization by NVP-AUY922 was verified for the first time in vivo in a human head and neck squamous cell carcinoma xenograft model in athymic mice, as measured by delayed tumor growth and increased surrogate end-point survival (p?=?<0.0001). NVP-AUY922 was shown to ubiquitously inhibit resolution of dsDNA damage repair correlating to delayed Rad51 foci formation in all cell lines tested. Additionally, NVP-AUY922 induced a stalled mitotic phenotype, in a cell line-dependent manner, in HeLa and HN5 cell lines irrespective of radiation exposure. Cell cycle analysis indicated that NVP-AUY922 induced aberrant mitotic entry in all cell lines tested in the presence of radiation-induced DNA damage due to ubiquitous CHK1 depletion, but resultant downstream cell cycle effects were cell line dependent. Conclusions These results identify NVP-AUY922 as the most potent HSP90-mediated radiosensitizer yet reported in vitro, and for the first time validate it in a clinically relevant in vivo model. Mechanistic analysis at clinically achievable concentrations demonstrated that radiosensitization is mediated by the combinatorial inhibition of cell growth and survival pathways, ubiquitous delay in Rad51-mediated homologous recombination and CHK1-mediated G2/M arrest, but that the contribution of cell cycle perturbation to radiosensitization may be cell line specific. PMID:22523597

Bhide, Shreerang A.; Eccles, Suzanne A.; Workman, Paul; Nutting, Christopher M.; Huddart, Robert A.; Harrington, Kevin J.

2012-01-01

321

Tumor Metabolism of Malignant Gliomas  

PubMed Central

Constitutively activated oncogenic signaling via genetic mutations such as in the EGFR/PI3K/Akt and Ras/RAF/MEK pathways has been recognized as a major driver for tumorigenesis in most cancers. Recent insights into tumor metabolism have further revealed that oncogenic signaling pathways directly promote metabolic reprogramming to upregulate biosynthesis of lipids, carbohydrates, protein, DNA and RNA, leading to enhanced growth of human tumors. Therefore, targeting cell metabolism has become a novel direction for drug development in oncology. In malignant gliomas, metabolism pathways of glucose, glutamine and lipid are significantly reprogrammed. Moreover, molecular mechanisms causing these metabolic changes are just starting to be unraveled. In this review, we will summarize recent studies revealing critical gene alterations that lead to metabolic changes in malignant gliomas, and also discuss promising therapeutic strategies via targeting the key players in metabolic regulation. PMID:24217114

Ru, Peng; Williams, Terence M.; Chakravarti, Arnab; Guo, Deliang

2013-01-01

322

Artemisinin derivative artesunate induces radiosensitivity in cervical cancer cells in vitro and in vivo  

PubMed Central

Objective Cervical cancer is the third most common type of cancer in women worldwide and radiotherapy remains its predominant therapeutic treatment. Artesunate (ART), a derivative of artemisinin, has shown radiosensitization effect in previous studies. However, such effects of ART have not yet been revealed for cervical cancer cells. Methods The effect of ART on radiosensitivity of human cervical cancer cell lines HeLa and SiHa was assessed using the clonogenic assay. Cell cycle progression and apoptosis alterations were analyzed by flow cytometry. For in vivo study, HeLa or SiHa cells were inoculated into nude mice to establish tumors. Tissues from xenografts were obtained to detect the changes of microvessel density, apoptosis and cell cycle distribution. Microarray was used to analyze differentially expressed genes. Results ART increased the radiosensitivity of HeLa cells (SER =?1.43, P radiosensitivity of HeLa cells in vitro and in vivo. PMID:24666614

2014-01-01

323

Familial malignant melanoma  

SciTech Connect

Characteristics associated with familial compared with nonfamilial malignant melanoma were assessed. These data were obtained from consecutive prospectively completed questionnaires on 1169 cases of cutaneous malignant melanoma. Of these, 69 patients indicated a positive family history for this cancer. Among the various clinical and histological variables compared, those that significantly correlated with the familial occurrence of malignant melanoma include younger age at first diagnosis, smaller diameter of the lesion, lower Clark level, decreased frequency of nonmelanoma skin cancer, and reduced prevalence of noncutaneous cancer. Increased awareness of malignant melanoma among family members could account for some of these observations. Identification of the familial variety of malignant melanoma has practical implications concerning early detection and prompt intervention.

Kopf, A.W.; Hellman, L.J.; Rogers, G.S.; Gross, D.F.; Rigel, D.S.; Friedman, R.J.; Levenstein, M.; Brown, J.; Golomb, F.M.; Roses, D.F.; Gumport, S.L.

1986-10-10

324

Interleukin6 Production in high-Grade B Lymphomas: Correlation With the Presence of Malignant Immunoblasts in Acquired Immunodeficiency Syndrome and in Human Immunodeficiency Virus-Seronegative Patients  

Microsoft Academic Search

NTERLEUKIN-6 (IL-6) is a pleiotropic cytokine with a I number of effects on cells of the B-lymphocyte lineage.' It is a major factor involved in the terminal differentiation of normal B lymphocytes. A number of reports have also outlined its role as a growth factor for Epstein-Barr virus (EBV)-infected and malignant lymphocytes. On the one hand, IL-6 is produced by

D. Emilie; J. Coumbaras; M. Raphael; H. J. Deleclbse; C. Gisselbrecht; J. F. Michiels; J. Van Damme; T. Taga; T. Kishimoto; M. C. Crevon; P. Galanaud

1992-01-01

325

Cumulative and Bolus In Vitro Contracture Testing with 4-Chloro-3-Ethylphenol in Malignant Hyperthermia Positive and Negative Human Skeletal Muscles  

Microsoft Academic Search

In this study we evaluated the in vitro effects of 4-chloro-3-ethylphenol (CEP) using cumulative (12.5- 200 mol\\/L) or bolus (75 and 100 mol\\/L) administra- tions, on muscle specimens from malignant hyperther- mia(MH)susceptibleandMHnonsusceptiblepatients, respectively. In the cumulative CEPin vitrocontracture test, contractures were significantly greater in the MH susceptible compared with the MH nonsusceptible muscles in all concentrations between 25 and 100

Mark Ulrich Gerbershagen; Marko Fiege; Ralf Weisshorn; Kerstin Kolodzie; Jochen Schulte am Esch; Frank Wappler

2005-01-01

326

Anti-Tac-H, a Humanized Antibody to the Interleukin 2 Receptor with New Features for Immunotherapy in Malignant and Immune Disorders  

Microsoft Academic Search

The M, 55,000 interleukin 2 receptor peptide (Tac; CD25) is not expressed by normal resting T-cells but is markedly up-regulated in adult T-cell leukemia and other malignancies, as well as on T-cells activated in normal immune, autoimmune, allograft, and graft-versus-host settings. Anti-Tac is a mouse monoclonal antibody directed against the Tac peptide. Our prior attempts to use this antibody in

R. P. Junghans; T. A. Waldmann; N. F. Landolfi; N. M. Avdalovic; W. P. Schneider; C. Queen

1990-01-01

327

Therapeutics, Targets, and Chemical Biology Prostate Cancer Radiosensitization through  

E-print Network

Therapeutics, Targets, and Chemical Biology Prostate Cancer Radiosensitization through Poly(P)H:quinone oxido- reductase 1 (NQO1) metabolic bioactivation, triggering a massive induction of reactive oxygen cancers are in great demand. -Lapachone (-lap; 3,4-dihydro-2,2-dimethyl-2H-naphtho [1,2-b]pyran-5,6-dione

Gao, Jinming

328

Radiosensitization of mammary carcinoma cells by telomere homolog oligonucleotide pretreatment  

Microsoft Academic Search

INTRODUCTION: Ionizing radiation (IR) is a widely used approach to cancer therapy, ranking second only to surgery in rate of utilization. Responses of cancer patients to radiotherapy depend in part on the intrinsic radiosensitivity of the tumor cells. Thus, promoting tumor cell sensitivity to IR could significantly enhance the treatment outcome and quality of life for patients. METHODS: Mammary tumor

Desheng Weng; Monique C Cunin; Baizheng Song; Brendan D Price; Mark S Eller; Barbara A Gilchrest; Stuart K Calderwood; Jianlin Gong

2010-01-01

329

Radiosensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector.  

PubMed

A tumor-selective non-lytic retroviral replicating vector (RRV), Toca 511, and an extended-release formulation of 5-fluorocytosine (5-FC), Toca FC, are currently being evaluated in clinical trials in patients with recurrent high-grade glioma (NCT01156584, NCT01470794 and NCT01985256). Tumor-selective propagation of this RRV enables highly efficient transduction of glioma cells with cytosine deaminase (CD), which serves as a prodrug activator for conversion of the anti-fungal prodrug 5-FC to the anti-cancer drug 5-fluorouracil (5-FU) directly within the infected cells. We investigated whether, in addition to its direct cytotoxic effects, 5-FU generated intracellularly by RRV-mediated CD/5-FC prodrug activator gene therapy could also act as a radiosensitizing agent. Efficient transduction by RRV and expression of CD were confirmed in the highly aggressive, radioresistant human glioblastoma cell line U87EGFRvIII and its parental cell line U87MG (U87). RRV-transduced cells showed significant radiosensitization even after transient exposure to 5-FC. This was confirmed both in vitro by a clonogenic colony survival assay and in vivo by bioluminescence imaging analysis. These results provide a convincing rationale for development of tumor-targeted radiosensitization strategies utilizing the tumor-selective replicative capability of RRV, and incorporation of radiation therapy into future clinical trials evaluating Toca 511 and Toca FC in brain tumor patients. PMID:25301172

Takahashi, M; Valdes, G; Hiraoka, K; Inagaki, A; Kamijima, S; Micewicz, E; Gruber, H E; Robbins, J M; Jolly, D J; McBride, W H; Iwamoto, K S; Kasahara, N

2014-10-01

330

Gold-loaded polymeric micelles for computed tomography-guided radiation therapy treatment and radiosensitization.  

PubMed

Gold nanoparticles (AuNPs) have generated interest as both imaging and therapeutic agents. AuNPs are attractive for imaging applications since they are nontoxic and provide nearly three times greater X-ray attenuation per unit weight than iodine. As therapeutic agents, AuNPs can sensitize tumor cells to ionizing radiation. To create a nanoplatform that could simultaneously exhibit long circulation times, achieve appreciable tumor accumulation, generate computed tomography (CT) image contrast, and serve as a radiosensitizer, gold-loaded polymeric micelles (GPMs) were prepared. Specifically, 1.9 nm AuNPs were encapsulated within the hydrophobic core of micelles formed with the amphiphilic diblock copolymer poly(ethylene glycol)-b-poly(?-capralactone). GPMs were produced with low polydispersity and mean hydrodynamic diameters ranging from 25 to 150 nm. Following intravenous injection, GPMs provided blood pool contrast for up to 24 h and improved the delineation of tumor margins via CT. Thus, GPM-enhanced CT imaging was used to guide radiation therapy delivered via a small animal radiation research platform. In combination with the radiosensitizing capabilities of gold, tumor-bearing mice exhibited a 1.7-fold improvement in the median survival time, compared with mice receiving radiation alone. It is envisioned that translation of these capabilities to human cancer patients could guide and enhance the efficacy of radiation therapy. PMID:24377302

Al Zaki, Ajlan; Joh, Daniel; Cheng, Zhiliang; De Barros, André Luís Branco; Kao, Gary; Dorsey, Jay; Tsourkas, Andrew

2014-01-28

331

Gold-Loaded Polymeric Micelles for Computed Tomography-Guided Radiation Therapy Treatment and Radiosensitization  

PubMed Central

Gold nanoparticles (AuNPs) have generated interest as both imaging and therapeutic agents. AuNPs are attractive for imaging applications since they are nontoxic and provide nearly three times greater X-ray attenuation per unit weight than iodine. As therapeutic agents, AuNPs can sensitize tumor cells to ionizing radiation. To create a nanoplatform that could simultaneously exhibit long circulation times, achieve appreciable tumor accumulation, generate computed tomography (CT) image contrast, and serve as a radiosensitizer, gold-loaded polymeric micelles (GPMs) were prepared. Specifically, 1.9 nm AuNPs were encapsulated within the hydrophobic core of micelles formed with the amphiphilic diblock copolymer poly(ethylene glycol)-b-poly(?-capralactone). GPMs were produced with low polydispersity and mean hydrodynamic diameters ranging from 25 to 150 nm. Following intravenous injection, GPMs provided blood pool contrast for up to 24 h and improved the delineation of tumor margins via CT. Thus, GPM-enhanced CT imaging was used to guide radiation therapy delivered via a small animal radiation research platform. In combination with the radiosensitizing capabilities of gold, tumor-bearing mice exhibited a 1.7-fold improvement in the median survival time, compared with mice receiving radiation alone. It is envisioned that translation of these capabilities to human cancer patients could guide and enhance the efficacy of radiation therapy. PMID:24377302

2013-01-01

332

Selective Targeting of Brain Tumors with Gold Nanoparticle-Induced Radiosensitization  

PubMed Central

Successful treatment of brain tumors such as glioblastoma multiforme (GBM) is limited in large part by the cumulative dose of Radiation Therapy (RT) that can be safely given and the blood-brain barrier (BBB), which limits the delivery of systemic anticancer agents into tumor tissue. Consequently, the overall prognosis remains grim. Herein, we report our pilot studies in cell culture experiments and in an animal model of GBM in which RT is complemented by PEGylated-gold nanoparticles (GNPs). GNPs significantly increased cellular DNA damage inflicted by ionizing radiation in human GBM-derived cell lines and resulted in reduced clonogenic survival (with dose-enhancement ratio of ?1.3). Intriguingly, combined GNP and RT also resulted in markedly increased DNA damage to brain blood vessels. Follow-up in vitro experiments confirmed that the combination of GNP and RT resulted in considerably increased DNA damage in brain-derived endothelial cells. Finally, the combination of GNP and RT increased survival of mice with orthotopic GBM tumors. Prior treatment of mice with brain tumors resulted in increased extravasation and in-tumor deposition of GNP, suggesting that RT-induced BBB disruption can be leveraged to improve the tumor-tissue targeting of GNP and thus further optimize the radiosensitization of brain tumors by GNP. These exciting results together suggest that GNP may be usefully integrated into the RT treatment of brain tumors, with potential benefits resulting from increased tumor cell radiosensitization to preferential targeting of tumor-associated vasculature. PMID:23638079

Joh, Daniel Y.; Sun, Lova; Stangl, Melissa; Al Zaki, Ajlan; Murty, Surya; Santoiemma, Phillip P.; Davis, James J.; Baumann, Brian C.; Alonso-Basanta, Michelle; Bhang, Dongha; Kao, Gary D.; Tsourkas, Andrew; Dorsey, Jay F.

2013-01-01

333

Cetuximab attenuates its cytotoxic and radiosensitizing potential by inducing fibronectin biosynthesis.  

PubMed

Inherent and acquired resistance to targeted therapeutics continues to emerge as a major clinical obstacle. For example, resistance to EGF receptor targeting occurs commonly, more so than was expected, on the basis of preclinical work. Given emerging evidence that cancer cell-substrate interactions are important determinants of therapeutic sensitivity, we examined the impact of cell-fibronectin interactions on the efficacy of the EGF receptor antibody cetuximab, which is used widely for lung cancer treatment. Our results revealed the potential for cell-fibronectin interactions to induce radioresistance of human non-small cell lung cancer cells. Cell adhesion to fibronectin enhanced tumor cell radioresistance and attenuated the cytotoxic and radiosensitizing effects of cetuximab. Both in vitro and in vivo, we found that cetuximab treatment led to a remarkable induction of fibronectin biosynthesis. Mechanistic analyses revealed the induction was mediated by a p38-MAPK-ATF2 signaling pathway and that RNAi-mediated inhibition of fibronectin could elevate the cytotoxic and radiosensitizing potential of cetuximab. Taken together, our findings show how cell adhesion blunts cetuximab, which, by inducing fibronectin, generates a self-attenuating mechanism of drug resistance. PMID:23950208

Eke, Iris; Storch, Katja; Krause, Mechthild; Cordes, Nils

2013-10-01

334

Eighth annual Juan del Regato lecture. Chemical modifiers of radiosensitivity--theory and reality: a review  

SciTech Connect

In this review the poor clinical gains from hyperbaric oxygen (HBO) and misonidazole (MISO) are discussed critically. The biggest factor reducing clinical gains is almost certainly reoxygenation. Other possible reasons include vasoconstrictive self-limitation of HBO and neurotoxicity of MISO, so that the radiosensitization of any hypoxic cells in human tumors was not adequate. Nevertheless, there have been some positive clinical results, so that hypoxic cells can sometimes be a problem in some tumors, especially those of the head and neck, even after multiple fraction radiotherapy. While hypoxic cell radioresistance is obviously only one form of radioresistance it is a large factor of resistance when hypoxic cells are present. Current developments are briefly reviewed: the new clinical sensitizers Ro-03-8799 and SR-2508 which should be 3 to 10 times more efficient than MISO if viable hypoxic cells are present; and methods of measuring which human tumors might have significant numbers of hypoxic viable cells. 77 references.

Fowler, J.F.

1985-04-01

335

Malignant cancer and invasive placentation  

PubMed Central

Cancer metastasis is an invasive process that involves the transplantation of cells into new environments. Since human placentation is also invasive, hypotheses about a relationship between invasive placentation in eutherian mammals and metastasis have been proposed. The relationship between metastatic cancer and invasive placentation is usually presented in terms of antagonistic pleiotropy. According to this hypothesis, evolution of invasive placentation also established the mechanisms for cancer metastasis. Here, in contrast, we argue that the secondary evolution of less invasive placentation in some mammalian lineages may have resulted in positive pleiotropic effects on cancer survival by lowering malignancy rates. These positive pleiotropic effects would manifest themselves as resistance to cancer cell invasion. To provide a preliminary test of this proposal, we re-analyze data from Priester and Mantel (Occurrence of tumors in domestic animals. Data from 12 United States and Canadian colleges of veterinary medicine. J Natl Cancer Inst 1971;47:1333-44) about malignancy rates in cows, horses, cats and dogs. From our analysis we found that equines and bovines, animals with less invasive placentation, have lower rates of metastatic cancer than felines and canines in skin and glandular epithelial cancers as well as connective tissue sarcomas. We conclude that a link between type of placentation and species-specific malignancy rates is more likely related to derived mechanisms that suppress invasion rather than different degrees of fetal placental aggressiveness. PMID:25324490

D'Souza, Alaric W.; Wagner, Gunter P.

2014-01-01

336

The prospective application of a hypoxic radiosensitizer, doranidazole to rat intracranial glioblastoma with blood brain barrier disruption  

PubMed Central

Background Glioblastoma is one of the intractable cancers and is highly resistant to ionizing radiation. This radioresistance is partly due to the presence of a hypoxic region which is widely found in advanced malignant gliomas. In the present study, we evaluated the effectiveness of the hypoxic cell sensitizer doranidazole (PR-350) using the C6 rat glioblastoma model, focusing on the status of blood brain barrier (BBB). Methods Reproductive cell death in the rat C6 glioma cell line was determined by means of clonogenic assay. An intracranial C6 glioma model was established for the in vivo experiments. To investigate the status of the BBB in C6 glioma bearing brain, we performed the Evans blue extravasation test. Autoradiography with [14C]-doranidazole was performed to examine the distribution of doranidazole in the glioma tumor. T2-weighted MRI was employed to examine the effects of X-irradiation and/or doranidazole on tumor growth. Results Doranidazole significantly enhanced radiation-induced reproductive cell death in vitro under hypoxia, but not under normoxia. The BBB in C6-bearing brain was completely disrupted and [14C]-doranidazole specifically penetrated the tumor regions. Combined treatment with X-irradiation and doranidazole significantly inhibited the growth of C6 gliomas. Conclusions Our results revealed that BBB disruption in glioma enables BBB-impermeable radiosensitizers to penetrate and distribute in the target region. This study is the first to propose that in malignant glioma the administration of hydrophilic hypoxic radiosensitizers could be a potent strategy for improving the clinical outcome of radiotherapy without side effects. PMID:23496909

2013-01-01

337

Gynecologic malignancy in pregnancy  

PubMed Central

Gynecologic malignancy during pregnancy is a stressful problem. For the diagnosis and treatment of malignancy during pregnancy, a multidisciplinary approach is needed. Patients should be advised about the benefits and risk of treatment. When selecting a treatment for malignancy during pregnancy, the physiologic changes that occur with the pregnancy should be considered. Various diagnostic procedures that do not harm the fetus can be used. Laparoscopic surgery or laparotomy may be safely performed. The staging approach and treatment should be standard. Systemic chemotherapy during the first trimester should be delayed if possible. Radiation therapy should preferably start postpartum. Although delivery should be delayed preferably until after 35 weeks of gestation, termination of pregnancy may be considered when immediate treatment is required. Subsequent pregnancies do not increase the risk of malignancy recurrence. PMID:24328018

Ji, Yong Il

2013-01-01

338

Localized malignant pleural mesothelioma.  

PubMed

Localized malignant pleural mesothelioma (LMPM) is a rare tumor; previously only 52 cases have been reported in the English literature. This type of tumor should be distinguished from diffuse malignant pleural mesothelioma, because a good outcome may be obtained by surgical resection. We report a case of LMPM which grew rapidly within 1 year. Surgical resection was performed, and at present, 6 months since the operation, the patient remains free of the disease. PMID:22566254

Nakano, Takayuki; Hamanaka, Rurika; Oiwa, Kana; Nakazato, Kenei; Masuda, Ryota; Iwazaki, Masayuki

2012-07-01

339

Thoracic Malignancy Steering Committee  

Cancer.gov

The TMSC functions to harmonize an efficient, cost-effective, science-driven, and transparent process that will identify and promote the "Best Science" in clinical research of lung and other thoracic malignancies by addressing the design and prioritization of phase III trials and large phase II studies in chest malignancies. In addition to focusing on lung cancer, the TMSC addresses oncology trials in other thoracic sites, such as mesothelioma. Esophageal cancer trials are reviewed by the Gastrointestinal Cancer Steering Committee.

340

[Malignant nail tumors].  

PubMed

Because of the large number of different tissues making up the distal phalanx of fingers and toes, a large variety of malignant tumors can be found in and around the nail apparatus. Bowen disease is probably the most frequent nail malignancy. It is usually seen as a verrucous plaque of the nail fold and nail bed in persons above the age of 40 years. It slowly grows over a period of years or even decades before degenerating to an invasive squamous cell carcinoma. The latter may also occur primarily often as a weeping onycholysis. The next most frequent nail malignancy is ungual melanoma. Those arising from the matrix are usually pigmented and often start with a longitudinal melanonychia whereas those originating from the nail bed remain amelanotic, are often nodular and mistaken for an ingrown nail in an elderly person. The treatment of choice for in situ and early invasive subungual melanomas is generous extirpation of the nail apparatus whereas distal amputation is only indicated for advanced melanomas. In addition to these frequent nail malignancies, nail-specific carcinomas, malignant vascular and osseous tumors, other sarcomas, nail involvement in malignant systemic disorders and metastases may occur. In most cases, they cannot be diagnosed accurately on clinical grounds. Therefore, a high degree of suspicion is necessary in all isolated or single-digit proliferations that do not respond to conservative treatment. PMID:24718507

Haneke, E

2014-04-01

341

The HSP90 inhibitor ganetespib has chemosensitizer and radiosensitizer activity in colorectal cancer.  

PubMed

The integration of targeted agents to standard cytotoxic regimens has improved outcomes for patients with colorectal cancer (CRC) over recent years; however this malignancy remains the second leading cause of cancer mortality in industrialized countries. Small molecule inhibitors of heat shock protein 90 (HSP90) are one of the most actively pursued classes of compounds for the development of new cancer therapies. Here we evaluated the activity of ganetespib, a second-generation HSP90 inhibitor, in models of CRC. Ganetespib reduced cell viability in a panel of CRC cell lines in vitro with low nanomolar potency. Mechanistically, drug treatment exerted concomitant effects on multiple oncogenic signaling pathways, cell cycle regulation, and DNA damage repair capacity to promote apoptosis. Combinations of ganetespib and low-dose ionizing radiation enhanced the radiosensitivity of HCT 116 cells and resulted in superior cytotoxic activity over either treatment alone. In vivo, the single-agent activity of ganetespib was relatively modest, suppressing HCT 116 xenograft tumor growth by approximately half. However, ganetespib significantly potentiated the antitumor efficacy of the 5-Fluorouracil (5-FU) prodrug capecitabine in HCT 116 xenografts, causing tumor regressions in a model that is intrinsically resistant to fluoropyrimidine therapy. This demonstration of combinatorial benefit afforded by an HSP90 inhibitor to a standard CRC adjuvant regimen provides an attractive new framework for the potential application of ganetespib as an investigational agent in this disease. PMID:24682747

He, Suqin; Smith, Donald L; Sequeira, Manuel; Sang, Jim; Bates, Richard C; Proia, David A

2014-08-01

342

In vivo growth-restricted and reversible malignancy induced by Human Herpesvirus-8/ KSHV: a cell and animal model of virally induced Kaposi's sarcoma  

PubMed Central

Transfection of a Kaposi's sarcoma (KS) herpesvirus (KSHV) Bacterial Artificial Chromosome (KSHVBac36) into mouse bone marrow endothelial lineage cells generates a cell (mECK36) that forms KS-like tumors in mice. mECK36 expressed most KSHV genes and were angiogenic, but didn't form colonies in soft agar. In nude mice, mECK36 formed KSHV-harboring vascularized spindle-cell sarcomas that were LANA+/podoplanin+, overexpressed VEGF and Angiopoietin ligands and receptors, and displayed KSHV and host transcriptomes reminiscent of KS. mECK36 that lost the KSHV episome reverted to non-tumorigenicity. siRNA suppression of KSHV vGPCR, an angiogenic gene up-regulated in mECK36 tumors, inhibited angiogenicity and tumorigenicity. These results show that KSHV malignancy is in vivo growth-restricted and reversible, defining mECK36 as a biologically sensitive animal model of KSHV-dependent KS. PMID:17349582

Mutlu, Agata D'Agostino; Cavallin, Lucas E.; Vincent, Loic; Chiozzini, Chiara; Eroles, Pilar; Duran, Elda M.; Asgari, Zahra; Hooper, Andrea T.; La Perle, Krista M. D.; Hilsher, Chelsey; Gao, Shou-Jiang; Dittmer, Dirk P.; Rafii, Shahin; Mesri, Enrique A.

2007-01-01

343

Potential Radiosensitizing Agents III: 2-Nitro-4-acetylimidazole analogs.  

PubMed

New analogs of 2-nitroimidazole have been synthesized in an effort to minimize the toxicity and increase selective sensitization of hypoxic mammalian cells toward lethal effects of ionizing radiation. 2-Nitro-4(5)-acetyl-5(4)-methylimidazole was synthesized from the corresponding 2-amino analog and then reacted with oxiranes to produce the corresponding 1-substituted 2-propanol and 3-methoxy-2-propanol derivatives. The biological results of radiosensitizing activity of these agents against Chinese hamster cells (V-79) indicated that the 3-methoxy-2-propanol derivative was a more effective radiosensitizer than misonidazole in vitro. Evaluation of the acute toxicity of these agents as determined by LD50 demonstrated no significant difference between these agents and misonidazole suggesting that the 3-methoxy-2-propanol analog may possess a therapeutic advantage over misonidazole. PMID:7175708

Sehgal, R K; Agrawal, K C

1982-11-01

344

Radiosensitivity, blood perfusion and tumour oxygenation after perflubron emulsion injection.  

PubMed

The effect of 90% and/or 100% w/v perflubron (perfluorooctyl bromide (PFOB); Alliance Pharmaceutical Corp.) emulsions on radiosensitivity, tumour relative perfusion and oxygenation was studied using EMT6 tumours in nude mice. Perflubron (2-15 ml/kg) emulsion was injected. The mice inhaled carbogen for 30 min and 60 min prior to irradiation. The radiosensitizing effect of the 90% w/v emulsion was maximal at 4 ml/kg. The tumour relative perfusion diminished after injection of both 100% and 90% w/v emulsions in carbogen-breathing mice at a dose of 15 ml/kg. This drop could explain the lack of efficiency of these treatments at this high concentration. Lastly, tumour oxygenation was increased after administration of perflubron emulsion plus carbogen. PMID:8356225

Vitu-Loas, L; Thomas, C; Chavaudra, N; Guichard, M

1993-05-01

345

Effects of connective tissue growth factor (CTGF) gene silencing on the radiosensitivity of glioblastoma  

PubMed Central

The effects of connective tissue growth factor (CTGF) gene silencing on the radiosensitivity of glioblastoma cells (GBM) were investigated. The lentivirus-mediated short hairpin RNA (shRNA) expression vector targeting CTGF was constructed and transinfected into U87MG human GBM cell line. The CTGF gene expression in U87MG cells was significantly down-regulated. After irradiation with 6 MV X-rays at a dose rate of 2.5 Gy/min, the clonogenicity, proliferation and migration of U87MG cells were assayed in vitro. The survival, proliferation and migration of U87MG cells were all remarkably inhibited by CTGF silencing (p < 0.05 vs control). Our results demonstrate that CTGF is important for GBM and CTGF gene silencing can be a potential tool to enhance the sensitivity of GBM to radiotherapy. PMID:25356109

Han, Na; Shahveranov, Allahverdi; Cheng, Yi; Qin, Kai; Yu, Shi-Ying; Zhang, Meng-Xian

2014-01-01

346

Expanding the therapeutic repertoire of epidermal growth factor receptor blockade: radiosensitization  

PubMed Central

Expression of epidermal growth factor receptor (EGFR) has been associated with radioresistance in cancer. Moreover, tumour cell recovery after irradiation paradoxically occurs, in part, as a result of activation of EGFR signalling by such treatment. A recent article by Huang, Li, Armstrong and Harari provides strong rationale for considering the anti-EGFR agent ZD1839 ('Iressa') as a radiosensitizing strategy. With the use of several in vitro and xenograft models of human squamous cell head and neck carcinoma, ZD1939 was shown to markedly improve radiotherapeutic response, with superior tumour inhibition and delayed tumour regrowth. Mechanisms underlying this effect included anti-proliferative and pro-apoptotic activity, with significant perturbation of tumour angiogenesis. PMID:12793892

Gee, Julia MW; Nicholson, Robert I

2003-01-01

347

Hops (Humulus lupulus) inhibits oxidative estrogen metabolism and estrogen-induced malignant transformation in human mammary epithelial cells (MCF-10A).  

PubMed

Long-term exposure to estrogens including those in traditional hormone replacement therapy (HRT) increases the risk of developing hormone-dependent cancers. As a result, women are turning to over-the-counter (OTC) botanical dietary supplements, such as black cohosh (Cimicifuga racemosa) and hops (Humulus lupulus), as natural alternatives to HRT. The two major mechanisms which likely contribute to estrogen and/or HRT cancer risk are: the estrogen receptor-mediated hormonal pathway; and the chemical carcinogenesis pathway involving formation of estrogen quinones that damage DNA and proteins, hence initiating and promoting carcinogenesis. Because, OTC botanical HRT alternatives are in widespread use, they may have the potential for chemopreventive effects on estrogen carcinogenic pathways in vivo. Therefore, the effect of OTC botanicals on estrogen-induced malignant transformation of MCF-10A cells was studied. Cytochrome P450 catalyzed hydroxylation of estradiol at the 4-position leads to an o-quinone believed to act as the proximal carcinogen. Liquid chromatography/tandem mass spectrometry analysis of estradiol metabolites showed that 4-hydroxylation was inhibited by hops, whereas black cohosh was without effect. Estrogen-induced expression of CYP450 1B1 and CYP450 1A1 was attenuated by the hops extract. Two phenolic constituents of hops (xanthohumol, XH; 8-prenylnaringenin, 8-PN) were tested: 8-PN was a potent inhibitor, whereas XH had no effect. Finally, estrogen-induced malignant transformation of MCF-10A cells was observed to be significantly inhibited by hops (5 ?g/mL) and 8-PN (50 nmol/L). These data suggest that hops extracts possess cancer chemopreventive activity through attenuation of estrogen metabolism mediated by 8-PN. PMID:21997247

Hemachandra, L P; Madhubhani, P; Chandrasena, R; Esala, P; Chen, Shao-Nong; Main, Matthew; Lankin, David C; Scism, Robert A; Dietz, Birgit M; Pauli, Guido F; Thatcher, Gregory R J; Bolton, Judy L

2012-01-01

348

A first-in-human, phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies  

PubMed Central

Background Dinaciclib, a small-molecule, cyclin-dependent kinase inhibitor, inhibits cell cycle progression and proliferation in various tumor cell lines in vitro. We conducted an open-label, dose-escalation study to determine the safety, tolerability, and bioactivity of dinaciclib in adults with advanced malignancies. Methods Dinaciclib was administered starting at a dose of 0.33 mg/m2, as a 2-hour intravenous infusion once weekly for 3 weeks (on days 1, 8, and 15 of a 28-day cycle), to determine the maximum administered dose (MAD), dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and safety and tolerability. Pharmacodynamics of dinaciclib were assessed using an ex vivo phytohemagglutinin lymphocyte stimulation assay and immunohistochemistry staining for retinoblastoma protein phosphorylation in skin biopsies. Evidence of antitumor activity was assessed by sequential computed tomography imaging after every 2 treatment cycles. Results Forty-eight subjects with solid tumors were treated. The MAD was found to be 14 mg/m2 and the RP2D was determined to be 12 mg/m2; DLTs at the MAD included orthostatic hypotension and elevated uric acid. Forty-seven (98%) subjects reported adverse events (AEs) across all dose levels; the most common AEs were nausea, anemia, decreased appetite, and fatigue. Dinaciclib administered at the RP2D significantly inhibited lymphocyte proliferation, demonstrating a pharmacodynamic effect. Ten subjects treated at a variety of doses achieved prolonged stable disease for at least 4 treatment cycles. Conclusions Dinaciclib administered every week for 3 weeks (on days 1, 8, and 15 of a 28-day cycle) was generally safe and well tolerated. Initial bioactivity and observed disease stabilization support further evaluation of dinaciclib as a treatment option for patients with advanced solid malignancies. Trial registration ClinicalTrials.gov # NCT00871663 PMID:24131779

2013-01-01

349

AZD5438, an Inhibitor of Cdk1, 2, and 9, Enhances the Radiosensitivity of Non-Small Cell Lung Carcinoma Cells  

SciTech Connect

Purpose: Radiation therapy (RT) is one of the primary modalities for treatment of non-small cell lung cancer (NSCLC). However, due to the intrinsic radiation resistance of these tumors, many patients experience RT failure, which leads to considerable tumor progression including regional lymph node and distant metastasis. This preclinical study evaluated the efficacy of a new-generation cyclin-dependent kinase (Cdk) inhibitor, AZD5438, as a radiosensitizer in several NSCLC models that are specifically resistant to conventional fractionated RT. Methods and Materials: The combined effect of ionizing radiation and AZD5438, a highly specific inhibitor of Cdk1, 2, and 9, was determined in vitro by surviving fraction, cell cycle distribution, apoptosis, DNA double-strand break (DSB) repair, and homologous recombination (HR) assays in 3 NSCLC cell lines (A549, H1299, and H460). For in vivo studies, human xenograft animal models in athymic nude mice were used. Results: Treatment of NSCLC cells with AZD5438 significantly augmented cellular radiosensitivity (dose enhancement ratio rangeing from 1.4 to 1.75). The degree of radiosensitization by AZD5438 was greater in radioresistant cell lines (A549 and H1299). Radiosensitivity was enhanced specifically through inhibition of Cdk1, prolonged G{sub 2}-M arrest, inhibition of HR, delayed DNA DSB repair, and increased apoptosis. Combined treatment with AZD5438 and irradiation also enhanced tumor growth delay, with an enhancement factor ranging from 1.2-1.7. Conclusions: This study supports the evaluation of newer generation Cdk inhibitors, such as AZD5438, as potent radiosensitizers in NSCLC models, especially in tumors that demonstrate variable intrinsic radiation responses.

Raghavan, Pavithra; Tumati, Vasu; Yu Lan [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States)] [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Chan, Norman [Departments of Medical Biophysics and Radiation Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Ontario (Canada)] [Departments of Medical Biophysics and Radiation Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Ontario (Canada); Tomimatsu, Nozomi [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States)] [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Burma, Sandeep [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States) [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Simmons Comprehensive Cancer Center, Dallas, Texas (United States); Bristow, Robert G. [Departments of Medical Biophysics and Radiation Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Ontario (Canada)] [Departments of Medical Biophysics and Radiation Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Ontario (Canada); Saha, Debabrata, E-mail: debabrata.saha@utsouthwestern.edu [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States) [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Simmons Comprehensive Cancer Center, Dallas, Texas (United States)

2012-11-15

350

AZD5438, an Inhibitor of Cdk1, 2, and 9, Enhances the Radiosensitivity of Non-Small Cell Lung Carcinoma Cells  

PubMed Central

Purpose Radiation therapy (RT) is one of the primary modalities for treatment of non-small cell lung cancer (NSCLC). However, due to the intrinsic radiation resistance of these tumors, many patients experience RT failure, which leads to considerable tumor progression including regional lymph node and distant metastasis. This preclinical study evaluated the efficacy of a new-generation cyclin-dependent kinase (Cdk) inhibitor, AZD5438, as a radiosensitizer in several NSCLC models that are specifically resistant to conventional fractionated RT. Methods and Materials The combined effect of ionizing radiation and AZD5438, a highly specific inhibitor of Cdk1, 2, and 9, was determined in vitro by surviving fraction, cell cycle distribution, apoptosis, DNA double-strand break (DSB) repair, and homologous recombination (HR) assays in 3 NSCLC cell lines (A549, H1299, and H460). For in vivo studies, human xenograft animal models in athymic nude mice were used. Results Treatment of NSCLC cells with AZD5438 significantly augmented cellular radiosensitivity (dose enhancement ratio rangeing from 1.4 to 1.75). The degree of radiosensitization by AZD5438 was greater in radioresistant cell lines (A549 and H1299). Radiosensitivity was enhanced specifically through inhibition of Cdk1, prolonged G2-M arrest, inhibition of HR, delayed DNA DSB repair, and increased apoptosis. Combined treatment with AZD5438 and irradiation also enhanced tumor growth delay, with an enhancement factor ranging from 1.2–1.7. Conclusions This study supports the evaluation of newer generation Cdk inhibitors, such as AZD5438, as potent radiosensitizers in NSCLC models, especially in tumors that demonstrate variable intrinsic radiation responses. PMID:22795803

Raghavan, Pavithra; Tumati, Vasu; Yu, Lan; Chan, Norman; Tomimatsu, Nozomi; Burma, Sandeep; Bristow, Robert G.; Saha, Debabrata

2013-01-01

351

Radiosensitization of EMT6 cells by four platinum complexes  

SciTech Connect

The compounds described here are dichloro complexes of bivalent platinum with one or two potentially radiosensitizing ligands. The radiosensitization of oxygenated and hypoxic exponentially growing EMT6 cells in vitro was measured. The dose modifying factors obtained with 200 ..mu..M and 400 ..mu..M trans-bis(2-nitroimidazole)dichloroplatinum II (NIPt) in hypoxic cells were 1.5 and 2.1, respectively. For trans-bis(2-amino-5-nitrothiazole)dichloroplatinum II (Plant) under the same conditions, the dose modifying factor was 1.5 at 200 ..mu..M and 1.8 at 400 ..mu..M. Neither compound sensitized oxygenated cells when tested similar protocols. Unlike the trans complexes (1,2-diamino-4-nitrobenzene)dichloroplatinum II (Plato) was cytotoxic toward the hypoxic cells in the absence of X rays. The time course of cytotoxicity for 100 ..mu..M Plato in exponentially growing cells showed rapid killing of hypoxic cells, and much less toxicity toward oxygenated cells. In radiosensitization studies, dose modifying factors of 1.6 and 2.0 were found with 200 ..mu..M and 400 ..mu..M Plato in hypoxic cells. The compound did not sensitize aerobic cells. The well-known platinum complex cis-dipyridinedichloroplatinum II (PyPt) represents a cis-platinum heterocyclic aromatic complex that does not have a nitro-functionality. The dose modifying factor obtained with 400 ..mu..M PyPt in hypoxic cells was 1.7. On a molar basis, the nitro-functional platinum complexes appear to be more effective as hypoxic cell radiosensitizers than the corresponding free ligands.

Teicher, B.A.; Rockwell, S.; Lee, J.B.

1985-05-01

352

Epidermodysplasia verruciformis: an unusual malignant transformation.  

PubMed

Epidermodysplasia verruciformis (EV) is a rare, life-long heritable disease caused due to a unique susceptibility to human papilloma virus. The disseminated verrucous lesions and pityriasis versicolor-like lesions persist from early childhood and can transform into a cutaneous malignancy in a fourth of patients. Malignant transformation into syringoid eccrine carcinoma (SEC) has been reported only once so far. SEC is an extremely invasive, rare, locally destructive, slowly growing adnexal tumor. We hereby report the association of EV with SEC in a 29-year-old male. PMID:23254737

Agrawal, Prachi G; Mahajan, Sunanda A; Khopkar, Uday S; Kharkar, Vidya D

2013-01-01

353

Radiosensitization: enhancing the radiation inactivation of foodborne bacteria  

NASA Astrophysics Data System (ADS)

Irradiation of meat products to kill pathogens can be limited by radiation-induced detriment of sensory quality. Since such detriment is directly related to dose, one approach to reduce it is by devising means to lower the dose of radiation required for processing. Increasing the radiation sensitivity of the target microorganisms would lower the dose required for a given level of microbial kill. In this work, the radiation sensitivities of inoculated Escherichia coli and Salmonella typhi in ground beef were examined under a variety of conditions. Results showed that specific manipulations of treatment conditions significantly increased the radiation sensitivity of the test organisms, ranging from a few percent to several-fold reduction in D10. In particular, radiation sensitization could be effected by certain additives, including carvacrol, thymol and trans-cinnamaldehyde, and also by certain compositions of modified atmosphere in the package headspace. A combination of additives and modified atmosphere effected a greater radiosensitization effect than could be achieved by either factor applied alone. Radiosensitization could be demonstrated with irradiation of either fresh or frozen ground meat. The radiosensitization phenomenon may be of practical utility in enhancing the technical effectiveness and feasibility of irradiation of a variety of meat and other food products.

Borsa, J.; Lacroix, M.; Ouattara, B.; Chiasson, F.

2004-09-01

354

Radiosensitization by quaternary salts of 5-nitroimidazole derivatives.  

PubMed

The radiosensitizing effects of five newly synthesized quaternary salts of 5-nitroimidazole derivatives on the survival of TC-SV40 mammalian cells have been measured. A toxicity study was carried out in order to determine the concentrations to be used in the radiosensitizing experiments. The oxygen enhancement ratio (OER) for TC-SV40 cells was 2.74. None of the five 5-nitroimidazole derivatives showed radiosensitizing activity in aerobic conditions, while in hypoxia their dose-modifying factors (DMF) at the concentration of 0.2 mmol dm-3 range from 1.52 to 1.03 in this order: unsubstitu