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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

Radiation-induced DNA damage and repair in cells of a radiosensitive human malignant glioma cell line  

Microsoft Academic Search

The induction and repair of DNA double-strand breaks were studied in cells of two isogenic human malignant glioma cell lines which vary in their SF2 values by a factor of â¼30.M059J cells are radiosensitive (SF2 = 0.02) and lack the p350 component of DNA-dependent protein kinase (DNA-PK); M059K cells are radioresistant (SF2 = 0.64) and express normal levels of DNA-PK.

M. J. Allalunis-Turner; P. K. Y. Zia; G. M. Barron

1995-01-01

3

Radiation-induced DNA damage and repair in cells of a radiosensitive human malignant glioma cell line  

SciTech Connect

The induction and repair of DNA double-strand breaks were studied in cells of two isogenic human malignant glioma cell lines which vary in their SF2 values by a factor of {approximately}30.M059J cells are radiosensitive (SF2 = 0.02) and lack the p350 component of DNA-dependent protein kinase (DNA-PK); M059K cells are radioresistant (SF2 = 0.64) and express normal levels of DNA-PK. Zero integrated field gel electrophoresis and alkaline sucrose gradient experiments indicated that equivalent numbers of DNA lesions were produced by ionizing radiation in M059J and M059K cells. To compare the capacity of both lines to repair sublethal damage, the split-dose recovery experiment after exposure to equitoxic doses of radiation was carried out. Significant sublethal damage repair was shown for M059K cells, with a 5.8-fold increase in relative survival peaking at 4 h, whereas M059J cells showed little repair activity. Electrophoresis studies indicated that more double-strand breaks were repaired by 30 min in M059K cells than in M059J cells. These results suggest that deficient DNA repair processes may be a major determinant of radiosensitivity in M059J cells. 24 refs., 5 figs., 2 tabs.

Allalunis-Turner, M.J.; Zia, P.K.Y.; Barron, G.M. [Cross Cancer Inst., Edmonton, Alberta (Canada)] [and others

1995-12-01

4

Adenovirus-Mediated Coexpression of DCX and SPARC Radiosensitizes Human Malignant Glioma Cells.  

PubMed

This study is designed to examine the radiosensitizing effects of coexpression of doublecortin (DCX) and secreted protein and rich in cysteine (SPARC). Previously, we showed that downregulation of SPARC by small interfering RNA increased radioresistance of U-87MG glioma cells. Therefore, overexpression of SPARC might increase radiosensitivity of glioma cells. But SPARC has been shown to promote glioma cell invasion both in vitro and vivo. In order to radiosensitize glioma cells without stimulating invasion, we chose DCX, which is a well-characterized anti-tumor gene, to coexpress with SPARC. An adenovirus-mediated double gene expression system was constructed and applied to U251 and A172 glioma cell lines. Our data showed that coexpression of DCX and SPARC collaboratively diminished radioresistance of glioma cells, interfered with cell cycle turnover and increased irradiation-induced apoptosis. In addition, transwell assay revealed that coexpression was able to counteract the invasion-promoting effects of SPARC, and even inhibited intrinsic invasion, evidenced by less invading cells in double gene overexpressed group than that of control adenovirus-treated group. In conclusion, genetic engineering combining two or more genes might be a more effective method to overcome radioresistance of glioma cells. PMID:23846421

Xu, Yuanyuan; Yang, Lei; Jiang, Xin; Yu, Jiahua; Yang, Jicheng; Zhang, Haowen; Tai, Guomei; Yuan, Xiaopeng; Liu, Fenju

2013-07-12

5

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

6

Microwave hyperthermia radiosensitized iridium-192 for recurrent brain malignancy  

SciTech Connect

Twenty-one patients whose solitary detectable biopsy proven recurrent brain malignancies produced Central Nervous System (CNS) symptoms warranting further intervention received 60-minute 43 degrees C (180 degree-minute) interstitial 2450 MHz microwave hyperthermia fractions. All received brain teletherapy prior to recurrence. The first 15 received no brachytherapy and served as a toxicity pilot. All 15 enjoyed neurologic improvement, 12 symptomatic improvement, and 12 objective response as mass reduction and/or tumor necrosis. The next 6 patients were selected with more favorable Karnofsky performance status, no known active malignancy elsewhere, and received afterloading Ir-192 interstitial implantation juxtaposed to radiosensitizing hyperthermia. Volume dose varied from 1000 to 2245 rad, and dose rate from 40 to 100 rad/hr. Dose selected varied as a function of pre-recurrence teletherapy dose, general condition, histologic type, and volume. Neurosurgical debulking, if technically indicated through no additional aperture or trauma, was permitted if consistent with preservation of neurological function. Six enjoyed neurologic improvement, symptom reduction, and objective tumor response; three remain alive, and one experienced transient improvement. Complications, histologic subtypes, autopsy findings, stereotactic approach, thermal monitoring methods and CT follow-up of objective response are presented along with computer dosimetry and isotherm chart. Our microtraumatic universal catheter technique for CT guided stereotactic biopsy, aspiration, decompression, thermal sensory loop, thermalization antennae, and brachytherapy without multiple trauma nor changing catheters is stressed. The rationale for combined modes peculiar to the CNS will be outlined.2+ Proposal for incorporating controlled-release ARA-C chemotherapy polymer micro-rods into the interstitial format will be offered.

Borok, T.L.; Winter, A.; Laing, J.; Paglione, R.; Sterzer, F.; Sinclair, I.; Plafker, J. (Metcalf Institute-Radiation Oncology, Orange, NJ (USA))

1988-03-01

7

Hypothermia-enhanced human tumor cell radiosensitivity.  

PubMed

Ablation of neoplastic disease by freezing has found increasing utility as a potential therapeutic modality. To assess the effect of cooling temperatures on cellular radiation response, an established human cervical carcinoma cell line (HTB35) was subjected to holding temperatures of 0, 5, or 15 degrees C for up to 24 h before irradiation. Survival was measured by in vitro clonogenic assay of colonies containing at least 50 cells. Cooling for up to 12 h did not significantly decrease survival, but after 24 h survival fell to 75% of control cultures grown at 37 degrees C. X-irradiation immediately after cooling for 24 h resulted in 1.6-fold enhanced radiosensitivity. However, the radiosensitizing effect decayed rapidly if the cooled cells were returned to normal growth temperature for 6 h or longer before irradiation and subculture. Both temperature and cooling duration influenced the radiation response. With 0, 5, or 15 degrees C, radiosensitivity increased after 3, 6, or 12 h, respectively, and progressively rose with up to 24 h of cooling. By flow cytometric analysis, no statistically significant difference was observed in the S-phase fraction between control cells and those cooled to 0 degree C for 24 h. These data demonstrate cooling-enhanced in vitro radiation sensitivity which is dependent upon cooling temperature, duration, and rewarming interval before irradiation. While cell cycle redistribution does not appear to be a factor in the increased radiosensitivity, differences in the radiation survival curves between cooled versus normothermic cells suggest that diminished capacity for sublethal damage repair may be a significant influence on the changes which were observed. PMID:9302769

Burton, S A; Paljug, W R; Kalnicki, S; Werts, E D

1997-08-01

8

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

9

Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line  

SciTech Connect

The radiosensitive rodent mutant cell lines xrs-5 is defective in DNA double-strand break repair and lacks the Ku component of the DNA-activated protein kinase, DNA-PK. Here radiosensitive human cell lines were analyzed for DNA-PK activity and for the presence of related proteins. The radiosensitive human malignant glioma M059J cell line was found to be defective in DNA double-strand break repair, but fails to express the p350 subunit of DNA-PK. These results suggest that DNA-PK kinase activity is involved in DNA double-strand break repair. 36 refs., 4 figs., 1 tab.

Lees-Miller, S.P.; Chan, D.W. [Univ. of Calgary, Alberta (Canada); Godbout, R.; Day, R.S. III; Weinfield, M.; Barron, G.M.; Allalunis-Turner, J. [Cross Cancer Institute, Edmonton, Alberta (Canada)

1995-02-24

10

A review of human cell radiosensitivity in vitro  

Microsoft Academic Search

The survival curves of 694 human cell lines irradiated in exponentially growing phase in vitro were collected from the literature. Among them, 271 were derived from tumors, 423 were nontransformed fibroblasts and other normal cell strains from healthy people or people with some genetic disorders. Seventy-six different cell types are identified, and a specific radiosensitivity could be associated with each,

Patrick J. Deschavanne; Bernard Fertil

1996-01-01

11

The radiosensitization effects of Endostar on human lung squamous cancer cells H-520  

Microsoft Academic Search

BACKGROUND: The present study mainly aimed to investigate the direct effects of Endostar (ES) on the proliferation and radiosensitivity of human lung squamous cancer cell line H-520. RESULTS: ES significantly inhibited H-520 cell proliferation in a time- and dose-dependent manner. According to the colony-forming assays, ES could increase the H-520 cell radiosensitivity. ES induced cell apoptosis, the apoptosis rate increased

Zhen Y You; Yong Zhao; Feng Liu; Ying D Zhang; Jun J Wang

2010-01-01

12

Inhibitor of Apoptosis (IAP) proteins as therapeutic targets for radiosensitization of human cancers.  

PubMed

Radiotherapy initiates a variety of signaling events in cancer cells that eventually lead to cell death in case the DNA damage cannot be repaired. However, the signal transduction pathways that mediate cell death in response to radiation-inflicted DNA damage are frequently disturbed in human cancers, contributing to radioresistance. For example, aberrant activation of antiapoptotic programs such as high expression of Inhibitor of Apoptosis (IAP) proteins has been shown to interfere with the efficacy of radiotherapy. Since IAP proteins have been linked to radioresistance in several malignancies, therapeutic targeting of IAP proteins may open new perspectives to overcome radioresistance. Therefore, molecular targeting of IAP proteins may provide novel opportunities to reactivate cell death pathways that mediate radiation-induced cytotoxicity. A number of strategies have been developed in recent years to antagonize IAP proteins for the treatment of cancers. Some of these approaches have already been translated into a clinical application. While IAP protein-targeting agents are currently being evaluated in early clinical trials alone or in combination with conventional chemotherapy, they have not yet been tested in combination with radiation therapy. Therefore, it is a timely subject to discuss the opportunities of antagonizing IAP proteins for radiosensitization. Preclinical studies demonstrating the potential of this concept in relevant in vitro and in vivo models underscore that this combination approach warrants further clinical investigation. Thus, combination protocols using IAP antagonists together with radiotherapy may pave the avenue to more effective radiation-based treatment options for cancer patients. PMID:22342104

Fulda, Simone

2012-02-18

13

Malignant transformation of human fibroblasts in vitro  

SciTech Connect

Although carcinogens cause human tumors, human cells in culture have not been successfully transformed to malignancy by exposure to carcinogens. It is now recognized that malignant transformation involves multiple changes within a cell and, therefore, successive clonal selection of cells containing such changes must occur. One explanation for the failure to induce in vitro malignant transformation of human cells could be inability to recognize cells that have undergone intermediate changes so as to expand the population, expose the cells a second time, cause further changes, etc. therefore, we transfected finite life span diploid human fibroblists with oncogenes known to be active in cells derived from human fibrosarcomas or effective in transforming animal fibroblasts to determine the phenotypes they produced. Transfection of a sis gene, or an H-, or H-ras oncogene caused the cells to acquire many characteristics of malignant cells, but not to acquire an infinite lift span or become malignant. We recently succeeded in developing an infinite life span human fibroblasts cell strain, designated MSU-1.1, which has a stable, near-diploid karyotype, composed of 45 chromosomes including two marker chromosomes. We have shown-that these cells can be transformed to malignancy by transfection of the H-, K-, or N-ras or the v-fes oncogene. All of the malignant H-, K-, or N-ras transfected derivatives examined have exhibited the stable karyotype of the parental MSU-1.1 cells. We have also found rare spontaneous clonal variants of MSU-1.1 that are malignantly transformed and have shown that malignant variants can also be induced by carcinogen treatment.

McCormick, J.J.; Maher, V.M.

1991-01-01

14

Malignant transformation of human fibroblasts in vitro  

SciTech Connect

Although carcinogens cause human tumors, human cells in culture have not been successfully transformed to malignancy by exposure to carcinogens. It is now recognized that malignant transformation involves multiple changes within a cell and, therefore, successive clonal selection of cells containing such changes must occur. One explanation for the failure to induce in vitro malignant transformation of human cells could be inability to recognize cells that have undergone intermediate changes so as to expand the population, expose the cells a second time, cause further changes, etc. therefore, we transfected finite life span diploid human fibroblists with oncogenes known to be active in cells derived from human fibrosarcomas or effective in transforming animal fibroblasts to determine the phenotypes they produced. Transfection of a sis gene, or an H-, or H-ras oncogene caused the cells to acquire many characteristics of malignant cells, but not to acquire an infinite lift span or become malignant. We recently succeeded in developing an infinite life span human fibroblasts cell strain, designated MSU-1.1, which has a stable, near-diploid karyotype, composed of 45 chromosomes including two marker chromosomes. We have shown-that these cells can be transformed to malignancy by transfection of the H-, K-, or N-ras or the v-fes oncogene. All of the malignant H-, K-, or N-ras transfected derivatives examined have exhibited the stable karyotype of the parental MSU-1.1 cells. We have also found rare spontaneous clonal variants of MSU-1.1 that are malignantly transformed and have shown that malignant variants can also be induced by carcinogen treatment.

McCormick, J.J.; Maher, V.M.

1991-12-31

15

Influence of buthionine sulfoximine and misonidazole on glutathione level and radiosensitivity of human tumor xenografts.  

PubMed

We have studied the effect of buthionine sulfoximine (BSO; a gamma-glutamylcysteine synthetase inhibitor) administration, either alone or combined with misonidazole (MISO), on five human tumor xenografts (three melanomas: Bell, Mall, and Nall; and two rectocolic adenocarcinomas: HT29 and HRT18) transplanted into mice. Two criteria were used, the nonprotein bound sulfhydryl (NPSH) level (glutathione (GSH) and cysteine (CYS] and the fraction of surviving tumor cells after gamma irradiation. GSH and CYS were estimated by HPLC and cell survival by in vivo-in vitro clonogenic assay. Administration of BSO alone (three injections of 10 mumol/g) prior to irradiation always produced a significant reduction in the GSH level while MISO administration (1 mg/g) did not consistently influence the NPSH level. While BSO had little or no radiosensitizing effect, MISO always induced radiosensitization (enhancement ratio between 1.6 and 1.8). This effect did not depend on the fraction of surviving hypoxic cells. An increase in MISO-induced radiosensitization produced by BSO was cell-line dependent. Results do not seem to support the hypothesis of a relationship between the GSH level at the time of irradiation and the radiosensitization induced by BSO or BSO + MISO. However, BSO treatment may not have been able to reduce endogenous thiols to a low enough level to test the hypothesis. PMID:3945723

Guichard, M; Lespinasse, F; Malaise, E P

1986-01-01

16

Paclitaxel is only a weak radiosensitizer of human cervical carcinoma cell lines.  

PubMed

Two human squamous cell cervical carcinoma cell lines, C-33A (HTB 31) and MS751 (HTB 34), were exposed to either paclitaxel alone or paclitaxel for 24 hr followed by graded doses of Cs-137 radiation. Each was then analyzed for both clonogenic survival and alterations to cell cycle progression. No radiosensitization or affect on the cell cycle was seen using 1 x 10(-9) M paclitaxel. Each line was equally sensitive to the drug with approximately 50% cell lethality seen after 1 x 10(-8) M of paclitaxel. This concentration of paclitaxel also produced substantial G2M arrest, seen immediately after drug exposure and lasting up to 2 days. Gamma radiation delivered during the time of G2M arrest showed only a small degree of radiosensitization by paclitaxel for the relatively radioresistant MS751 line at 4 Gy (SF4 = 16.0 +/- 3.2% --> 5.7 +/- 1.1%, P = 0.049) but no sensitization using radiation doses of conventional fraction size [sensitizer enhancement ratios 1.1 (0.80-1.40) and 1.3 (0.95-1.65) for the C-33A and MS751 cell lines, respectively]. It is concluded that paclitaxel produces only a modest radiosensitization effect, indicating that this compound will have limited benefit as a radiosensitizer for the treatment of cervical cancer. PMID:8631547

Erlich, E; McCall, A R; Potkul, R K; Walter, S; Vaughan, A

1996-02-01

17

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

2013-06-24

18

In vitro radiosensitivity of six human cell lines. A comparative study with different statistical models  

Microsoft Academic Search

The intrinsic radiosensitivity of human cell lines (five tumor and one nontransformed fibroblastic) was studied in vitro. The survival curves were fitted by the single-hit multitarget, the two-hit multitarget, the single-hit multitarget with initial slope, and the quadratic models. The accuracy of the experimental results permitted evaluation of the various fittings. Both a statistical test (comparison of variances left unexplained

B. Fertil; P. J. Deschavanne; B. Lachet; E. P. Malaise

1980-01-01

19

The radiosensitizing effect of CpG ODN107 on human glioma cells is tightly related to its antiangiogenic activity via suppression of HIF-1?/VEGF pathway.  

PubMed

Malignant glioma displays invasive growth and is difficult to be completely excised; surgery combined with subsequent radiotherapy is a standard treatment for patients. CpG oligodeoxynucleotides (CpG ODN) can enhance radiotherapeutic effect in some tumors. Angiogenesis is crucial for tumor progression and metastasis. Anti-angiogenic strategy thus may be effective for tumor treatment. Herein, the antiangiogenic activity and radiosensitizing effect of CpG ODN107 on glioma were investigated. Our results showed that the growth of glioma cell line U87 was significantly inhibited by CpG ODN107 (10?g/ml) in combination with irradiation (5Gy) in vitro. In orthotopic implantation model of nude mice, the survival rate of mice significantly increased after treatment with CpG ODN107 (0.083mg/kg) in combination with radiotherapy (10Gy) as compared with treatment with local radiotherapy alone. CpG ODN107 in combination with radiotherapy significantly decreased microvessel density (MVD), VEGF level and HIF-1? expression in orthotopic implantation glioma. In conclusion, CpG ODN107 significantly increased the radiosensitivity of U87 human glioma cells in vitro and in vivo. The radiosensitizing effect of CpG ODN 107 is tightly related to its anti-angiogenic activity via suppression of HIF-1?/VEGF pathway. PMID:23791618

Liu, Dan; Cao, Guanqun; Cen, Yanyan; Liu, Tao; Peng, Wei; Sun, Jianguo; Li, Xiaoli; Zhou, Hong

2013-06-19

20

A novel Chk inhibitor, XL-844, increases human cancer cell radiosensitivity through promotion of mitotic catastrophe.  

PubMed

Check point kinases (Chk) play a major role in facilitating DNA repair upon radiation exposure. We tested the potency of a novel inhibitor of Chk1 and Chk2, XL-844 (provided by Exelixis Inc., CA, USA), to radiosensitize human cancer cells grown in culture and investigated the underlying mechanisms. HT-29 cells (a human colon cancer line) were exposed to XL-844, radiation, or both, and assessed for clonogenic cell survival. Treatment-dependent effects on phosphorylated forms of Chk proteins were assessed by Western blots. Further mechanistic investigations in HT-29 cells included cell cycle analysis by flowcytometry and assessment of DNA repair kinetics by immuno-cytochemistry (ICC) for nuclear appearance of the phosphorylated form of histone 2AX protein (?-H2AX) staining. Cells undergoing mitotic catastrophe were identified by irregular pattern of mitotic spindle markers ? and ?-tubulin staining by ICC. XL-844 enhanced radiosensitivity in a dose and schedule-dependent manner and the enhancement factor was 1.42 at 0.5 survival fraction. Mechanistically XL-844 abrogated radiation-induced Chk2 phosphorylation, induced pan-nuclear ?-H2AX, and prolonged the presence of radiation-induced ?-H2AX foci, and promoted mitotic catastrophe. In conclusion, our data showed that inhibition of Chk2 activity by XL-844 enhanced cancer cell radiosensitivity that was associated with inhibition of DNA repair and induction of mitotic catastrophe. PMID:20024691

Riesterer, Oliver; Matsumoto, Fumihiko; Wang, Li; Pickett, Jessica; Molkentine, David; Giri, Uma; Milas, Luka; Raju, Uma

2009-12-22

21

Enhanced radiosensitization by liposome-encapsulated pimonidazole for anticancer effects on human melanoma cells.  

PubMed

The nitroimidazole-related hypoxic radiosensitizer, pimonidazole (Pmz) was encapsulated in liposome composed of dipalmitoylphosphatidylcholine, cholesterol and dipalmitoylphosphatidylglycerol (molar ratio = 1:1:0.2; diameter = 112.9 nm), and the radiosensitization was evaluated in human melanoma cells HMV-II. Cell proliferation was examined by WST-8 assay after X-ray irradiation in the presence of liposomal Pmz or free-Pmz under hypoxic conditions. On 7th day after X-ray irradiation of 5 Gy, cell proliferation decreased more markedly in the administration of liposomal Pmz than free-Pmz at equivalent Pmz doses. Chromatin fragmentation or nuclear condensation was observed in liposomal Pmz-treated HMV-II cells. Radiosensitization was enhanced dose-dependently along with Pmz amounts of 250-2000 microM contained in liposomal Pmz. Intracellular uptake was more abundant for liposomal Pmz for 60-240 min than for free-Pmz. Thus liposomal Pmz has a potential to overcome radiation resistance in hypoxia, owing to enhanced intracellular uptake by melanoma cells. PMID:22905487

Kato, Shinya; Kimura, Masatsugu; Kageyama, Katsuhiro; Tanaka, Hiroshi; Miwa, Nobuhiko

2012-06-01

22

Silencing of microRNA-21 confers radio-sensitivity through inhibition of the PI3K/AKT pathway and enhancing autophagy in malignant glioma cell lines.  

PubMed

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 G?/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

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

2012-10-15

23

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.

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

24

Cancer stem cells and human malignant melanoma  

PubMed Central

Summary Cancer stem cells (CSC) have been identified in hematological malignancies and several solid cancers. Similar to physiological stem cells, CSC are capable of self-renewal and differentiation and have the potential for indefinite proliferation, a function through which they may cause tumor growth. Although conventional anti-cancer treatments might eradicate most malignant cells in a tumor, they are potentially ineffective against chemoresistant CSC, which may ultimately be responsible for recurrence and progression. Human malignant melanoma is a highly aggressive and drug-resistant cancer. Detection of tumor heterogeneity, undifferentiated molecular signatures, and increased tumorigenicity of melanoma subsets with embryonic-like differentiation plasticity strongly suggest the presence and involvement of malignant melanoma stem cells (MMSC) in the initiation and propagation of this malignancy. Here, we review these findings in the context of functional properties ascribed to melanocyte stem cells and CSC in other cancers. We discuss the association of deregulated signaling pathways, genomic instability, and vasculogenic mimicry phenomena observed in melanoma subpopulations in light of the CSC concept. We propose that a subset of MMSC may be responsible for melanoma therapy-resistance, tumor invasiveness, and neoplastic progression and that targeted abrogation of a MMSC compartment could therefore ultimately lead to stable remissions and perhaps cures of metastatic melanoma.

Schatton, Tobias; Frank, Markus H

2010-01-01

25

Cancer stem cells and human malignant melanoma.  

PubMed

Cancer stem cells (CSC) have been identified in hematological malignancies and several solid cancers. Similar to physiological stem cells, CSC are capable of self-renewal and differentiation and have the potential for indefinite proliferation, a function through which they may cause tumor growth. Although conventional anti-cancer treatments might eradicate most malignant cells in a tumor, they are potentially ineffective against chemoresistant CSC, which may ultimately be responsible for recurrence and progression. Human malignant melanoma is a highly aggressive and drug-resistant cancer. Detection of tumor heterogeneity, undifferentiated molecular signatures, and increased tumorigenicity of melanoma subsets with embryonic-like differentiation plasticity strongly suggest the presence and involvement of malignant melanoma stem cells (MMSC) in the initiation and propagation of this malignancy. Here, we review these findings in the context of functional properties ascribed to melanocyte stem cells and CSC in other cancers. We discuss the association of deregulated signaling pathways, genomic instability, and vasculogenic mimicry phenomena observed in melanoma subpopulations in light of the CSC concept. We propose that a subset of MMSC may be responsible for melanoma therapy-resistance, tumor invasiveness, and neoplastic progression and that targeted abrogation of a MMSC compartment could therefore ultimately lead to stable remissions and perhaps cures of metastatic melanoma. PMID:18353142

Schatton, Tobias; Frank, Markus H

2008-02-01

26

Prediction of human cell radiosensitivity: Comparison of clonogenic assay with chromosome aberrations scored using premature chromosome condensation with fluorescence in situ hybridization  

Microsoft Academic Search

The purpose of the present investigation was to determine whether chromosome aberrations scored by premature chromosome condensation (PCC) and fluorescence in situ hybridization (FISH) can predict the radiosensitivity of human cell lines, thereby providing a possible means of assessing the in situ radiosensitivity of normal tissues and the radiocurability of individual human cancers. We used four cells lines of different

K. Sasai; J. W. Evans; M. S. Kovacs

1994-01-01

27

Bowman-Birk proteinase inhibitor (BBI) modulates radiosensitivity and radiation-induced differentiation of human fibroblasts in culture  

Microsoft Academic Search

The radiosensitivity and differentiation pattern of cultured normal human fibroblasts was analysed as a function of treatment of the cells with the Bowman-Birk proteinase inhibitor (BBI). Upon irradiation with doses from 0 to 8 Gy normal human fibroblasts are induced to a premature terminal differentiation within 14–21 days of postirradiation incubation. Treatment of the cells with 10 ?M BBI for

Klaus Dittmann; Heidi Löffler; Michael Bamberg; H. Peter Rodemann

1995-01-01

28

Cyclopamine increases the radiosensitivity of human pancreatic cancer cells by regulating the DNA repair signal pathway through an epidermal growth factor receptor?dependent pathway.  

PubMed

Pancreatic cancer is an aggressive malignancy with a characteristic metastatic course of disease and resistance to conventional radiotherapy. As a result, the continual development of novel therapeutic agents is required to improve the current situation. In the present study, the effect of the hedgehog pathway inhibitor, cyclopamine, on cellular radiosensitivity was determined in K?RASwt Colo?357 and K?RASmt SW?1990 human pancreatic cancer cell lines using the clonogenic survival assay. Apoptosis and cell cycle distribution were detected using flow cytometry assay. Following irradiation (30 mins), residual double?strand breaks were quantified by identification of ??H2AX foci of micronuclei and radiation?induced ??H2AX, p?ATM, DNA?PKcs and Ku70 expression was analyzed using western blot analysis. The epidermal growth factor (EGF) and EGF receptor (EGFR) inhibitor, gefitinib, were utilized to determine the related mechanisms. The results revealed that cyclopamine treatment significantly reduced cell clonogenic survival but failed to induce apoptosis and radiation?induced G2 arrest. Flow cytometry revealed that cyclopamine treatment enhanced ??H2AX foci in Colo?357 and SW?1990 cells exposed to irradiation. In addition, radiation?induced p?ATM, DNA?PKcs and Ku70 were all inhibited. EGF also rescued pancreatic cancer cells from cyclopamine?induced H2AX phosphorylation following irradiation. Thus, cyclopamine enhanced the radiosensitivity of human pancreatic cancer cells, in part, through an EGFR?dependent pathway, indicating a rational approach in combination with radiotherapy. PMID:23903906

Wu, Xiao-Yang; Che, Jun; Sun, Ke-Kang; Shen, Xiao-Jun; Yang, Dong; Zhong, Ning; Zhao, Hua

2013-07-30

29

Adenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure.  

PubMed

These studies define a new mechanism-based approach to radiosensitize tumor cure by single dose radiotherapy (SDRT). Published evidence indicates that SDRT induces acute microvascular endothelial apoptosis initiated via acid sphingomyelinase (ASMase) translocation to the external plasma membrane. Ensuing microvascular damage regulates radiation lethality of tumor stem cell clonogens to effect tumor cure. Based on this biology, we engineered an ASMase-producing vector consisting of a modified pre-proendothelin-1 promoter, PPE1(3x), and a hypoxia-inducible dual-binding HIF-2?-Ets-1 enhancer element upstream of the asmase gene, inserted into a replication-deficient adenovirus yielding the vector Ad5H2E-PPE1(3x)-ASMase. This vector confers ASMase over-expression in cycling angiogenic endothelium in vitro and within tumors in vivo, with no detectable enhancement in endothelium of normal tissues that exhibit a minute fraction of cycling cells or in non-endothelial tumor or normal tissue cells. Intravenous pretreatment with Ad5H2E-PPE1(3x)-ASMase markedly increases SDRT cure of inherently radiosensitive MCA/129 fibrosarcomas, and converts radiation-incurable B16 melanomas into biopsy-proven tumor cures. In contrast, Ad5H2E-PPE1(3x)-ASMase treatment did not impact radiation damage to small intestinal crypts as non-dividing small intestinal microvessels did not overexpress ASMase and were not radiosensitized. We posit that combination of genetic up-regulation of tumor microvascular ASMase and SDRT provides therapeutic options for currently radiation-incurable human tumors. PMID:23936314

Stancevic, Branka; Varda-Bloom, Nira; Cheng, Jin; Fuller, John D; Rotolo, Jimmy A; García-Barros, Mónica; Feldman, Regina; Rao, Shyam; Weichselbaum, Ralph R; Harats, Dror; Haimovitz-Friedman, Adriana; Fuks, Zvi; Sadelain, Michel; Kolesnick, Richard

2013-08-02

30

In vitro radiosensitivity of primary human fibroblasts. Lack of correlation with acute radiation toxicity in patients with head and neck cancer  

Microsoft Academic Search

Background and purpose: There is a considerable hope among clinicians and radiobiologists to detect genetically radiosensitive patients prior to radiotherapy. A predictive assay would enable adjustment of the total irradiation dose to the individual at a constant risk of normal tissue complications. In this prospective study, the clonogenic survival assay for primary human fibroblasts to determine radiosensitivity in vitro was

Volker Rudat; Andreas Dietz; Christian Conradt; Klaus-Josef Weber; Michael Flentje

1997-01-01

31

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.

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

2011-01-01

32

Relationship between radiosensitivity and Nrf2 target gene expression in human hematopoietic stem cells.  

PubMed

NFE2-related factor 2 (Nrf2), which belongs to the cap "n" collar family of basic region leucine zipper transcription factors, is a key protein in the coordinated transcriptional induction of expression of various antioxidant genes. The purpose of this study was to analyze the expression of Nrf2 target genes, such as heme oxygenase 1 (HO-1), ferritin heavy polypeptide 1 (FTH1), NAD(P)H dehydrogenase, quinone 1 (NQO1), glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase modifier subunit, glutathione reductase (GSR) and thioredoxin reductase 1 (TXNRD1), after X irradiation of CD34(+) cells that were prepared from human placental/umbilical cord blood hematopoietic stem cells (HSCs). We evaluated the relationship between radiosensitivity and expression of Nrf2 target genes in HSCs. The number of colony-forming cells derived from 2-Gy-irradiated HSCs decreased to approximately 20% of the nonirradiated control. At the same time, the mRNA expression of HO-1, FTH1, NQO1, GSR and TXNRD1 was significantly increased after X irradiation. A statistically significant negative correlation was observed between the surviving fraction of HSCs and the intrinsic NQO1 mRNA expression, indicating that HSCs in which NQO1 mRNA levels are low may also be radioresistant. The present results suggest that the antioxidant system associated with Nrf2 is involved in the radiosensitivity of HSCs. PMID:20681784

Kato, Kengo; Takahashi, Kenji; Monzen, Satoru; Yamamoto, Hiroyuki; Maruyama, Atsushi; Itoh, Ken; Kashiwakura, Ikuo

2010-08-01

33

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

34

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.

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

2012-01-01

35

Human hybridomas from patients with malignant disease.  

PubMed Central

Lymphocytes from 180 patients with a variety of malignant diseases were collected and fused with a human myeloma-derived line, LON-LICR-HMy2/CAM1. A total of 162 hybridomas was obtained. Only B lymphocyte markers were found on the surface of the fusion products. Flow cytometric analysis revealed a stably increased DNA content in the hybridoma cells. Some hybridoma supernatants were found to contain new Ig chains. Anti-tumour binding activity was found in 12 supernatants. Images Figure 1 Figure 4

Sikora, K.; Alderson, T.; Ellis, J.; Phillips, J.; Watson, J.

1983-01-01

36

Radiosensitivity enhancement of human hepatocellular carcinoma cell line SMMC-7721 by sorafenib through the MEK/ERK signal pathway.  

PubMed

Abstract Purpose: Sorafenib, an oral multikinase inhibitor, is the first agent that has demonstrated an improved overall survival benefit in advanced hepatocellular carcinoma, setting a new standard for first-line treatment. However, the association between radiosensitivity and sorafenib remains unclear. The purpose of this study was to investigate whether sorafenib could enhance radiosensitivity and the possible mechanisms of sorafenib-mediated radiosensitization in human hepatocellular carcinoma cell line SMMC-7721. Experimental design: The cell viability of human hepatocellular carcinoma cell line SMMC-7721 was determined by the 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. The radiosensitization of sorafenib in SMMC-7721 cells was evaluated by clonogenic assays, and immunofluorescence for DNA double-strand break detection, and Western blotting for protein detection. Results: The MTT results clearly showed that sorafenib affected cell viability in human hepatocellular cell line SMMC-7721. Sorafenib administered 1 h before the radiation treatment resulted in radiosensitization with a sensitivity enhancement ratio (SER) of 1.65 as shown by clonogenic assays. Furthermore, sorafenib pretreatment led to decreased phosphorylation levels of extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) in SMMC-7721 cells. Interestingly, pretreatment of mitogen-activated protein kinase kinases/extracellular signal-regulated kinase (MEK/ERK) signaling inhibitor U0126 had a similar effect as that of sorafenib pretreatment in hepatocellular carcinoma cells, whereas pretreatment of phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling inhibitor LY294002 in the same cells had no effect on radiosensitization. The group treated with sorafenib and radiation was more sensitive to irradiation alone as demonstrated by the results of the DNA double-strand break detection. Conclusions: The combination of sorafenib and radiation affected cell viability more effectively than radiation alone. Sorafenib significantly enhanced the sensitivity of SMMC-7721 cells to radiation showing significantly reduced repair of DNA double-strand breaks. The MEK/ERK signaling pathway may be a pathway responsible for the radiosensitivity enhancement of sorafenib. Our data provided experimental support for the possible combination of sorafenib with radiation for the treatment of hepatocellular carcinoma and other cancers. PMID:23682582

Dai, Xiao-Fang; Ding, Jie; Zhang, Rui-Guang; Ren, Jing-Hua; Ma, C-M Charlie; Wu, Gang

2013-05-31

37

Autotaxin Inhibition with PF-8380 Enhances the Radiosensitivity of Human and Murine Glioblastoma Cell Lines.  

PubMed

Purpose: Glioblastoma multiforme (GBM) is an aggressive primary brain tumor that is radio-resistant and recurs despite aggressive surgery, chemo, and radiotherapy. Autotaxin (ATX) is over expressed in various cancers including GBM and is implicated in tumor progression, invasion, and angiogenesis. Using the ATX specific inhibitor, PF-8380, we studied ATX as a potential target to enhance radiosensitivity in GBM. Methods and Materials: Mouse GL261 and Human U87-MG cells were used as GBM cell models. Clonogenic survival assays and tumor transwell invasion assays were performed using PF-8380 to evaluate role of ATX in survival and invasion. Radiation dependent activation of Akt was analyzed by immunoblotting. Tumor induced angiogenesis was studied using the dorsal skin fold model in GL261. Heterotopic mouse GL261 tumors were used to evaluate the efficacy of PF-8380 as a radiosensitizer. Results: Pre-treatment of GL261 and U87-MG cells with 1??M PF-8380 followed by 4?Gy irradiation resulted in decreased clonogenic survival, decreased migration (33% in GL261; P?=?0.002 and 17.9% in U87-MG; P?=?0.012), decreased invasion (35.6% in GL261; P?=?0.0037 and 31.8% in U87-MG; P?=?0.002), and attenuated radiation-induced Akt phosphorylation. In the tumor window model, inhibition of ATX abrogated radiation induced tumor neovascularization (65%; P?=?0.011). In a heterotopic mouse GL261 tumors untreated mice took 11.2?days to reach a tumor volume of 7000?mm(3), however combination of PF-8380 (10?mg/kg) with irradiation (five fractions of 2?Gy) took more than 32?days to reach a tumor volume of 7000?mm(3). Conclusion: Inhibition of ATX by PF-8380 led to decreased invasion and enhanced radiosensitization of GBM cells. Radiation-induced activation of Akt was abrogated by inhibition of ATX. Furthermore, inhibition of ATX led to diminished tumor vascularity and delayed tumor growth. These results suggest that inhibition of ATX may ameliorate GBM response to radiotherapy. PMID:24062988

Bhave, Sandeep R; Dadey, David Y A; Karvas, Rowan M; Ferraro, Daniel J; Kotipatruni, Rama P; Jaboin, Jerry J; Hallahan, Andrew N; Dewees, Todd A; Linkous, Amanda G; Hallahan, Dennis E; Thotala, Dinesh

2013-09-17

38

Autotaxin Inhibition with PF-8380 Enhances the Radiosensitivity of Human and Murine Glioblastoma Cell Lines  

PubMed Central

Purpose: Glioblastoma multiforme (GBM) is an aggressive primary brain tumor that is radio-resistant and recurs despite aggressive surgery, chemo, and radiotherapy. Autotaxin (ATX) is over expressed in various cancers including GBM and is implicated in tumor progression, invasion, and angiogenesis. Using the ATX specific inhibitor, PF-8380, we studied ATX as a potential target to enhance radiosensitivity in GBM. Methods and Materials: Mouse GL261 and Human U87-MG cells were used as GBM cell models. Clonogenic survival assays and tumor transwell invasion assays were performed using PF-8380 to evaluate role of ATX in survival and invasion. Radiation dependent activation of Akt was analyzed by immunoblotting. Tumor induced angiogenesis was studied using the dorsal skin fold model in GL261. Heterotopic mouse GL261 tumors were used to evaluate the efficacy of PF-8380 as a radiosensitizer. Results: Pre-treatment of GL261 and U87-MG cells with 1??M PF-8380 followed by 4?Gy irradiation resulted in decreased clonogenic survival, decreased migration (33% in GL261; P?=?0.002 and 17.9% in U87-MG; P?=?0.012), decreased invasion (35.6% in GL261; P?=?0.0037 and 31.8% in U87-MG; P?=?0.002), and attenuated radiation-induced Akt phosphorylation. In the tumor window model, inhibition of ATX abrogated radiation induced tumor neovascularization (65%; P?=?0.011). In a heterotopic mouse GL261 tumors untreated mice took 11.2?days to reach a tumor volume of 7000?mm3, however combination of PF-8380 (10?mg/kg) with irradiation (five fractions of 2?Gy) took more than 32?days to reach a tumor volume of 7000?mm3. Conclusion: Inhibition of ATX by PF-8380 led to decreased invasion and enhanced radiosensitization of GBM cells. Radiation-induced activation of Akt was abrogated by inhibition of ATX. Furthermore, inhibition of ATX led to diminished tumor vascularity and delayed tumor growth. These results suggest that inhibition of ATX may ameliorate GBM response to radiotherapy.

Bhave, Sandeep R.; Dadey, David Y. A.; Karvas, Rowan M.; Ferraro, Daniel J.; Kotipatruni, Rama P.; Jaboin, Jerry J.; Hallahan, Andrew N.; DeWees, Todd A.; Linkous, Amanda G.; Hallahan, Dennis E.; Thotala, Dinesh

2013-01-01

39

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

40

Cholesteryl esters in human malignant neoplasms.  

PubMed

Cholesteryl esters (CholE) were detected in human malignant neoplasms by means of in vitro nuclear magnetic resonance spectroscopy. Spectroscopic analysis of the total lipid extracts obtained from cerebral tumors revealed appreciable amount of esterified cholesterol in high grade gliomas such as glioblastomas and anaplastic oligodendrogliomas, characterized by prominent neovascularity. The finding that no CholE were detected in the healthy brain and in low grade and benign tumors supports a possible correlation between this class of lipids and histological vascular proliferation. Compared with high grade gliomas, renal cell carcinomas show higher levels of CholE, absent in the healthy renal parenchyma and in benign oncocytomas. In nefro-carcinomas, cytoplasmic lipid inclusions and prominent vascularization contribute to the increased levels of CholE present mainly as oleate. CholE are discussed as potential biochemical markers of cancer and as a target for new therapeutic strategies. PMID:12469226

Tosi, M R; Bottura, G; Lucchi, P; Reggiani, A; Trinchero, A; Tugnoli, V

2003-01-01

41

Radiosensitizing potential of the selective cyclooygenase-2 (COX2) inhibitor meloxicam on human glioma cells  

Microsoft Academic Search

The COX-2 protein is frequently overexpressed in human malignant gliomas. This expression has been associated with their aggressive\\u000a growth characteristics and poor prognosis for patients. Targeting the COX-2 pathway might improve glioma therapy. In this\\u000a study, the effects of the selective COX-2 inhibitor meloxicam alone and in combination with irradiation were investigated\\u000a on human glioma cells in vitro. A panel

Irene V. Bijnsdorp; Jaap van den Berg; Gitta K. Kuipers; Laurine E. Wedekind; Ben J. Slotman; Johannes van Rijn; M. Vincent M. Lafleur; Peter Sminia

2007-01-01

42

Late ROS-accumulation and Radiosensitivity in CuZnSOD Overexpressing Human Glioma Cells  

PubMed Central

This study investigates the hypothesis that CuZn-superoxide dismutase (SOD1) overexpression confers radioresistance to human glioma cells by regulating the late accumulation of reactive oxygen species (ROS) and G2/M checkpoint pathway. U118-9 human glioma cells (wild type, neo vector control, and stably overexpressing SOD1) were irradiated (0-10 Gy) and assayed for cell survival, cellular ROS levels, cell cycle phase distributions, and cyclin B1 expression. SOD1 overexpressing cells were radioresistant compared to wild type (wt) and neo vector control (neo) cells. Irradiated wt and neo cells showed a significant increase (~2-fold) in DHE-fluorescence beginning at 2 d post-irradiation, which remained elevated at 8 d post-irradiation. Interestingly, the late accumulation of ROS was suppressed in irradiated SOD1-overexpressing cells. The increase in ROS levels was followed by a decrease in cell growth and viability, and an increase in the percentage of cells with sub G1 DNA content. SOD1 overexpression enhanced radiation-induced G2-accumulation within 24 h post-irradiation, which was accompanied with a decrease in cyclin B1 mRNA and protein levels. These results support the hypothesis that long after the radiation exposure a “metabolic redox-response” regulates radiosensitivity of human glioma cells.

Gao, Zhen; Sarsour, Ehab H.; Kalen, Amanda L.; Li, Ling; Kumar, Maneesh G.; Goswami, Prabhat C.

2008-01-01

43

Late ROS accumulation and radiosensitivity in SOD1-overexpressing human glioma cells.  

PubMed

This study investigates the hypothesis that CuZn superoxide dismutase (SOD1) overexpression confers radioresistance to human glioma cells by regulating the late accumulation of reactive oxygen species (ROS) and the G(2)/M-checkpoint pathway. U118-9 human glioma cells (wild type, neo vector control, and stably overexpressing SOD1) were irradiated (0-10 Gy) and assayed for cell survival, cellular ROS levels, cell-cycle-phase distributions, and cyclin B1 expression. SOD1-overexpressing cells were radioresistant compared to wild-type (wt) and neo vector control (neo) cells. Irradiated wt and neo cells showed a significant increase (approximately twofold) in DHE fluorescence beginning at 2 days postirradiation, which remained elevated at 8 days postirradiation. Interestingly, the late accumulation of ROS was suppressed in irradiated SOD1-overexpressing cells. The increase in ROS levels was followed by a decrease in cell growth and viability and an increase in the percentage of cells with sub-G(1) DNA content. SOD1 overexpression enhanced radiation-induced G(2) accumulation within 24 h postirradiation, which was accompanied by a decrease in cyclin B1 mRNA and protein levels. These results support the hypothesis that long after radiation exposure a "metabolic redox response" regulates radiosensitivity of human glioma cells. PMID:18790046

Gao, Zhen; Sarsour, Ehab H; Kalen, Amanda L; Li, Ling; Kumar, Maneesh G; Goswami, Prabhat C

2008-08-14

44

Correlation between radiosensitivity, percentage hypoxic cells and pO2 measurements in one rodent and two human tumor xenografts.  

PubMed

Computerized pO2 histography has been used to measure the intratumor pO2 in patients for the past few years, and there is now evidence that these tumors contain hypoxic cells. One of the major questions that remains to be answered is the relevance of such data to radiosensitivity. The present study looks for a correlation between intratumor pO2, the percentage of hypoxic cells in the tumor and the radiosensitization induced by carbogen and/or the oxygen carrier, perflubron emulsion. Two human tumor xenografts (HRT18, Na11+) and one rodent tumor (EMT6) were used. The radiosensitivity (clonogenic assay) and the oxygen tension (computerized pO2 histography) were measured. All experiments were performed under similar conditions. Carbogen increased tumor radiosensitivity; sensitization was greatest when 4 ml/kg perflubron emulsion was used in conjunction with carbogen. The pO2 distribution was shifted to higher pO2 values in the tumors whatever the treatment; the shift was greater for perflubron emulsion plus carbogen. The low pO2 values (< 0.4 kPa) were lost for the HRT18 cells. A correlation (EMT6, HRT18) or a link (Na11+) between the radiosensitization and the oxygen tension measurements was found for values below 1.07 or 1.33 kPa. A trend between the percentage of hypoxic cells and pO2 measurements was found taking into account pO2 measurements comprised between 0.27 and 0.67 kPa. PMID:8016297

Thomas, C D; Chavaudra, N; Martin, L; Guichard, M

1994-07-01

45

The gangliosides as a possible molecular coupling factor between the proportion of radiosensitive cells in vitro and the metastatic potential in vivo within a human melanoma cell line.  

PubMed Central

With an experimental model of spontaneous lung metastases in immunosuppressed newborn rats, seven clones and variants with different metastatic potential and gangliosides expression were derived from a single parental human melanoma cell line M4Be. The cellular radiosensitivity of M4Be and its seven sublines was estimated using an in vitro colony assay. The total amount of gangliosides in M4Be and its seven sublines was determined by cell extraction and thin-layer chromatography, while the expression of GD3 gangliosides was estimated by flow cytometry with a monoclonal antibody. The radiation-cell survival curves of most clones and variants derived from M4Be showed a zero dose extrapolation clearly lower than 100%, suggesting that two populations of cells of very different radiosensitivity coexist within each of these clones and variants. Although the proportion of radiosensitive cells could be estimated from the shape of the survival curve, its radiosensitivity is too high to be properly evaluated by the colony assay. The eight survival curves differ essentially in the proportion of radiosensitive cells--which varied from 0% to 40% among M4Be and its seven sublines--whereas the cellular radiosensitivity of the radioresistant population was similar among them. The metastatic potential in vivo of M4Be and its seven sublines was not significantly related to the cellular radiosensitivity of their corresponding radioresistant population, but significantly increased with the fraction of radiosensitive cells. This relationship is valid only when the highly metastatic cells are cultured for no more than five passages in vitro as the fraction of radiosensitive cells is rapidly lost during subcultures. The relationship remains valid in vivo as metastatic melanoma-bearing newborn rats whole body irradiated with 20 cGy show no lung metastasis compared with controls. The radiosensitive cell fraction is inversely correlated with both the total ganglioside content (r = 0.84, P < 0.02) and the number of cells positively labelled with the monoclonal antibody directed to GD3 (r = 0.92, P < 0.001). The incubation of a radiosensitive clone with the exogenous bovine brain ganglioside GM1 significantly increases the proportion of radioresistant cells and suppresses its metastatic potential, while the inhibition of the endogenous gangliosides synthesis in the radioresistant cell line M4Be increases the proportion of radiosensitive cells. This study provides a possible explanation for the correlation between the metastatic potential and the proportion of radiosensitive cells within the seven sublines derived from a single parental human melanoma cell line.

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

1997-01-01

46

Influences of cyclooxygenase-1 and -2 expression on the radiosensitivities of human cervical cancer cell lines.  

PubMed

We utilized three cervical cancer cell lines (HeLa, HT-3, and C33A) and clonogenic assays to determine whether cyclooxygenase (COX) expression is related to radiosensitivity. Using COX DNA transfection and COX inhibition by siRNA, we also examined changes in radiosensitivity caused by variations in COX expression. The survival fractions of HeLa and HT-3 cell lines, which both with COX-1 and COX-2 activity, were found to be significantly higher than that of the C33A cell line which had neither COX-1 nor COX-2 activity. Moreover, the acquisition of COX-1 in C33A cell line significantly reduced its radiosensitivity, but COX-2 transfection increased radiosensitivity in this cell line. In addition, the inhibition of COX-1 activity in HT-3 cell line using siRNA resulted in an increased radiosensitivity, but this phenomenon was not observed for COX-2 inhibition. The same experiment in HeLa cells using siRNA also showed no significant change in radiosensitivity. The results obtained during this study suggest that COX expression is associated with the radiosensitivity in uterine cervical cancer cell lines and COX-1 might have more important role than COX-2. PMID:17601662

Jeon, Yong-Tark; Song, Yoo-Cheol; Kim, Su-Hyeong; Wu, Hong-Gyun; Kim, Il-Han; Park, In-Ae; Kim, Jae Weon; Park, Noh-Hyun; Kang, Soon-Beom; Lee, Hyo-Pyo; Song, Yong-Sang

2007-06-29

47

Radiosensitivity of human normal and tumoral thyroid cells using fluorescence in situ hybridization and clonogenic survival assay  

Microsoft Academic Search

Purpose: By using cell survival as a reference, we evaluated the radiosensitivity of human normal and tumoral thyroid cells using of radiation-induced translocations.Methods and Materials: Tissue samples were obtained from patients undergoing thyroidectomy. Cell cultures were established, irradiated with 60Co, and metaphases painted using commercial whole-chromosome 4 hybridization probe and pancentromeric probe. The clonogenic survival was assessed by conventional colony

Anthony Gaussen; Jean-Denis Legal; Nadine Beron-Gaillard; Agnés Laplanche; Jean-Paul Travagli; Bernard Caillou; Claude Parmentier

1999-01-01

48

Influences of cyclooxygenase-1 and -2 expression on the radiosensitivities of human cervical cancer cell lines  

Microsoft Academic Search

We utilized three cervical cancer cell lines (HeLa, HT-3, and C33A) and clonogenic assays to determine whether cyclooxygenase (COX) expression is related to radiosensitivity. Using COX DNA transfection and COX inhibition by siRNA, we also examined changes in radiosensitivity caused by variations in COX expression. The survival fractions of HeLa and HT-3 cell lines, which both with COX-1 and COX-2

Yong-Tark Jeon; Yoo-Cheol Song; Su-Hyeong Kim; Hong-Gyun Wu; Il-Han Kim; In-Ae Park; Jae Weon Kim; Noh-Hyun Park; Soon-Beom Kang; Hyo-Pyo Lee; Yong-Sang Song

2007-01-01

49

Hyperthermia radiosensitization in human glioma cells comparison of recovery of polymerase activity, survival, and potentially lethal damage repair  

SciTech Connect

DNA polymerase inactivation is compared to thermal radiosensitization and inhibition of damage recovery in human glioma cells. Two human glioma cell lines (U87MG and U373MG) were exposed to hyperthermia and irradiation. Hyperthermia was given at 43[degrees]C and 45[degrees]C and DNA polymerase [alpha] + [delta] + [epsilon] and [beta] activities were measured. Hyperthermia was given at various times before irradiation and the degree of radiosensitization and polymerase activity was assessed at various times after heating. In addition the ability of cells to undergo repair of potentially lethal radiation damage was assessed for cells irradiated at various times after heating. Polymerase [alpha] + [delta] + [epsilon] and polymerase [beta] both recovered after heating but polymerase [beta] was faster and was complete in U373MG but not in the U87MG cell lines after 48 h incubation after heating (45[degrees]C, 60 min). Incubation, between hyperthermia and irradiation resulted in a loss of radiosensitization and a loss of inhibition of repair of potentially lethal damage. These changes correlated well with recovery of polymerase [beta] but not with polymerase [alpha] + [delta] + [epsilon]. The correlation of polymerase [beta] activity and thermoradiosensitization and its recovery indicate that polymerase [beta] may be one of the mechanisms involved in thermoradiosensitization. 35 refs., 7 figs.

Raaphorst, G.P.; Feeley, M.M. (Ottawa Regional Cancer Centre, Ontario (Canada))

1994-04-30

50

Fluorescence Spectroscopy of Human Nonmalignant and Malignant Cells and Tissues.  

NASA Astrophysics Data System (ADS)

This thesis explores steady state and time resolved fluorescence spectroscopy from human malignant and non -malignant cells and tissues. The focus of these studies are the analysis of the excitation spectra, emission spectra, and decay time based on the contribution from several key intrinsic fluorophors: NAD(P)H, flavins, tryptophan, elastin and collagen that exist in different amounts in the human tissues and cells. The comparison between the spectra from malignant and non-malignant cells and tissues gives information on the changes that occur from non-malignancy to malignancy in the cells and tissues. The spectra of tissues and cells are also compared to help in understanding what fluorophors are responsible for fluorescence spectral differences between the malignant and non-malignant tissues and cells. The results in this thesis show that the spectral differences between the normal and cancerous tissues and cells exist in various wavelength ranges. The experimental data from GYN tissues have shown with over 95% of the sensitivity and specificity to separate malignant from non-malignant tissues using 300nm excitation. The 340nm band, which is mostly in response to intrinsic fluorophor (amino acid tryptophan), from malignant tissues were relatively higher then that from the non-malignant tissues. This might have been caused by the higher concentration of free tryptophan in the malignant tumor when compared to that of the normal tissue. This has been found in medical clinical study. The experimental data in this thesis also show that the fluorescence intensities around 450nm-460nm, which are mostly due to the intrinsic fluorophor coenzyme NADH, from both malignant cells in vitro and tissues in vitro are relatively higher than from non-malignant cells in vitro and tissues in vitro. These findings are reinforced by the faster decay time of the NADH fluorescence from normal cells in vitro than from neoplasm cells in vitro. Thus, the NADH in the mitochondria might be bound less tight in the malignant cells then that in the non-malignant cells because of metabolism changes from non-malignance to malignance. This thesis contributes to the new field of "mediphotonics" in life science.

Glassman, Wenling Sha

51

Photosensitizing and radiosensitizing effects of mitoxantrone: combined chemo-, photo-, and radiotherapy of DFW human melanoma cells.  

PubMed

This study evaluated the effects of mitoxantrone (MX), an antitumor agent, as a sensitizer to both photodynamic and radiation therapy in DFW human melanoma cells. Cells were incubated with MX at different concentrations for 90 min and then exposed to non-coherent light at different fluence rates and/or X-ray ionizing radiation at different dose rates. Combinatorial effects of this chemo-, photo-, and radiotherapy were also evaluated. MX had no significant effects on viability at moderate doses but had a strong cytotoxic effect on cancer cells when used as a photosensitizer. MX also acted as a potent radiosensitizer. We observed a dose-dependent effect on cell viability in cells exposed to MX in combination with phototherapy and radiotherapy. Strong synergistic effects were observed for combinations of two or more treatment methods, which, in some cases, induced complete cell death. Thus, a combination of ionizing radiation with MX-mediated photodynamic therapy could serve as a new method for cancer therapy with fewer adverse side effects. PMID:23371053

Sazgarnia, Ameneh; Montazerabadi, Ali Reza; Bahreyni-Toosi, Mohammad Hossein; Ahmadi, Amirhossein

2013-02-01

52

Radiosensitization of tumor-targeted radioimmunotherapy with prolonged topotecan infusion in human breast cancer xenografts.  

PubMed

Clinical radioimmunotherapy (RIT) of solid tumors holds great promise, but as yet has been unable to deliver tumoricidal radiation doses without unacceptable toxicity. Our experimental approach aims to potentiate the therapeutic action of radioimmunoconjugates at the tumor site and thus improve the efficacy of RIT by combination with other treatment modalities. The topoisomerase I inhibitors are a unique class of chemotherapeutic agents that interfere with DNA breakage-reunion by inhibiting the action of topoisomerase I. Preclinical studies suggest that prolonged infusion of topoisomerase I inhibitors enhances cell toxicity due to ionizing radiation. We evaluated the efficacy of combined treatment with continuous administration of topotecan and 90Y-MX-DPTA BrE3 monoclonal antibody (which recognizes an epitope of breast epithelial mucin expressed in most breast cancers) on human mammary carcinoma xenografts in nude mice. Topotecan or 90Y-BrE3 treatment alone delayed overall tumor growth rate transiently but did not affect survival. The combination of RIT with topotecan substantially reduced growth of relatively large established tumors and caused complete tumor regressions and prolonged tumor-free survival in a substantial proportion of treated animals. In vitro studies demonstrated an increase in apoptotic rate and a decrease in cell proliferation of tumor cell lines treated with this combination. We combined the radiosensitization property of topotecan and the specificity of systemic RIT to establish a novel therapy for solid tumors in an experimental tumor xenograft model. PMID:11306478

Ng, B; Kramer, E; Liebes, L; Wasserheit, C; Hochster, H; Blank, E; Ceriani, R; Furmanski, P

2001-04-01

53

Radiosensitivity of human natural killer cells: Binding and cytotoxic activities of natural killer cell subsets  

SciTech Connect

The sensitivity of human natural killer (NK) cell activities (both binding and killing) after exposure of peripheral blood mononuclear cells to different doses of gamma radiation was studied. A panel of monoclonal antibodies was used to identify the NK and T-lymphocyte subsets and to evaluate their radiosensitivity. Peripheral blood mononuclear cells were irradiated with low (2-6 Gy) and high (10-30 Gy) doses and NK cell binding and cytotoxic activity against K562 target cells were studied after 3 h and 48 h in culture. The primary damage to NK cell activity was identified at the postbinding level and affected mainly the lytic machinery. After 48 h culture postirradiation, an overall depression of cytotoxic activity was observed, but ionizing radiation produced either a selection of the more cytotoxic NK cell subsets, which therefore might be considered more resistant to radiation damage than the less cytotoxic NK cells, or a long-term stimulation of cytotoxic activity in surviving cells.

Rana, R.; Vitale, M.; Mazzotti, G.; Manzoli, L.; Papa, S. (Universita di Bologna (Italy))

1990-10-01

54

Effect of restoration of retinoblastoma gene function on the radiosensitivity of cells of human tumor cell lines  

SciTech Connect

To assess the role of expression of the retinoblastoma (RB) gene on the sensitivity of cells to the cytotoxic effects of ionizing radiation, we transfected a normal RB gene into cells of RB{sup +} and RB{sup {minus}} osteosarcoma cell lines and an RB{sup {minus}} prostate carcinoma line and studied the radiosensitivity of the cells before and after transfection. Four transfected clones were isolated from the two RB{sup {minus}} tumor cell lines that expressed the product of the transfected normal RB gene and contained no mutations in the pocket and C-terminal regions by sequencing. A small increase in radiosensitivity was observed in cell lines transfected with the pDOL plasmid vector alone, containing the neo gene and a long terminal repeat (LTR) promoter. However, no significant change in radiosensitivity occurred in transfected cells expressing the normal RB gene compared to controls transfected with an RB{sup {minus}} plasmid. Based on this and other information, we conclude that RB gene function is not involved in the response of these human tumor cells to the cytotoxic effects of radiation. 38 refs., 5 figs., 4 tabs.

Tsang, N.M.; Little, J.B. [Harvard School of Public Health, Boston, MA (United States)

1994-11-01

55

[The effect of low-dose irradiation and of age on the in vitro radiosensitivity of human lymphocytes].  

PubMed

The effect of low-dose irradiation and of age on the radiosensitivity of human lymphocytes was studies in two groups: control (67 people) and exposed to uncontrolled low-dose irradiation in past (165 people). Radiosensitivity of lymphocytes was estimated by the level of chromosome aberrations induced in vitro by gamma-radiation Cs137 at the dose 1.5 Gy. In exposed children the frequency of induced chromosome aberrations was higher and in the exposed adults--lower in comparison to the coresponding controls. To investigate an age response of the number of chromosome aberrations three statistical approaches were used: the correlation analysis of individual data, the correlation analysis of means for 10-years intervals, the comparison of 3 age groups. In control group no significant alteration in the level of induced chromosome aberrations with age was found. However the significant negative correlation between these two parameters was revealed in exposed group, which likely is due to the opposite direction of differences in radiosensitivity of exposed children and adults from the corresponding controls. PMID:18666646

Liubimova, N E; Vorobtsova, I E

56

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

57

Hypomethylation of DNA from Benign and Malignant Human Colon Neoplasms  

NASA Astrophysics Data System (ADS)

The methylation state of DNA from human colon tissue displaying neoplastic growth was determined by means of restriction endonuclease analysis. When compared to DNA from adjacent normal tissue, DNA from both benign colon polyps and malignant carcinomas was substantially hypomethylated. With the use of probes for growth hormone, ? -globin, ? -chorionic gonadotropin, and ? -crystallin, methylation changes were detected in all 23 neoplastic growths examined. Benign polyps were hypomethylated to a degree similar to that in malignant tissue. These results indicate that hypomethylation is a consistent biochemical characteristic of human colonic tumors and is an alteration in the DNA that precedes malignancy.

Goelz, Susan E.; Vogelstein, Bert; Hamilton, Stanley R.; Feinberg, Andrew P.

1985-04-01

58

Radio-responsive gene therapy for malignant glioma cells without the radiosensitive promoter: Caspase3 gene therapy combined with radiation  

Microsoft Academic Search

Caspase-3 plays a critical role as an executioner of apoptosis. The aim of this study is to evaluate the potential of the combination of caspase-3 gene therapy and radiation treatment. We prepared a plasmid (pCI-CSP3) that contained the human caspase-3 gene and the cytomegalovirus promoter. We introduced this plasmid into U251 and U87 human glioma cells and subjected the cells

Hideo Tsurushima; Xuan Yuan; Larry E. Dillehay; Kam W. Leong

2007-01-01

59

Radiosensitizing effect of misonidazole in acute and fractionated irradiation of a human osteosarcoma xenograft. [/sup 60/Co  

SciTech Connect

The radiosensitizing effect of misonidazole (Ro-07-0582) in acute and fractionated irradiation of a human osteosarcoma grown in the athymic mutant nude mouse was studied. Tumor regrowth delay was used as a measure of response. The enhancement ratio of misonidazole was found to be 1.45 for an actue dose of 12.50 Gy and 1.25 for four fractions of 3.75 Gy, delivered over four consecutive days. It is concluded that the present osteosarcoma xenograft reoxygenated inadequately during the three day period which elapsed from the first to the fourth fraction of 3.75 Gy.

Rofstad, E.K.; Brustad, T.

1980-09-01

60

Infrared absorption spectra of human malignant tumor tissues  

NASA Astrophysics Data System (ADS)

We used infrared spectroscopy methods to study the molecular structure of tissues from human organs removed during surgery. The IR spectra of the surgical material from breast, thyroid, and lung are compared with data from histological examination. We show that in malignant neoplasms, a change occurs in the hydrogen bonds of protein macromolecules found in the tissue of the studied organs. We identify the spectral signs of malignant pathology.

Skornyakov, I. V.; Tolstorozhev, G. B.; Butra, V. A.

2008-05-01

61

Adiponectin Receptor Expression in Human Malignant Tissues  

Microsoft Academic Search

Adiponectin has been proposed to be a mediator of obesity-associated malignancies and to have direct antineoplastic effects\\u000a acting via adiponectin receptors AdipoR1 and AdipoR2. We describe herein the expression of AdipoR1 and AdipoR2 in several\\u000a cancers not previously studied. We used immunohistochemistry to assess expression of adiponectin receptors in archival specimens\\u000a of renal cell carcinoma (n?=?64), hepatocellular carcinoma (n?=?123), melanoma

Sharon H. Chou; Sofia Tseleni-Balafouta; Hyun-Seuk Moon; John P. Chamberland; Xiaowen Liu; Nikolaos Kavantzas; Christos S. Mantzoros

2010-01-01

62

Enhanced radiosensitization of human glioma cells by combining inhibition of poly(ADP-ribose) polymerase with inhibition of heat shock protein 90.  

PubMed

Glioblastoma multiforme (GBM) are the most common primary brain tumor and are resistant to standard therapies. The nondividing nature of normal brain provides an opportunity to enhance the therapeutic ratio by combining radiation with inhibitors of replication-specific DNA repair pathways. Based on our previous findings that inhibition of poly(ADP-ribose) polymerase (PARP) increases radiosensitivity of human glioma cells in a replication-dependent manner and generates excess DNA breaks that are repaired by homologous recombination (HR), we hypothesized that inhibition of HR would amplify the replication-specific radiosensitizing effects of PARP inhibition. Specific inhibitors of HR are not available, but the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) has been reported to inhibit HR function. The radiosensitizing effects of 17-AAG and the PARP inhibitor olaparib were assessed, and the underlying mechanisms explored. 17-AAG down-regulated Rad51 and BRCA2 protein levels, abrogated induction of Rad51 foci by radiation, and inhibited HR measured by the I-Sce1 assay. Individually, 17-AAG and olaparib had modest, replication-dependent radiosensitizing effects on T98G glioma cells. Additive radiosensitization was observed with combination treatment, mirrored by increases in gammaH2AX foci in G(2)-phase cells. Unlike olaparib, 17-AAG did not increase radiation sensitivity of Chinese hamster ovary cells, indicating tumor specificity. However, 17-AAG also enhanced radiosensitivity in HR-deficient cells, indicating that its effects were only partially mediated by HR inhibition. Additional mechanisms are likely to include destabilization of oncoproteins that are up-regulated in GBM. 17-AAG is therefore a tumor-specific, replication-dependent radiosensitizer that enhances the effects of PARP inhibition. This combination has therapeutic potential in the management of GBM. PMID:19671736

Dungey, Fiona A; Caldecott, Keith W; Chalmers, Anthony J

2009-08-11

63

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

64

Radiobiological properties of radiosensitive XR-1 Chinese hamster cells and hybrids from these and human A-T cells  

SciTech Connect

Results indicate that XR-1 cells were very radiosensitive to gamma-irradiation compared to its parental type, and that this radiosensitivity is cell cycle dependent. Irradiating the cells the G{sub 1} or plateau phase did not induce any delay entering S-phase but mitotic delays were observed in both XR-1 and the wild-type cells. The delays per unit dose were much longer for XR-1. A delay in subculture from plateau phase reduced the mitotic delay in both cell lines. Unlike the wild-type cells which expressed virtually all chromosome-type aberrations after irradiation of G{sub 1} cells, the XR-1 cells expressed both chromatid- as well as chromosome-type aberrations. There was a one-to-one correlation between total aberrations induced and lethality for both cells. Many of these radiobiological properties of XR-1 cells relative to the wild-type cells, mimic the response of A-T cells relative to the normal human cells. However, the restoration of radioresistance and cytogenetic response in the XR1/AT5BI(4) hybrid cells suggest that the XR-1 and A-T cells have different defects because of the complementation in the hybrids. It also appears that this genetic defect is recessive in nature.

Bahari, I.B.

1989-01-01

65

Malignant transformation of mammalian cells in culture, including human cells  

SciTech Connect

This overview of the malignant transformation of mammalian cells in culture, including human cells, describes the earliest evidence of spontaneous, virus-induced, and carcinogen-induced transformation. It discusses several systems developed to assay the carcinogen-induced transformation of highly selected infinite life span (established) cell lines as well as finite life span diploid cells. Evidence is presented to support the multistep hypothesis of the process of malignant transformation, and the theoretical requirement for acquisition of an infinite, or greatly extended, life span in culture if a cell is to become malignant is explained in light of the multistep nature of the process. The use of oncogene transfection studies to analyze the number and kinds of changes involved is discussed, with emphasis on studies using human cells. Finally, the results of earlier studies on viral- and carcinogen-induced transformation of mammalian cells (or chicken cells) are reinterpreted in the light of more recent insights into the process of carcinogenesis.

McCormick, J.J.; Maher, V.M. (Michigan State Univ., East Lansing (USA))

1989-01-01

66

Halogenated pyrimidine sensitization of low dose rate irradiation in human malignant glioma  

SciTech Connect

The purpose was to determine the potential advantage of combining halogenated pyrimidine radiosensitization and continuous low dose rate irradiation in human malignant glioma. An established glioma line (U-251) was incubated with 5-bromo-2-doxyuridine (BrdUrd) at clinically achievable concentrations at three dose rates of interest - 100 cGy/min (typical of external beam therapy), 43 cGy/hr (typical of temporary afterloaded implants), and 12 cGy/hr (typical of permanent implants). After exposure to 1 [mu]M BrdUrd, the greatest enhancement ratio was seen at the 12 cGy/hr dose rate, implying a BrdUrd induced inverse dose rate effect independent of a G[sub 2]M block. Under these conditions, the mean inactivation dose after 1 [mu]M BrdUrd exposure was equivalent for 100 cGy/min and 12 cGy/hr. These results support the use of halopyrimidines as sensitizers of temporary afterloaded and permanent implants. 26 refs., 3 figs., 1 tab.

McLaughlin, P.W.; Mancini, W.R.; Stetson, P.L.; Greenberg, H.S.; Nguyen, N.; Seabury, H.; Heidorn, D.B.; Lawrence, T.S. (Univ. of Michigan Medical Center, Ann Arbor, MI (United States))

1993-07-15

67

Specific Chromosomal Abnormalities in Malignant Human Gliomas1  

Microsoft Academic Search

Karyotypic analysis of 54 malignant human gliomas (5 anaplastic asina-)tomas, 43 glioblastoma multiformes, 3 gliosarcomas, 2 giant cell glioblastomas, 1 anaplastic mixed glioma) has demonstrated that 12 tumors contained normal stemlines or only lacked one sex chromosome. The 42 tumors with abnormal karyotypes included 38 tumors which could be completely analyzed. Six of these 38 cases had near-triploid or near-

Sandra H. Bigner; Joachim Mark; Peter C. Burger; M. Stephen; Dennis E. Bullan; Lawrence H. Muhlbaier; Dareil D. Bigner

1988-01-01

68

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.

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

69

Enhancement of radiosensitivity in human glioblastoma cells by the DNA N-mustard alkylating agent BO-1051 through augmented and sustained DNA damage response  

PubMed Central

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 BO-1051. DNA histogram and propidium iodide-Annexin V staining were used to determine the cell cycle distribution and the apoptosis, respectively. DNA damage and repair state were determined by ?-H2AX foci, and mitotic catastrophe was measure using nuclear fragmentation. Xenograft tumors were measured with a caliper, and the survival rate was determined using Kaplan-Meier method. Results BO-1051 inhibited growth of human gliomas in a dose- and time-dependent manner. Using the dosage at IC50, BO-1051 significantly enhanced radiosensitivity to different extents [The sensitizer enhancement ratio was between 1.24 and 1.50 at 10% of survival fraction]. The radiosensitive G2/M population was raised by BO-1051, whereas apoptosis and mitotic catastrophe were not affected. ?-H2AX foci was greatly increased and sustained by combined BO-1051 and ?-rays, suggested that DNA damage or repair capacity was impaired during treatment. In vivo studies further demonstrated that BO-1051 enhanced the radiotherapeutic effects on GBM-3-beared xenograft tumors, by which the sensitizer enhancement ratio was 1.97. The survival rate of treated mice was also increased accordingly. Conclusions These results indicate that BO-1051 can effectively enhance glioma cell radiosensitivity in vitro and in vivo. It suggests that BO-1051 is a potent radiosensitizer for treating human glioma cells.

2011-01-01

70

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

71

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

72

HCG variants, the growth factors which drive human malignancies  

PubMed Central

The term human chorionic gonadotropin (hCG) refers to a group of 5 molecules, each sharing the common amino acid sequence but each differing in meric structure and carbohydrate side chain structure. The 5 molecules are each produced by separate cells and each having separate biological functions. hCG and sulfated hCG are hormones produced by placental syncytiotrophoblast cells and pituitary gonadotrope cells. Hyperglycosylated hCG is an autocrine produced by placental cytotrophoblast cells. Hyperglycosylated hCG drives malignancy in placental cancers, and in testicular and ovarian germ cell malignancies. hCG? and hyperglycosylated hCG? are autocrines produce by most advanced malignancies. These molecules, particularly the malignancy promoters are presented in this review on hCG and cancer. hCG? and hyperglycosylated hCG? are critical to the growth and invasion, or malignancy of most advanced cancers. In many ways, while hCG may appear like a nothing, a hormone associated with pregnancy, it is not, and may be at the center of cancer research.

Cole, Laurence A

2012-01-01

73

Surface expression of GD3 disialogangliosides in human melanoma cells is correlated to both metastatic potential in vivo and radiosensitivity in vitro.  

PubMed

With an experimental model of spontaneous lung metastases of melanoma developed in this laboratory, 7 sublines (variants and clones) with different metastatic potential and ganglioside expression were established from a single human melanoma cell line M4Be. Clones and variants derived from M4Be have been characterized at their surface by their gangliosides expression that were determined by flow cytometry with monoclonal antibodies. Gangliosides are membrane glycolipids containing sialic acid. Using an in vitro clonogenic assay and provided that cells were cultured for no more than 5 passages, variations in the cellular radiosensitivity of M4Be and of the 7 sublines were detected. This study shows that the lower the expression of GD3 disialoganglioside at the cell surface, both the higher their radiosensitivity in vitro and their metastatic potential in vivo. These results suggest that highly metastatic human melanoma cells are radiosensitive and deficient in surface gangliosides. Strengthening of this hypothesis arise from experiments showing that the incubation of radiosensitive cells with exogenous ganglioside significantly increases their radioresistance in vitro and reduces their metastatic potential in vivo. PMID:8745638

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

1995-12-01

74

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

75

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

76

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

77

Immortalization of human cells and their malignant conversion by high risk human papillomavirus genotypes  

Microsoft Academic Search

Papillomaviruses cause certain common human cancers, most notably carcinoma of the cervix. The viral oncoproteins E6 and E7 are essential components in malignant conversion, although, in spite of being necessary, they are not sufficient for the development of the malignant phenotype. High risk HPV oncogenes fulfill dual functions in genome-harboring cells: their derived oncoproteins stimulate cell growth by pleiotropic effects.

Harald zur Hausen

1999-01-01

78

Correlation between radiosensitivity, percentage hypoxic cells and pO{sub 2} measurements in one rodent and two human tumor xenografts  

SciTech Connect

Computerized pO{sub 2} histography has been used to measure the intratumor pO{sub 2} in patients for the past few years, and there is now evidence that these tumors contain hypoxic cells. One of the major questions that remains to be answered is the relevance of such data to radiosensitivity. The present study looks for a correlation between intratumor pO{sub 2}, the percentage of hypoxic cells in the tumor and the radiosensitization induced by carbogen and/or the oxygen carrier, perflubron emulsion. Two human tumor xenografts (HRT18, Na11+) and one rodent tumor (EMT6) were used. The radiosensitivity (clonogenic assay) and the oxygen tension (computerized pO{sub 2} histography) were measured. All experiments were performed under similar conditions. Carbogen increased tumor radiosensitivity; sensitization was greatest when 4ml/kg perflubron emulsion was used in conjunction with carbogen. The pO{sub 2} distribution was shifted to higher pO{sub 2} values in the tumors whatever the treatment; the shift was greater for perflubron emulsion plus carbogen. The low pO{sub 2} values were lost for the HRT18 cells. A correlation (EMT6, HRT18) or a link (Na11+) between the radiosensitization and the oxygen tension measurements was found for values below 1.07 and 1.33 kPa. A trend between the percentage of hypoxic cells and pO{sub 2} measurements was found taking into account pO{sub 2} measurements comprised between 0.27 and 0.67 kPa.

Thomas, C.D.; Chavaudra, N.; Martin, L.; Guichard, M. [Institut Gustave-Roussy, Villejuif (France)

1994-07-01

79

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.

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

80

Cytotoxicity of restriction enzyme-induced DNA strand breaks in radiosensitive and radioresistant human tumor cell lines  

SciTech Connect

The purpose was to examine the role of sensitivity to specific types of DNA double strand breaks in human tumor cell response. The X ray-sensitive human squamous carcinoma cell line SCC-61 and the X ray-resistant line SQ-20B were exposed to the restriction enzymes HaeIII, HinfI, PvuII, BamHI by electroporation. Cyotoxicity of these restriction endonucleases was measured by a colony formation assay. Cell killing by each enzyme occurred in a concentration-dependent manner. The radiosensitive cell line was more sensitive to all four restriction enzymes than the radioresistant line, paralleling the response to ionizing radiation. However, the magnitude of the difference was smaller than for radiation. The 5-base sticky ended cutter HinfI and 6-base blunt ended cutter PvuII were much more effective in killing cells from both lines than BamHI, a 6-base sticky ended cutter, whereas the 4-base blunt ended cutter HaeIII was intermediate in its effectiveness. Thus, enzyme sensitivity could not be related to the type of cutter or the distance between cutting sites. 14 refs., 1 fig., 2 tabs.

Kinashi, Y.; Nagasawa, H.; Little, J.B. (Harvard School of Public Health, Boston, MA (United States))

1993-09-20

81

Malignant transformation of human skin fibroblasts by two alternative pathways.  

PubMed

We developed a telomerase-positive, infinite life span human fibroblast cell strain (MSU-1.0) by transfection of a v-MYC oncogene and spontaneous over-expression of transcription factors SP1/SP3. Loss of expression of p14(ALT) and enhanced expression of SPRY2 gave rise to the MSU-1.1 cell strain. Unlike MSU-1.0 cells, the MSU-1.1 cells can be malignantly transformed by expression of N-RAS(LYS61) or H-Ras(v12) oncoproteins (driven by their original promoters) and expression of a SRC-family protein, v-FES. MSU-1.1 cells can also be malignantly transformed by high expression of these RAS oncogenes or the v-K-RAS oncogene. PDGF-B transformed MSU-1.1 cells give rise to benign tumors (fibromas) in athymic mice. A second route to malignant transformation of the MSU-1.1 cells involves loss of functional TP53 protein by carcinogen treatment and loss of expression of wild type p16(INK). These studies indicate 6-8 "hits" are required to activate the oncogenes and inactivate the suppressor genes we identified. PMID:21901629

McCormick, J Justin; Maher, Veronica M

2011-01-01

82

Chromosomal radiosensitivity during the G2 cell-cycle period of skin fibroblasts from individuals with familial cancer  

SciTech Connect

The authors reported previously that human cells after neoplastic transformation in culture had acquired an increased susceptibility to chromatid damage induced by x-irradiation during the G2 phase of the cell cycle. Evidence suggested that this results from deficient DNA repair during G2 phase. Cells derived from human tumors also showed enhanced G2-phase chromosomal radiosensitivity. Furthermore, skin fibroblasts from individuals with genetic diseases predisposing to a high risk of cancer, including ataxia-telangiectasia, Bloom syndrome, Fanconi anemia, and xeroderma pigmentosum exhibited enhanced G2-phase chromosomal radiosensitivity. The present study shows that apparently normal skin fibroblasts from individuals with familial cancer--i.e., from families with a history of neoplastic disease--also exhibit enhanced G2-phase chromosomal radiosensitivity. This radiosensitivity appears, therefore, to be associated with both a genetic predisposition to cancer and a malignant neoplastic state. Furthermore, enhanced G2-phase chromosomal radiosensitivity may provide the basis for an assay to detect genetic susceptibility to cancer.

Parshad, R.; Sanford, K.K.; Jones, G.M.

1985-08-01

83

Chromosomal radiosensitivity during the G2 cell-cycle period of skin fibroblasts from individuals with familial cancer.  

PubMed Central

We reported previously that human cells after neoplastic transformation in culture had acquired an increased susceptibility to chromatid damage induced by x-irradiation during the G2 phase of the cell cycle. Evidence suggested that this results from deficient DNA repair during G2 phase. Cells derived from human tumors also showed enhanced G2-phase chromosomal radiosensitivity. Furthermore, skin fibroblasts from individuals with genetic diseases predisposing to a high risk of cancer, including ataxia-telangiectasia, Bloom syndrome, Fanconi anemia, and xeroderma pigmentosum exhibited enhanced G2-phase chromosomal radiosensitivity. The present study shows that apparently normal skin fibroblasts from individuals with familial cancer--i.e., from families with a history of neoplastic disease--also exhibit enhanced G2-phase chromosomal radiosensitivity. This radiosensitivity appears, therefore, to be associated with both a genetic predisposition to cancer and a malignant neoplastic state. Furthermore, enhanced G2-phase chromosomal radiosensitivity may provide the basis for an assay to detect genetic susceptibility to cancer.

Parshad, R; Sanford, K K; Jones, G M

1985-01-01

84

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

85

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

86

Human RGM249-derived small RNAs potentially regulate tumor malignancy.  

PubMed

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

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

2013-10-01

87

Somatostatin binding in normal and malignant human gastrointestinal mucosa.  

PubMed Central

Somatostatin is a regulatory peptide implicated in the control of cellular proliferation in epithelial tissues and this regulation may occur directly via membrane bound receptor activation. The aim of this study was to investigate somatostatin binding in human gastrointestinal cancer and normal mucosa. Plasma membranes were prepared from specimens of tumour and normal mucosa from 51 patients undergoing surgical resection for malignancy (28 gastric, 23 colorectal). Using a competitive displacement assay, specific 125I-tyrosine-11-somatostatin-14 binding to plasma membranes was assessed and and characterised in terms of receptor affinity (Kd) and maximum binding capacity (Bmax) as determined by Scatchard analysis. Specific low affinity (Kd = 166 nM), high capacity (Bmax = 1.2 pmol mg-1 protein) somatostatin binding was demonstrated in 22 of the gastric cancers and 17 of the colorectal cancers (Kd = 140 nM, Bmax = 1.8 pmol mg-1 protein). Similar affinity and binding capacity was demonstrable in normal mucosal samples. High affinity receptors for somatostatin were expressed by one gastric carcinoma (Kd = 0.9 nM; Bmax = 0.23 pmol mg-1 protein). Thus, low affinity, high capacity binding is a common feature of gastrointestinal tumours and normal mucosa, and high affinity receptors may occasionally be demonstrated. The functional significance of these low affinity binding sites requires elucidation to determine whether long-acting somatostatin analogues may have therapeutic benefit in gastrointestinal malignancy.

Miller, G. V.; Farmery, S. M.; Woodhouse, L. F.; Primrose, J. N.

1992-01-01

88

Histone recognition by human malignant brain tumor domains.  

PubMed

Histone methylation has emerged as an important covalent modification involved in a variety of biological processes, especially regulation of transcription and chromatin dynamics. Lysine methylation is found in three distinct states (monomethylation, dimethylation and trimethylation), which are recognized by specific protein domains. The malignant brain tumor (MBT) domain is one such module found in several chromatin regulatory complexes including Polycomb repressive complex 1. Here, we present a comprehensive characterization of the human MBT family with emphasis on histone binding specificity. SPOT-blot peptide arrays were used to screen for the methyllysine-containing histone peptides that bind to MBT domains found in nine human proteins. Selected interactions were quantified using fluorescence polarization assays. We show that all MBT proteins recognize only monomethyllysine and/or dimethyllysine marks and provide evidence that some MBT domains recognize a defined consensus sequence while others bind in a promiscuous, non-sequence-specific manner. Furthermore, using structure-based mutants, we identify a triad of residues in the methyllysine binding pocket that imparts discrimination between monomethyllysine and dimethyllysine. This study represents a comprehensive analysis of MBT substrate specificity, establishing a foundation for the rational design of selective MBT domain inhibitors that may enable elucidation of their role in human biology and disease. PMID:22954662

Nady, Nataliya; Krichevsky, Liubov; Zhong, Nan; Duan, Shili; Tempel, Wolfram; Amaya, Maria F; Ravichandran, Mani; Arrowsmith, Cheryl H

2012-09-04

89

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

90

Comparison of radiosensitivity of human lymphocytes stimulated with PHA Con A and PWM.  

National Technical Information Service (NTIS)

The transformation, DNA strand breaks and its repair ability in human peripheral blood lymphocytes stimulated with PHA, Con A and PWM were respectively assessed following exposure to (sup 60)Co gamma rays by (sup 3)H-thymidine uptake and hydroxylapatite c...

Y. Geng L. Su

1989-01-01

91

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

92

Rapamycin sensitizes Akt inhibition in malignant human breast epithelial cells  

PubMed Central

Akt and mTOR are therapeutic targets for the treatment of cancer. The effects of inhibiting mTOR, with rapamycin, and Akt, with A-443654, concurrently, on cell morphology, cell proliferation, the cell cycle, and apoptosis were examined using the benign MCF10A and malignant MCF10CA1a human breast epithelial cells. Rapamycin and A-443654 in combination produced the greatest morphological changes and inhibited cell proliferation by G2/M arrest. Rapamycin and A-443654 in combination induced apoptosis at earlier times and at lower A-443654 concentrations in MCF10CA1a tumor cells than in the benign MCF10A cells. Rapamycin and A-443654 increased p53 and p15INK4B protein levels, decreased anti-apoptotic Bcl-2 levels, and increased Bad levels in the MCF10CA1a tumor cells by ~ 5-fold. These results suggest that the combined inhibition of Akt and mTOR may have beneficial therapeutic and safety margin effects.

Zheng, Jie; Hudder, Alice; Zukowski, Kim; Novak, Raymond F.

2010-01-01

93

Malignant transformation of diploid human fibroblasts by transfection of oncogenes  

SciTech Connect

This document consist of brief reports prepared by postdoctoral students supported by the project, each describing his accomplishments under the grant. Topics include (1) Malignant Transformation of MSU-1. 1 Cells by Gamma Radiation, (2) Correlation between Levels of ras Expression and Presence of Transformed Phenotypes Including Tumorigenicity, Using a Modulatable Promoter, (3) Relation between Specific rad Oncogene Expression, (4) Correlation of Genetic Changes in Fibroblastic Tumors with Malignancies, (5)Transformation of MSU-1.1 Cells by sis Oncogene, (6) Malignant Transformation of MSU-1.0 Cells, (7) Correlation of Urokinase Plasminogen Activation (mu-PA) with Malignant Phenotype, (8)Two Dimensional Gel Electrophoresis Studies of the Proteins of the Major Cell Strains of the MSU-1 Family of Cells, and (9) Correlation between Proteinase Activity Levels and Malignancy.

McCormick, J.J.

1992-01-01

94

Detection of HPV16 genome in human oral cancers and potentially malignant lesions from India  

Microsoft Academic Search

The presence of high risk human papilloma virus (HPV) 16 and 18 was examined in 100 oral cancer patients of Indian descent, 80 patients with potentially malignant oral lesions and corresponding clinically normal mucosa from 48 of these patients. Additionally, presence of HPV-33, -6 and -11 was also studied in 86 oral cancers, 50 potentially malignant oral lesions and 30

Jenice D'Costa; Dhananjaya Saranath; Pratiksha Dedhia; Vikram Sanghvi; Ashok R Mehta

1998-01-01

95

Second malignancies in B-cell chronic lymphocytic leukaemia: possible association with human papilloma virus.  

PubMed

Second primary malignancies have long been associated with chronic lymphocytic leukaemia (CLL). We assessed secondary tumour samples from CLL and control patients for the presence of human papilloma virus (HPV). 132 CLL patients with 44 second malignancies were compared to a matched randomly-identified control population of 264 non-CLL patients with 54 solid malignancies. Polymerase chain reaction was performed with the highly conserved MY09/MY11 HPV primer. None of control samples were HPV-positive, while 53% of samples from the CLL group were positive. This report describes preliminary evidence for the presence of HPV in secondary malignancies, in patients with CLL. PMID:20230400

Flynn, Joseph M; Andritsos, Leslie; Lucas, David; Byrd, John C

2010-03-08

96

Normal Sequence and Activity but Reduced Levels of DNA-Pkcs in Human Lymphoblastic Cells Implicate Impaired Protein Stability with Radiosensitive Phenotype  

PubMed Central

Background: Non-homologous end joining (NHEJ) is the main repair pathway for DNA double strand breaks (DSBs) induced by ionizing radiation in mammalian cells. Subsets of cancer patients are hypersensitive to radiotherapy after standard doses. We sought to determine the radiosensitivity of human lymphoblastic cells (LB0005) for the abnormality in NHEJ components. Methods: Lymphoblastic (LB0005) cells are derived from an adult cancer patient with late radionecrosis. A low magnesium in vitro DNA-end joining assay was performed to examine for any defect in NHEJ activity. Single-nucleotide polymorphism (SNP) and sequence analysis were performed to examine for abnormality if any, in the genetic sequence of known NHEJ components. Results: LB0005 cells showed a gain of functional abnormality in the NHEJ pathway. While genetic sequence analysis showed no apparent mutational variations in the known classical NHEJ components, DNA-PKcs (DNA-dependent protein kinase catalytic subunit) protein is reduced in quantity compared to normal control, in spite of higher transcript levels. Conclusions: Taken together cells derived from a radiosensitive patient showed an abnormality in NHEJ activity. Proteins other than the classical NHEJ factors may regulate the NHEJ activity. Furthermore, the defect in theses regulatory proteins may have an impact on the stability of DNA-PKcs.

Yap, Seow Fong; Boo, Cynthia SK; Loong, Susan LE; Baskar, Rajamanickam

2013-01-01

97

Differential chromosomal radiosensitivity within the first G1-phase of the cell cycle of early-dividing human leukocytes in vitro after stimulation with PHA.  

PubMed

Human leukocyte cultures were irradiated with 200 RX-rays before the addition of phytohemagglutinin (PHA) in the Go-stage and at different times up to 25 h within the first G1-phase of the cell cyle after the addition of PHA. The results of the analysis of chromosomal aberrations show that the frequencies of dicentric chromosomes increase significantly when leukocytes leave the Go-stage, reaching a miximum yield of aberrations about halfway through the first G1-phase. After that, toward the end of the G1-phase, the frequencies of dicentric chromosomes decrease again to a level similar to that found in the Go-stage. Different possible explanations for the differential chromosomal radiosensitivity of human leukocytes within the first post-stimulation G1-phase are discussed. PMID:844868

Beek, B; Obe, G

1977-02-11

98

Analysis of human herpes virus-6 genomes in lymphoid malignancy in Japan.  

PubMed Central

Ninety cases of malignant lymphoma and 56 cases of reactive lymphadenopathy were studied using Southern blot analysis and the polymerase chain reaction to identify human herpes virus-6 (HHV-6) DNA. This was detected in cases of lymphoid malignancy at a rate which ranged from 50.0% to 68.8%. There were no differences in rates for different types of lymphoid malignancies. Herpes virus-6 DNA was detected by PCR in lymphoid malignancies less frequently than in reactive lymphadenopathies. It was not detected in lymphoid malignancies using Southern blotting. These results suggest that HHV-6 DNA was not related to lymphoid malignancy and was only a latent infection of non-neoplastic cells in tumour tissue.

Sumiyoshi, Y; Kikuchi, M; Ohshima, K; Takeshita, M; Eizuru, Y; Minamishima, Y

1993-01-01

99

Impaired Pten expression in human malignant peripheral nerve sheath tumours.  

PubMed

Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that develop in about 10% of patients with the genetic disease neurofibromatosis type 1 (NF1). Molecular alterations contributing to MPNST formation have only partially been resolved. Here we examined the role of Pten, a key regulator of the Pi3k/Akt/mTOR pathway, in human MPNST and benign neurofibromas. Immunohistochemistry showed that Pten expression was significantly lower in MPNST (n=16) than in neurofibromas (n=16) and normal nervous tissue. To elucidate potential mechanisms for Pten down-regulation or Akt/mTOR activation in MPNST we performed further experiments. Mutation analysis revealed absence of somatic mutations in PTEN (n=31) and PIK3CA (n=38). However, we found frequent PTEN promotor methylation in primary MPNST (11/26) and MPNST cell lines (7/8) but not in benign nerve sheath tumours. PTEN methylation was significantly associated with early metastasis. Moreover, we detected an inverse correlation of Pten-regulating miR-21 and Pten protein levels in MPNST cell lines. The examination of NF1-/- and NF1+/+Schwann cells and fibroblasts showed that Pten expression is not regulated by NF1. To determine the significance of Pten status for treatment with the mTOR inhibitor rapamycin we treated 5 MPNST cell lines with rapamycin. All cell lines were sensitive to rapamycin without a significant correlation to Pten levels. When rapamycin was combined with simvastatin a synergistic anti-proliferative effect was achieved. Taken together we show frequent loss/reduction of Pten expression in MPNST and provide evidence for the involvement of multiple Pten regulating mechanisms. PMID:23139750

Bradtmöller, Maren; Hartmann, Christian; Zietsch, Jan; Jäschke, Sebastian; Mautner, Victor-F; Kurtz, Andreas; Park, Su-Jin; Baier, Michael; Harder, Anja; Reuss, David; von Deimling, Andreas; Heppner, Frank L; Holtkamp, Nikola

2012-11-06

100

Abundant expression of chemokines in malignant and infective human lymphadenopathies.  

PubMed

Lymph nodes can be the primary target of infection or malignant transformation and may exhibit characteristic patterns of leukocyte infiltration analogous to those seen in inflammation of other tissues. Leukocyte migration to lymph nodes in vivo is a highly regulated, multi-step process that depends upon adhesion molecules and as yet, uncharacterized chemotactic signals. Chemokines are a key part of the orchestrated code of signals that directs leukocyte subsets to sites of inflammation or immune response. The potential role of these chemoattractants in selective trafficking of leukocyte subsets into lymph nodes was assessed by determining the expression of chemokines on a range of pathological and normal human lymph nodes and by evaluating the cellular composition of each lymph node. In situ hybridization using chemokine riboprobes and immunohistochemistry using specific antibodies were performed in order to correlate the mRNA and protein expression of the chemokines. The cellular source(s) of each chemokine was assessed by immunohistochemical staining of adjacent sections using antibodies directed against distinctive cellular markers. Substantial, but varied, expression of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, RANTES, macrophage chemotactic protein (MCP)-1, eotaxin, and interleukin 8 (IL-8) were detected in the pathological lymph nodes by diverse cell types. Control lymph nodes showed expression only of RANTES, mainly by high endothelial venules. In all lymph nodes, except the nodes infiltrated with breast cancer, chemokine mRNA expression was highly concordant with the corresponding protein. In contrast with in vitro studies that have suggested discrete target cell specificity of chemokines, this study showed that with the possible exception of the neutrophil chemoattractant, IL-8, no chemokine appeared to be uniquely associated with the accumulation of a specific leukocyte subset. These data implicate chemokines in the recruitment of leukocytes to lymph nodes affected by diverse disease states. PMID:10419655

Tedla, N; Palladinetti, P; Wakefield, D; Lloyd, A

1999-07-01

101

Reduced GNG2 expression levels in mouse malignant melanomas and human melanoma cell lines  

PubMed Central

Heterotrimeric G protein is composed of a G?-subunit and a G??-dimer. Previous studies have revealed that G??-dimers including the G?2 subunit (Gng2/GNG2) are associated with cell proliferation, differentiation, invasion and angiogenesis. At present, however, there is no information on the expression level of Gng2/GNG2 alone in any kind of tumor. In this study, we performed DNA microarray analysis in a benign melanocytic tumor and a malignant melanoma from RET-transgenic mice (RET-mice). Gng2 transcript expression levels in a malignant melanoma were less than 1/10 of the level in a benign tumor. The difference in Gng2 transcript expression levels between benign tumors and malignant melanomas was greatest among all of the G protein ? subunits examined in this study. Moreover, protein expression levels of Gng2 were decreased in malignant melanomas compared with those in benign melanocytic tumors in RET-mice. Analysis of human malignant melanomas also showed reduced GNG2 protein expression levels in five human malignant melanoma cell lines compared with the expression levels in normal human epithelial melanocytes (NHEM). Thus, we demonstrated for the first time that Gng2/GNG2 expression levels are reduced in malignant melanoma, suggesting that GNG2 could be a novel biomarker for malignant melanoma.

Yajima, Ichiro; Kumasaka, Mayuko Y; Naito, Yuji; Yoshikawa, Toshikazu; Takahashi, Hiro; Funasaka, Yoko; Suzuki, Tamio; Kato, Masashi

2012-01-01

102

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

PubMed

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

2009-06-25

103

Type I collagen gene suppresses tumor growth and invasion of malignant human glioma cells  

Microsoft Academic Search

BACKGROUND: Invasion is a hallmark of a malignant tumor, such as a glioma, and the progression is followed by the interaction of tumor cells with an extracellular matrix (ECM). This study examined the role of type I collagen in the invasion of the malignant human glioma cell line T98G by the introduction of the human collagen type I ?1 (HCOL1A1)

Kimi Honma; Teruo Miyata; Takahiro Ochiya

2007-01-01

104

Radiosensitization by Inhibiting STAT1 in Renal Cell Carcinoma  

SciTech Connect

Purpose: Renal cell carcinoma (RCC) has been historically regarded as a radioresistant malignancy, but the molecular mechanism underlying its radioresistance is not understood. This study investigated the role of signal transducer and activator of transcription 1 (STAT1), a transcription factor downstream of the interferon-signaling pathway, in radioresistant RCC. Methods and Materials: The expressions of STAT1 and STAT3 in 164 human clear cell RCC samples, 47 papillary RCC samples, and 15 normal kidney tissue samples were examined by microarray expression profiling and immunohistochemistry. Western blotting was performed to evaluate the total and phosphorylated STAT1 expression in CRL-1932 (786-O) (human clear cell RCC), SKRC-39 (human papillary RCC), CCL-116 (human fibroblast), and CRL-1441 (G-401) (human Wilms tumor). STAT1 was reduced or inhibited by fludarabine and siRNA, respectively, and the effects on radiation-induced cell death were investigated using clonogenic assays. Results: STAT1 expression, but not STAT3 expression, was significantly greater in human RCC samples (p = 1.5 x 10{sup -8} for clear cell; and p = 3.6 x 10{sup -4} for papillary). Similarly, the expression of STAT1 was relatively greater in the two RCC cell lines. STAT1 expression was reduced by both fludarabine and siRNA, significantly increasing the radiosensitivity in both RCC cell lines. Conclusion: This is the first study reporting the overexpression of STAT1 in human clear cell and papillary RCC tissues. Radiosensitization in RCC cell lines was observed by a reduction or inhibition of STAT1 signaling, using fludarabine or siRNA. Our data suggest that STAT1 may play a key role in RCC radioresistance and manipulation of this pathway may enhance the efficacy of radiotherapy.

Hui Zhouguang [Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX (United States); Department of Radiation Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing (China); Tretiakova, Maria [Department of Pathology, University of Chicago Pritzker School of Medicine, Chicago, IL (United States); Zhang Zhongfa; Li Yan [Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI (United States); Wang Xiaozhen [Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX (United States); Department of Radiation Oncology, Cancer Hospital (Institute), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing (China); Zhu, Julie Xiaohong [Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX (United States); Gao Yuanhong [Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX (United States); Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou (China); Mai Weiyuan [Department of Radiology, Division of Radiation Oncology, Baylor College of Medicine, Houston, TX (United States); Furge, Kyle [Laboratory of Computational Biology, Van Andel Research Institute, Grand Rapids, MI (United States); Qian Chaonan [Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI (United States); Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou (China); Amato, Robert [Department of Genitourinary Oncology, Methodist Hospital, Houston, TX (United States); Butler, E. Brian [Department of Radiation Oncology, Methodist Hospital and Methodist Hospital Research Institute, Houston, TX (United States)] (and others)

2009-01-01

105

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

106

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.

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

2013-01-01

107

Normal human colon cells suppress malignancy when fused with colon cancer cells  

SciTech Connect

Normal human colon mucosa cells and cells obtained from histologically normal tissues near that cancer were fused with human colon cancer cells. Resultant hybrid populations of normal and malignant cell fusions behaved as nonmalignant cells in culture, were unable to grow in soft agar, did not express tumor-associated antigens, and were nontumorigenic in nude mice. Autofusion of the cancer cell population led to a phenotype intermediate between normal and malignant cells. That is, the cultures had a much lower plating efficiency in soft agar, and the tumors had a longer latency and slower growth rate in nude mice. This is the first cell culture system to demonstrate that normal epithelial cells can suppress malignancy of their autologous cancer cells, and is a prelude to more extensive studies of genetic events involved in malignant conversion of human colonic epithelium.

Johnson, T.L.; Moyer, M.P. (Univ. of Texas Health Science Center, San Antonio (USA))

1990-11-01

108

On the radiosensitivity of man in space  

NASA Astrophysics Data System (ADS)

Astronauts' radiation exposure limits are based on experimental and epidemiological data obtained on Earth. It is assumed that radiation sensitivity remains the same in the extraterrestrial space. However, human radiosensitivity is dependent upon the response of the hematopoietic tissue to the radiation insult. It is well known that the immune system is affected by microgravity. We have developed a mathematical model of radiation-induced myelopoiesis which includes the effect of microgravity on bone marrow kinetics. It is assumed that cellular radiosensitivity is not modified by the space environment, but repopulation rates of stem and stromal cells are reduced as a function of time in weightlessness. A realistic model of the space radiation environment, including the HZE component, is used to simulate the radiation damage. A dedicated computer code was written and applied to solar particle events and to the mission to Mars. The results suggest that altered myelopoiesis and lymphopoiesis in microgravity might increase human radiosensitivity in space.

Esposito, R. D.; Durante, M.; Gialanella, G.; Grossi, G.; Pugliese, M.; Scampoli, P.; Jones, T. D.

109

Prevalence of human papillomavirus in archival samples obtained from patients with cervical pre-malignant and malignant lesions from Northeast Brazil  

Microsoft Academic Search

BACKGROUND: Human Papillomavirus (HPV) is considered as a necessary, but not sufficient, cause of cervical cancer. In this study, we aimed to assess the prevalence of HPV in a series of pre-malignant and malignant cervical lesion cases, to identify the virus genotypes, and to assess their distribution pattern according to lesion type, age range, and other considered variables. The samples

José V Fernandes; Rosely V Meissner; Maria GF Carvalho; Thales AAM Fernandes; Paulo RM Azevedo; João S Sobrinho; José CM Prado; Luisa L Villa

2010-01-01

110

Progression of human papillomavirus type 18-immortalized human keratinocytes to a malignant phenotype.  

PubMed Central

We have developed a model system for progression of human epithelial cells to malignancy, using a human papillomavirus type 18 (HPV-18)-immortalized human keratinocyte cell line. Cells of cell line FEP-1811 were nontumorigenic in athymic mice through at least 12 passages in culture, but after 32 passages were weakly tumorigenic, producing tumors that regressed. After 62 passages they produced invasive squamous cell carcinomas that grew progressively. The progression to malignancy was associated with an increase in the efficiency of forming colonies in soft agar and with altered differentiation properties. In an organotypic culture system, FEP-1811 cells at passages 12 and 32 exhibited features typical of premalignant intraepithelial neoplasia in vivo, and cells at passage 68 exhibited features consistent with squamous cell carcinomas. No change in copy number of the transfected HPV-18 genome or in the level of expression of the viral transforming gene products E6 and E7 was detected between tumorigenic and nontumorigenic cells. Cytogenetic analysis of cells at early, middle, and late passage levels and cells cultured from tumors revealed that several chromosomal abnormalities segregated with the tumorigenic cell populations. Images

Hurlin, P J; Kaur, P; Smith, P P; Perez-Reyes, N; Blanton, R A; McDougall, J K

1991-01-01

111

'Decoy' and 'non-decoy' functions of DcR3 promote malignant potential in human malignant fibrous histiocytoma cells  

PubMed Central

Decoy receptor 3 (DcR3) is a soluble secreted protein that belongs to the tumor necrosis factor receptor (TNFR) superfamily. DcR3 inhibits the Fas ligand (FasL)/Fas apoptotic pathway by binding to FasL, competitively with Fas receptor. Previous studies have reported that overexpression of DcR3 has been detected in various human malignancies and that DcR3 functions as a ‘decoy’ for FasL to inhibit FasL-induced apoptosis. In addition, recent studies have revealed that DcR3 has ‘non-decoy’ functions to promote tumor cell migration and invasion, suggesting that DcR3 may play important roles in tumor progression by decoy and non-decoy functions. We have previously reported that overexpression of DcR3 was observed in human malignant fibrous histiocytoma (MFH), however, the roles of DcR3 in MFH have not been studied. In the present study, to elucidate the roles of DcR3 in tumor progression of MFH, we examined the effects of DcR3 inhibition on cell apoptosis, migration and invasion in human MFH cells. siRNA knockdown of DcR3 enhanced the FasL-induced apoptotic activity and significantly decreased cell migration and invasion with a decrease in the activation of phosphatidylinositol 3 kinase (PI3K)/Akt and matrix metalloproteinase (MMP)-2. The findings in this study strongly suggest that DcR3 plays important roles in tumor progression of human MFH by decoy as well as non-decoy functions and that DcR3 may serve as a potent therapeutic target for human MFH.

TODA, MITSUNORI; KAWAMOTO, TERUYA; UEHA, TAKESHI; KISHIMOTO, KENTA; HARA, HITOMI; FUKASE, NAOMASA; ONISHI, YASUO; HARADA, RISA; MINODA, MASAYA; KUROSAKA, MASAHIRO; AKISUE, TOSHIHIRO

2013-01-01

112

In vitro measurements of ultraweak luminescence of human malignant tumors and healthy tissues  

NASA Astrophysics Data System (ADS)

In vitro measurements of levels of ultraweak luminescence were carried out using healthy and malignant tissues obtained from 63 patients undergoing surgical operations for cancers of colon, stomach and breast. The results obtained support recent reports that there is a difference in mean intensities of the ultraweak luminescence emitted from healthy and malignant tissues. This work demonstrates, however, that because of a large scatter among the intensities detected for samples obtained from different patients the differences found for the mean intensities cannot serve as a parameter for differentiating between the malignant and normal human tissues.

Chwirot, B. W.; Chwirot, S.; Jedrzejczyk, W.; Pozniak, V.; Dziczek, D.; Michniewicz, Z.; Jackowski, M.; Raczynska, A. M.; Winczakiewicz, J.

2001-07-01

113

REIC/Dkk-3 induces cell death in human malignant glioma  

PubMed Central

The progression of glioma to more malignant phenotypes results from the stepwise accumulation of genetic alterations and the consequent disruption of the apoptotic pathway and augmentation of survival signaling. REIC/Dkk-3, a member of the human Dickkopf (Dkk) family, plays a role as a suppressor of the growth of several human cancers; however, to date it has not been identified in brain tumors. We compared the gene and protein expression of REIC/Dkk-3 in human malignant glioma and normal brain tissues using quantitative real-time PCR, Western blotting, and immunohistochemistry. We also performed small interfering REIC/Dkk-3 (siREIC/Dkk-3) knockdown and REIC/Dkk-3 overexpression experiments to examine the role of REIC/Dkk-3 in human malignant glioma cells in vitro. In brain tissue from patients with malignant glioma, the gene and protein expression of REIC/Dkk-3 was lower than in normal brain tissue and was related to the malignancy grade. In the primary glioblastoma cell line, REIC/ Dkk-3 transfection led to apoptosis owing to the activation of phosphorylated JUN, caspase-9, and caspase-3 and the reduction of ?-catenin; in REIC/Dkk-3 knockdown experiments, cell growth was augmented. Our results suggest that REIC/Dkk-3 regulates the growth and survival of these cells in a caspase-dependent and -independent way via modification of the Wnt signaling pathway. Our work is the first documentation that the gene and protein expression of REIC/Dkk-3 is down- regulated in human malignant glioma. Our demonstration of the mechanisms underlying REIC/Dkk-3-induced cell death indicates that REIC/Dkk-3 plays a pivotal role in the biology of human malignant glioma and suggests that REIC/Dkk-3 is a promising candidate for molecular target therapy.

Mizobuchi, Yoshifumi; Matsuzaki, Kazuhito; Kuwayama, Kazuyuki; Kitazato, Keiko; Mure, Hideo; Kageji, Teruyoshi; Nagahiro, Shinji

2008-01-01

114

Recombinant human erythropoietin in the treatment of anemic patients with hematological malignancies  

Microsoft Academic Search

Patients with malignant diseases frequently develop anemia. An alternative to blood transfusions is the application of recombinant human erythropoietin. Several nonrandomized and prospective, placebo-controlled studies have demonstrated the effect and safety of erythropoietin in patients with hematological malignancies, particularly in patients with multiple myeloma and low- to intermediate-grade non-Hodgkin's lymphoma. However, in patients with myelodysplastic syndromes, the rather low response

C. Kasper

2001-01-01

115

Increased radiosensitivity and radiothermosensitivity of human pancreatic MIA PaCa-2 and U251 glioblastoma cell lines treated with the novel Hsp90 inhibitor NVP-HSP990  

PubMed Central

Background and purpose Heat shock Protein 90 (Hsp90) is a molecular chaperone that folds, stabilizes, and functionally regulates many cellular proteins involved in oncogenic signaling and in the regulation of radiosensitivity. It is upregulated in response to stress such a heat. Hyperthermia is a potent radiosensitizer, but induction of Hsp90 may potentially limit its efficacy. Our aim was to investigate whether the new Hsp90 inhibitor NVP-HSP990 increases radiosensitivity, thermosensitivity and radiothermosensitivity of human tumor cell lines. Material and methods U251 glioblastoma and MIA PaCa-2 pancreatic carcinoma cells were used. To determine clonogenic survival, colony forming assays were performed. Cell viability and proliferation were assesed by Trypan blue staining. Cell cycle and apoptosis analyses were performed by flow cytometry. DAPI staining was used to detect mitotic catastrophe. Results NVP-HSP990 increased the thermosensitivity, radiosensitivity and radio-thermosensitivity of both cell lines in clonogenic assays. 72?hours after irradiation with 4?Gy, a significant reduction in cell number associated with considerable G2/M acumulation and mitotic catastrophe as well as cell death by apoptosis/necrosis was observed. Conclusions Treatment with NVP-HSP990 strongly sensitized U251 and MIA PaCa-2 cells to hyperthermia and ionizing radiation or combination thereof through augmentation of G2/M arrest, mitotic catastrophe and associated apoptosis.

2013-01-01

116

Prostate cancer radiosensitization through PARP-1 hyperactivation  

PubMed Central

The clinical experimental agent, ?-lapachone (Arq 501), can act as a potent radiosensitizer in vitro through an unknown mechanism. In this study, we analyzed the mechanism to determine whether ?-lapachone may warrant clinical evaluation as a radiosensitizer. ?-lapachone killed prostate cancer cells by NAD(P)H:quinone oxidoreductase 1 (NQO1) metabolic bioactivation, triggering a massive induction of reactive oxygen species (ROS), irreversible DNA single strand breaks (SSBs), PARP-1 hyperactivation, NAD+/ATP depletion, and ?-calpain-induced programmed necrosis. In combination with ionizing radiation (IR), ?-lapachone radiosensitized NQO1+ prostate cancer cells, under conditions where nontoxic doses of either agent alone achieved threshold levels of SSBs required for hyperactivation of PARP-1. Combination therapy significantly elevated SSBs, ?-H2AX foci formation, and poly(ADP-ribosylation) of PARP-1, which were associated with ATP loss and induction of ?-calpain-induced programmed cell death. Radiosensitization by ?-lapachone was blocked by the NQO1 inhibitor, dicoumarol, or the PARP-1 inhibitor, DPQ. In a mouse xenograft model of prostate cancer, ?-lapachone synergized with IR to promote antitumor efficacy. NQO1 levels were elevated in ~60% of human prostate tumors evaluated relative to adjacent normal tissue, where ?-lapachone might be efficacious alone or in combination with radiation. Our findings offer a rationale for clinical assessment of ?-lapachone (Arq501) as a radiosensitizer in prostate cancers that overexpress NQO1, offering a potentially synergistic targeting strategy to exploit PARP-1 hyperactivation.

Dong, Ying; Bey, Erik A.; Li, Long-Shan; Kabbani, Wareef; Yan, Jingsheng; Xie, Xian-Jin; Hsieh, Jer-Tsong; Gao, Jinming; Boothman, David A.

2010-01-01

117

Cell Surface Antigens of Human Malignant Melanoma: Definition of Six Antigenic Systems with Mouse Monoclonal Antibodies  

Microsoft Academic Search

Eighteen mouse monoclonal antibodies were selected for reactivity with cell surface antigens of the immunizing human melanoma cell line SK-MEL-28. Six distinct antigenic systems were defined by direct serological assays and absorption tests with a panel of 41 cell lines derived from normal and malignant human tissues. Biochemical analysis indicated that two of the antigens are glycoproteins with molecular sizes

Wolfgang G. Dippold; Kenneth O. Lloyd; Lucy T. C. Li; Hisami Ikeda; Herbert F. Oettgen; Lloyd J. Old

1980-01-01

118

Spectrumof MelanomaAntigenson CulturedHumanMalignantMelanoma Cells as Detectedby MonkeyAntibodies1  

Microsoft Academic Search

To characterize the antigen present on the surface of cultured human malignant melanoma, three monkey xeno geneic antisera were raised. After appropriate absorption with pooled human erythrocytes, peripheral blood leuko cytes, and liven homogenate, no blood group or HLA neac tivity was detectable. Analysis of melanoma antigenic spec ificity was performed by the mixed hemadsonption microas say on live monolayer

Shuen-KueI Llao; Pak C. Kwong; James C. Thompson; Peter B. Dent

119

Cell cycle checkpoint status in human malignant mesothelioma cell lines: response to gamma radiation  

Microsoft Academic Search

Knowledge of the function of the cell cycle checkpoints in tumour cells may be important to develop treatment strategies for human cancers. The protein p53 is an important factor that regulates cell cycle progression and apoptosis in response to drugs. In human malignant mesothelioma, p53 is generally not mutated, but may be inactivated by SV40 early region T antigen (SV40

C Vivo; C Lecomte; F Levy; K Leroy; Y Kirova; A Renier; L Kheuang; P Piedbois; D Chopin; M C Jaurand

2003-01-01

120

On the radiosensitivity of man in space  

Microsoft Academic Search

Astronauts' radiation exposure limits are based on experimental and epidemiological data obtained on Earth. It is assumed that radiation sensitivity remains the same in the extraterrestrial space. However, human radiosensitivity is dependent upon the response of the hematopoietic tissue to the radiation insult. It is well known that the immune system is affected by microgravity. We have developed a mathematical

R. D. Esposito; M. Durante; G. Gialanella; G. Grossi; M. Pugliese; P. Scampoli; T. D. Jones

2001-01-01

121

Retinoblastoma protein-interacting zinc-finger gene 1 (RIZ1) dysregulation in human malignant meningiomas.  

PubMed

Retinoblastoma protein-interacting zinc-finger gene 1 (RIZ1) expression is often silenced in many types of human tumors. However, the relationship between RIZ1 expression and malignant meningiomas remains unclear. Here we have found for the first time that the expression of RIZ1 genes are associated with meningiomas progression through extensive analyses of Affymetrix GeneChip microarray data. Further validation methods for gene expression included quantitative PCR (qPCR), western blot and immunohistochemistry analysis, and these methods confirmed that RIZ1 is significantly downregulated in malignant meningioma tissues, as compared with benign meningiomas. In addition, malignant meningioma cells were stably transfected with ectogenic RIZ1 using Lentivirus-mediated transfection, and the transfections were followed by an in vitro 5-bromo-2-deoxyuridin incorporation assay, colony formation assay, cell cycle analysis, invasive analysis, apoptotic assay and western blot analysis. Our results demonstrate that the forced expression of RIZ1 in a malignant meningioma cell line inhibited cellular proliferation and arrested the cells in the G2/M phase of the cell cycle. We also confirmed that overexpression of RIZ1 may induce apoptosis of malignant meningioma cells. Furthermore, RIZ1 overexpression in malignant meningioma cells was associated with the downregulation of c-myc expression. These results from our study indicate that RIZ1 expression is significantly downregulated as the formation of meningiomas progressed, and suggest that RIZ1 may represent a promising candidate tumor suppressor gene that contributes to malignant meningiomas. PMID:22614009

Liu, Z Y; Wang, J Y; Liu, H H; Ma, X M; Wang, C L; Zhang, X P; Tao, Y Q; Lu, Y C; Liao, J C; Hu, G H

2012-05-21

122

Chemosensitivity and radiosensitivity profiles of four new human epithelial ovarian cancer cell lines exhibiting genetic alterations in BRCA2 , TGFß-RII , KRAS2 , TP53 and\\/or CDNK2A  

Microsoft Academic Search

To address the cellular basis for the response to ovarian cancer treatment, we characterized the chemosensitivity and radiosensitivity of four human epithelial ovarian cancer cell lines that harbor different genetic alterations. The TOV-21G, TOV-81D, OV-90, and TOV-112D cell lines were derived from ovarian tumors (TOV) or ascites (OV) from chemotherapy- and radiotherapy-naive patients and were characterized by their mutation spectrum

V. Samouëlian; C. M. Maugard; M. Jolicoeur; R. Bertrand; S. L. Arcand; P. N. Tonin; D. M. Provencher; A.-M. Mes-Masson

2004-01-01

123

Radiosensitization by inhibiting complex I activity in human hepatoma HepG2 cells to X-ray radiation.  

PubMed

The purpose of this study is to investigate the influence of mitochondrial respiratory chain complex I inhibition on the radiosensitivity of HepG2 cells. The complex I inhibitor rotenone was used to inhibit complex I activity on HepG2 cells before X-ray irradiation. The cytotoxicity of rotenone was analyzed by MTT assay at various doses. Rotenone induced dissipation of mitochondrial membrane potential and increase of intracellular ROS production were observed. Intracellular ATP production level was determined using luciferin-luciferase assay kit. We further analyzed cell survival and cell cycle distribution of a combined treatment which HepG2 cells underwent 0.5 µM rotenone pretreatment firstly and irradiated with different doses of X-ray radiation afterwards. Our results suggest rotenone pretreatment prior to X-ray irradiation could induce a sensitizing effect on HepG2 cells by enhancing X-ray radiation induced proliferation inhibition and cell apoptosis. PMID:22510598

Zhang, Xin; Zhou, Xin; Chen, Ruping; Zhang, Hong

2012-01-01

124

Adenovirus-mediated transfer of siRNA against survivin enhances the radiosensitivity of human non-small cell lung cancer cells.  

PubMed

Expression of survivin has been reported to be correlated with shorter survival in patients with non-small cell lung cancer (NSCLC), and overexpression of survivin may lead to radioresistance in various human cancers. In this study, we inhibited survivin expression by using an adenoviral vector (AdsiSurvivin)-mediated RNA interference to elucidate the combined effect of survivin-targeting gene therapy and radiotherapy on the NSCLC cells. Our data showed that AdsiSurvivin exerted survivin gene silencing, induced apoptosis, and significantly attenuated the growth potential in NSCLC cells within 72 h after infection. The combined treatment modalities with AdsiSurvivin infection and radiation were significantly more potent on cell-growth inhibition than monotherapy. In H1650, H460, A549, and H1975 human NSCLC cells, the survival ratios of AdsiSurvivin-treated groups at multiplicity of infection of 25 and 50 were significantly lower than those of control groups at varying radiation dose (0-8 Gy; three-way analysis of variance, P<0.05). The cytotoxicity of combined AdsiSurvivin infection and irradiation increased in a dose-dependent manner in both the virus and the irradiation treatment. Knockdown of the survivin gene expression seems to be a promising treatment strategy for NSCLC. Our data warrant the need for further effort to develop survivin-targeted radiosensitizer for lung cancer treatment. PMID:19730451

Yang, C-T; Li, J-M; Weng, H-H; Li, Y-C; Chen, H-C; Chen, M-F

2009-09-04

125

Comparative analysis of two-dimensional protein patterns in malignant and normal human breast tissue.  

PubMed

Malignant and normal human breast tissue were compared by evaluating two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) maps of frozen tissue samples. Image analyzing software was used to scan and process 34 gels. Eight (8/34) of these gels (4 malignant breast tumor samples, 4 normal tissue samples) were selected on the basis of gel and image quality to build a database to identify and measure the expression of a previously unidentified proteome. Growth factor receptor proteins (GFRs), including ERBB2 (HER2) and ERBB3 (HER3), were expressed in the malignant tissue samples. Growth factor receptor proteins were not expressed in the normal tissue. Also, expression of PS2-protein (pS2) was detected in neither malignant nor normal tissue. In benign breast samples a higher intensity of protein expression could be observed for maspin, desmoglein 3 and keratin 8 than in malignant samples. Other proteins expressed in malignant breast tissue include mitogen-activated protein kinase 3 (MK03), heat shock protein 27 kDa (HS27), growth factor receptor-bound protein (GRB2), cathepsin D, G1/S specific cyclin E1 (CGEI), glucose transporter type 5 (GTR5), and a number of as yet unidentified proteins. PMID:11425269

Czerwenka, K F; Manavi, M; Hosmann, J; Jelincic, D; Pischinger, K I; Battistutti, W B; Behnam, M; Kubista, E

2001-01-01

126

Deleted in liver cancer protein family in human malignancies (Review)  

PubMed Central

The Deleted in Liver Cancer (DLC) protein family comprises proteins that exert their function mainly by the Rho GTPase-activating protein (GAP) domain and by regulation of the small GTPases. Since Rho GTPases are key factors in cell proliferation, polarity, cytoskeletal remodeling and migration, the aberrant function of their regulators may lead to cell transformation. One subgroup of these proteins is the DLC family. It was found that the first identified gene from this family, DLC1, is often lost in hepatocellular carcinoma and may be involved as a tumor suppressor in the liver. Subsequent studies evaluated the hypothesis that the DLC1 gene acts as a tumor suppressor, not only in liver cancer, but also in other types of cancer. Following DLC1, two other members of the DLC protein family, DLC2 and DLC3, were identified. However, limited published data are available concerning the role of these proteins in malignant transformation. This review focuses on the structure and the role of DLC1 and its relatives in physiological conditions and summarizes data published thus far regarding DLC function in the neoplastic process.

Lukasik, D.; Wilczek, E.; Wasiutynski, A.; Gornicka, B.

2011-01-01

127

Detection of an Antigen Related to Mason-Pfizer Virus in Malignant Human Breast Tumors  

Microsoft Academic Search

An antigen related to the major structural protein (p27) of Mason-Pfizer monkey virus has been found in malignant human breast tumors by radioimmunoassays. This antigen was not detected in normal placental tissues or in tumors that were not of breast origin.

J. Yeh; M. Ahmed; S. A. Mayyasi; A. Alessi

1975-01-01

128

Selective Killing of Human Malignant Cell Lines Deficient in Methylthioadenosine Phosphorylase, a Purine Metabolic Enzyme.  

National Technical Information Service (NTIS)

Seven out of 31 (23%) human malignant tumor cell lines had no detectable methylthioadenosine phosphorylase activity assayed with ClAdo as substrate. The enzyme-deficient cell lines were derived from five leukemias, one melanoma, and breast cancer. None of...

N. Kamatani W. A. Nelson-Rees D. A. Carson

1981-01-01

129

Enhancement of drug sensitivity of human malignancies by epidermal growth factor  

Microsoft Academic Search

We have previously shown that epidermal growth factor (EGF) enhances the in vitro and in vivo sensitivity of human ovarian carcinoma 2008 cells to cisplatin. EGF was found to enhance selectively the in vivo toxicity of cisplatin to 2008 cell xenografts without altering the toxicity of cisplatin to non-malignant target tissues such as the kidney or bone marrow. We now

R Kröning; JA Jones; DK Hom; CC Chuang; R Sanga; G Los; SB Howell

1995-01-01

130

Pathology of Human Malignant Mesothelioma. Preliminary Analysis of 1,517 Mesothelioma Cases  

Microsoft Academic Search

The author reviewed 1,517 human malignant mesothelioma cases from 1975 through August 2000. These mesothelioma cases were definite or probable in diagnostic certainty. Sources of these cases varied including asbestos insulation workers, UNARCO workers, Cancer and Leukemia B mesothelioma panel cases and random cases. Pathology materials consisted of autopsy, biopsy and rare cytology specimens. 92.3% of these patients were male,

Yasunosuke SUZUKI

2001-01-01

131

Establishment and characterization of five cell lines derived from human malignant gliomas  

Microsoft Academic Search

We established and characterized five cell lines derived from human malignant gliomas (four glioblastomas multiforme and one highly anaplastic astrocytoma). All cell lines exhibited tumor cell morphology and growth kinetics, and anchorage-independent growth in soft agar. Cytogenetic analysis revealed significant aneuploidy in all five cases as well as clonal chromosomal alterations unique to each cell line. No cell line was

J. T. Rutka; J. R. Giblin; D. Y. Dougherty; H. C. Liu; J. R. McCulloch; C. W. Bell; R. S. Stern; C. B. Wilson; M. L. Rosenblum

1987-01-01

132

Nutritional Requirements of Human Malignant (Leukemic) Cell Lines: Implications for Adjuvant Therapy1  

Microsoft Academic Search

Metabolic requirements of malignant cell lines derived from patients with chronic myelogenous and acute lymphoblastic leukemias were com pared to those of proliferating normal cells (mitogen-stimulated human lymphocytes) and circulating blasts from acute myeloblastic and acute lymphoblastic leukemias. Requirements were judged by degree of amino acid (AA) utilization in short-term cultures and assessed by the effect of selective AA deprivation

Deborah P. Beebe; Guy B. Faguet

1987-01-01

133

Human papillomavirus E6 and E7 oncoproteins alter cell cycle progression but not radiosensitivity of carcinoma cells treated with low-dose-rate radiation  

Microsoft Academic Search

Purpose: Low-dose-rate radiation therapy has been widely used in the treatment of urogenital malignancies. When continuously exposed to low-dose-rate ionizing radiation, target cancer cells typically exhibit abnormalities in replicative cell-cycle progression. Cancer cells that arrest in the G2 phase of the cell cycle when irradiated may become exquisitely sensitive to killing by further low-dose-rate radiation treatment. Oncogenic human papillomaviruses (HPVs),

Theodore L. DeWeese; Jonathan C. Walsh; Larry E. Dillehay; Theodore D. Kessis; Lora Hedrick; Kathleen R. Cho; William G. Nelson

1997-01-01

134

Screening of gastric carcinoma cells in the human malignant gastric mucosa by confocal Raman microspectroscopy  

Microsoft Academic Search

Confocal Raman microspectroscopy was used to characterize gastric carcinoma cell in both cultured cells and human gastric mucosa tissues. Based on the spectra of single cultured cell, gastric carcinoma cells were screened out in the malignant gastric mucosa successfully and the positive ratio is about 58.06%. The high SNR (signal-to-noise) spectra from human gastric mucosa tissues and cells were obtained

A. G. Shen; Y. Ye; J. W. Zhang; X. H. Wang; J. M. Hu; W. Xie; J. Shen

2005-01-01

135

Ideutilication and Characterization of Human ß2-Chimaerin: Association with Malignant Transformation in Astrocytoma1  

Microsoft Academic Search

Molecular processes resulting in the malignant transformation from low- to high-grade astrocytoma remain poorly understood. Using reverse transcriptase PCR, we identified a gene that is differentially expressed in normal brain and low-grade astrocytoma compared to glioblastoma tis sues. This gene is identical to human ß2-chimaerin, which encodes a 468-amino acid GTPase-activating protein for pllrac. The gene was localized to human

Shixing Yuan; David W. Miller; Gene H. Barnett; Joseph F. Hahn; Bryan R. G. Williams

1995-01-01

136

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2  

Microsoft Academic Search

Arsenic is a well-known human skin carcinogen but the underlying mechanisms of carcinogenesis are unclear. Transcription factor Nrf2-mediated antioxidant response represents a critical cellular defense mechanism, and emerging data suggest that constitutive activation of Nrf2 contributes to malignant phenotype. In the present study when an immortalized, nontumorigenic human keratinocyte cell line (HaCaT) was continuously exposed to an environmentally relevant level

Jingbo Pi; Bhalchandra A. Diwan; Yang Sun; Jie Liu; Wei Qu; Yuying He; Miroslav Styblo; Michael P. Waalkes

2008-01-01

137

Malignant progression of an HPV16-immortalized human keratinocyte cell line (HPKIA) in vitro  

Microsoft Academic Search

The DNA of human papillomavirus (HPV) types found in cervical carcinomas can immortalize primary human keratinocytes. However, in analogy to tumor progression in vivo, HPV-immortalized keratinocytes require secondary events for malignant conversion. Here, we report on an HPV16-immortalized keratinocyte cell line (HPKIA) which after gamma-irradiation and long term culturing in vitro has acquired the ability to form squamous cell carcinomas

Matthias Dürst; Sibylle Seagon; Sylke Wanschura; Harald zur Hausen; Jörn Bullerdiek

1995-01-01

138

The Interaction between Two Radiosensitizers: 5Iododeoxyuridine and Caffeine  

Microsoft Academic Search

Iododeoxyuridine (IUdR) and caffeine are recognized as potential radiosensitizers with different mechanisms of interaction with ionizing radiation (IR). To assess the interaction of these two types of radiosensitizers, we com- pared treatment responses to these drugs alone and in combination with IR in two p53-proficient and p53-deficient pairs of human colon cancer cell lines (HCT116 versus HCT116 p53? \\/? and

Yuji Seo; Jane E. Schupp; Kazuhiko Yamane; Tomas Radivoyevitch; Timothy J. Kinsella

2006-01-01

139

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.

Cheung, Mitchell; Testa, Joseph R.

2013-01-01

140

CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis  

Microsoft Academic Search

Ras acts with other proteins to induce neoplasia. By itself, however, strong Ras signaling can suppress proliferation of normal cells. In primary epidermal cells, we found that oncogenic Ras transiently decreases cyclin-dependent kinase (CDK) 4 expression in association with cell cycle arrest in G1 phase. CDK4 co-expression circumvents Ras growth suppression and induces invasive human neoplasia resembling squamous cell carcinoma.

Mirella Lazarov; Yoshiaki Kubo; Ti Cai; Maya Dajee; Masahito Tarutani; Qun Lin; Min Fang; Shiying Tao; Cheryl L. Green; Paul A. Khavari

2002-01-01

141

The role of PML ubiquitination in human malignancies  

PubMed Central

Tumor suppressors are frequently downregulated in human cancers and understanding of the mechanisms through which tumor cells restrict the expression of tumor suppressors is important for the prognosis and intervention of diseases. The promyelocytic leukemia (PML) protein plays a critical role in multiple tumor suppressive functions, such as growth inhibition, apoptosis, replicative senescence, suppression of oncogenic transformation, and inhibition of migration and angiogenesis. These tumor suppression functions are recapitulated in several mouse models. The expression of PML protein is frequently downregulated in diverse types of human tumors and this downregulation often correlates with tumor progression. Recent evidence has emerged that PML is aberrantly degraded in various types of tumors through ubiquitination-dependent mechanisms. Here, we summarize our current understanding of the PML ubiquitination/degradation pathways in human cancers. We point out that multiple pathways lead to PML ubiquitination and degradation. Furthermore, the PML ubiquitination processes are often dependent on other types of posttranslational modifications, such as phosphorylation, prolylisomerization, and sumoylation. Such feature indicates a highly regulated nature of PML ubiquitination in different cellular conditions and cell contexts, thus providing many avenues of opportunity to intervene PML ubiquitination pathways. We discuss the potential of targeting PML ubiquitination pathways for anti-cancer therapeutic strategies.

2012-01-01

142

Melatonin inhibits cell proliferation and induces caspase activation and apoptosis in human malignant lymphoid cell lines.  

PubMed

Melatonin exerts strong anti-tumour activity via several mechanisms, including anti-proliferative and pro-apoptotic effects in addition to its potent antioxidant activity. Several studies have investigated the effects of melatonin on haematological malignancies. However, the previous studies investigating lymphoid malignancies have been largely restricted to a single type of malignancy, Burkitt's lymphoma (BL). Thus, we examined the actions of melatonin on the growth and apoptosis in a small panel of cell lines representing different human lymphoid malignancies including Ramos (Epstein-Barr virus-negative BL), SU-DHL-4 (diffuse large B cell lymphoma), DoHH2 (follicular B non-Hodgkin lymphoma) and JURKAT (acute T cell leukaemia). We showed that melatonin promotes cell cycle arrest and apoptosis in all these cells, although there was marked variations in responses among different cell lines (sensitivity; Ramos/DoHH2 > SU-DHL-4 > JURKAT). Melatonin-induced apoptosis was relatively rapid, with increased caspase 3 and PARP cleavage detected within 0.5-1 h following melatonin addition. Moreover, there was evidence for rapid processing of both caspase 9, as well as a breakdown of the mitochondrial inner transmembrane potential. On the contrary, caspase activation was detected only in SU-DHL-4 and Ramos cells following melatonin treatment suggesting that the extrinsic pathway does not make a consistent contribution to melatonin-induced apoptosis in malignant lymphocytes. Although all cell lines expressed the high-affinity melatonin receptors, MT1 and MT2, melatonin-induced caspase activation appeared to be independent these receptors. Our findings confirm that melatonin could be a potential chemotherapeutic/preventive agent for malignant lymphocytes. However, it is necessary to take into account that different lymphoid malignancies may differ in their response to melatonin. PMID:22582944

Sánchez-Hidalgo, Marina; Lee, Melanie; de la Lastra, Catalina A; Guerrero, Juan M; Packham, Graham

2012-05-14

143

Mutational analysis of 9 different tumour-associated genes in human malignant mesothelioma cell lines.  

PubMed

Seven tumour suppressor genes (Chk1, Chk2, Apaf1, Rb1, p53, p16(INK4a) and p14(ARF)) and two oncogenes (N-ras and BRAF) were screened in nine human malignant melanoma (HMM) cell lines for point mutations or small deletions/insertions by DGGE, TGGE and SCCP analysis. For the first time in human mesothelioma, Chk1 gene mutations were detected in two of the nine investigated HMM cell lines. P53 gene mutations were found in three cell lines and p16(INK4a) mutations in 5. Mutation of the Chk1 gene implies a novel disruption mechanism of the p53 pathway in HMM, without affecting p53 itself. According to our knowledge, this is the first mutation screening of Chk1, Chk2, Apaf1 and Rb1 in human malignant mesothelioma. PMID:16077986

Kumar, Krishan; Rahman, Qamar; Schipper, Holger; Matschegewski, Claudia; Schiffmann, Dietmar; Papp, Thilo

2005-09-01

144

HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers.  

PubMed

Heat-Shock Factor 1 (HSF1), master regulator of the heat-shock response, facilitates malignant transformation, cancer cell survival, and proliferation in model systems. The common assumption is that these effects are mediated through regulation of heat-shock protein (HSP) expression. However, the transcriptional network that HSF1 coordinates directly in malignancy and its relationship to the heat-shock response have never been defined. By comparing cells with high and low malignant potential alongside their nontransformed counterparts, we identify an HSF1-regulated transcriptional program specific to highly malignant cells and distinct from heat shock. Cancer-specific genes in this program support oncogenic processes: cell-cycle regulation, signaling, metabolism, adhesion and translation. HSP genes are integral to this program, however, many are uniquely regulated in malignancy. This HSF1 cancer program is active in breast, colon and lung tumors isolated directly from human patients and is strongly associated with metastasis and death. Thus, HSF1 rewires the transcriptome in tumorigenesis, with prognostic and therapeutic implications. PMID:22863008

Mendillo, Marc L; Santagata, Sandro; Koeva, Martina; Bell, George W; Hu, Rong; Tamimi, Rulla M; Fraenkel, Ernest; Ince, Tan A; Whitesell, Luke; Lindquist, Susan

2012-08-01

145

From The Cover: Reconstruction of functionally normal and malignant human breast tissues in mice  

NASA Astrophysics Data System (ADS)

The study of normal breast epithelial morphogenesis and carcinogenesis in vivo has largely used rodent models. Efforts at studying mammary morphogenesis and cancer with xenotransplanted human epithelial cells have failed to recapitulate the full extent of development seen in the human breast. We have developed an orthotopic xenograft model in which both the stromal and epithelial components of the reconstructed mammary gland are of human origin. Genetic modification of human stromal cells before the implantation of ostensibly normal human mammary epithelial cells resulted in the outgrowth of benign and malignant lesions. This experimental model allows for studies of human epithelial morphogenesis and differentiation in vivo and underscores the critical role of heterotypic interactions in human breast development and carcinogenesis.

Kuperwasser, Charlotte; Chavarria, Tony; Wu, Min; Magrane, Greg; Gray, Joe W.; Carey, Loucinda; Richardson, Andrea; Weinberg, Robert A.

2004-04-01

146

Cellular morphological parameters of the human urinary bladder (malignant and normal)  

PubMed Central

The normal and malignant cellular morphological parameters (intra- and extracellular spaces of the human urinary bladder) were obtained from analysis of digital images of bladder histology sections. Then these cellular morphological parameters were compared with the same parameters obtained from the literature for the bladder tissue. However, the limited quantitative data about these parameters available in the literature for bladder cell sizes and other geometrical parameters such as extra-cellular space does not provide a scientific basis to construct accurate structural models of normal and malignant bladder tissue. Therefore, there is usually no quantitative discussion of cell sizes in literature but the measured data in this work can provide a reasonable estimation of expected morphological parameter changes of bladder tissue with pathology. To produce this quantitative information, and also, to build a suitable models in another study using electrical properties of the tissue, 10 digital images of histological sections of normal, and six sections from malignant areas of the human urinary bladder, were chosen randomly (ex vivo). Finally, the measured data showed that there is a significant difference between the cell dimensions (in basal and intermediate layers) of normal and malignant bladder tissues.

Keshtkar, Ahmad; Keshtkar, Asghar; Lawford, Pat

2007-01-01

147

Confocal reflectance imaging of excised malignant human bladder biopsies  

NASA Astrophysics Data System (ADS)

To evaluate the potential of reflectance confocal scanning laser microscopy (CM) for rapid imaging of non-processed freshly excised human bladder biopsies and cystectomy specimens. Freshly excised bladder tumors from three cystectomy specimens and random biopsies from twenty patients with a history of superficial bladder tumors were imaged with CM. Additional acetic acid washing prior to CM imaging was performed in some of the samples. Confocal images were compared to corresponding routine histologic sections. CM allows imaging of unprocessed bladder tissue at a subcellular resolution. Urothelial cell layers, collagen, vessels and muscle fibers can be rapidly visualized, in native state. In this regard, umbrella cells, basement membrane elucidated. Besides obvious limitations partly due to non-use of exogenous dyes, CM imaging offers several advantages: rapid imaging of the tissue in its native state like the basement membrane, normally seen only by using immunohistopathology. Reflectance CM opens a new avenue for imaging bladder cancer.

Daniltchenko, Dmitri I.; Kastein, Albrecht; Koenig, Frank; Sachs, Markus; Schnorr, Dietmar; Al-Shukri, Salman; Loening, Stefan A.

2004-08-01

148

High prevelance of human parvovirus infection in patients with malignant tumors.  

PubMed

It is well known that the immunity of patients with malignant tumors decreases significantly. An increased parvovirus B19 (B19) infection rate has been observed in immunocompromised hosts. However, only a small amount of literature regarding the risk of human parvovirus infection in patients with malignant tumors is available. To evaluate the correlation of human parvovirus infection with malignant tumors, 288 serum samples from patients with malignant tumors were screened for B19 DNA by nested-PCR. The serum samples, 156 of which were from known clinicopathological cancer patients, were subjected to analysis of the seropositive rate of human bocavirus (HBoV), hepatitis B virus (HBV) and transfusion transmitted virus (TTV) by PCR. A total of 800 normal population sera and 941 aspirate samples from children with respiratory tract infections were used as controls for the detection of B19 and HBoV, respectively. Pairwise comparison between cancerous serum and control samples, and the correlation between parvovirus infection and clinicopathological variables, including gender and cancer type, were evaluated using the ?2 test, Fisher's exact test or the t-test. P<0.05 was considered to indicate a statistically significant difference. The overall prevalence of B19 DNA in cancer patients was 50.69% (146/288), which was significantly higher than that of the healthy controls with 4.5% (36/800) (?2 test, P<0.0001). Similar results were obtained for HBoV with a 39.74% (62/156) prevalence in cancer patients. However, the infection prevalence of HBV and TTV in the cancer patients was 5.13 (8/156) and 6.41% (10/156), respectively (P<0.0001), which was much less than that of B19 and HBoV. These results revealed that a high risk of B19 and HBoV infection occurred in cancer patients, and a potential correlation exists between parvovirus infection and occurrence of malignant tumors. PMID:22740966

Li, Yasha; Dong, Yanming; Jiang, Jun; Yang, Yongbo; Liu, Kaiyu; Li, Yi

2012-01-01

149

High prevelance of human parvovirus infection in patients with malignant tumors  

PubMed Central

It is well known that the immunity of patients with malignant tumors decreases significantly. An increased parvovirus B19 (B19) infection rate has been observed in immunocompromised hosts. However, only a small amount of literature regarding the risk of human parvovirus infection in patients with malignant tumors is available. To evaluate the correlation of human parvovirus infection with malignant tumors, 288 serum samples from patients with malignant tumors were screened for B19 DNA by nested-PCR. The serum samples, 156 of which were from known clinicopathological cancer patients, were subjected to analysis of the seropositive rate of human bocavirus (HBoV), hepatitis B virus (HBV) and transfusion transmitted virus (TTV) by PCR. A total of 800 normal population sera and 941 aspirate samples from children with respiratory tract infections were used as controls for the detection of B19 and HBoV, respectively. Pairwise comparison between cancerous serum and control samples, and the correlation between parvovirus infection and clinicopathological variables, including gender and cancer type, were evaluated using the ?2 test, Fisher’s exact test or the t-test. P<0.05 was considered to indicate a statistically significant difference. The overall prevalence of B19 DNA in cancer patients was 50.69% (146/288), which was significantly higher than that of the healthy controls with 4.5% (36/800) (?2 test, P<0.0001). Similar results were obtained for HBoV with a 39.74% (62/156) prevalence in cancer patients. However, the infection prevalence of HBV and TTV in the cancer patients was 5.13 (8/156) and 6.41% (10/156), respectively (P<0.0001), which was much less than that of B19 and HBoV. These results revealed that a high risk of B19 and HBoV infection occurred in cancer patients, and a potential correlation exists between parvovirus infection and occurrence of malignant tumors.

LI, YASHA; DONG, YANMING; JIANG, JUN; YANG, YONGBO; LIU, KAIYU; LI, YI

2012-01-01

150

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

151

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

152

Evaluation of cell lysis methods for platinum metallomic studies of human malignant cells  

Microsoft Academic Search

Three cell lysis methods—freeze–thaw, osmosis, and a chemical detergent-based method—were evaluated as sample treatment procedures for platinum metallomic studies of in vitro grown human malignant cells exposed to cisplatin. The lysis methods are relatively mild, resemble those commonly used in proteomic studies, and were selected because of the proven reactivity of platinum drug metabolites and indications that platinum in exposed

Mai Quynh Thanh Tran; Yvonne Nygren; Christina Lundin; Peter Naredi; Erik Björn

2010-01-01

153

Alteration of integrin expression relates to malignant progression of human papillomavirus-immortalized esophageal keratinocytes  

Microsoft Academic Search

To investigate cellular changes related to the malignant progression of keratinocytes, we studied the serum-resistant clones from CHEK-1, a human papillomavirus type 16 E6\\/E7-immortalized esophageal cell line cultured in a serum-free medium. Established clones exhibited morphologic variety. Slow growing clones presented in cuboidal shapes with tight cellular adhesion and highly expressed ?2 and ?6?4 integrins. Moderately proliferating clones showed loose

Hiroshi Sashiyama; Yuji Shino; Seiichiro Sakao; Hideaki Shimada; Susumu Kobayashi; Takenori Ochiai; Hiroshi Shirasawa

2002-01-01

154

Expression of TRPC6 in benign and malignant human prostate tissues  

Microsoft Academic Search

We investigated the expression of transient receptor potential canonical 6 (TRPC6) protein in benign and malignant human prostate tissues and in prostate cancer cell lines and the association with the stage, grade and androgen responsiveness of the tumors. Immunohistochemical techniques, Western blot and reverse transcription polymerase chain reaction (RT-PCR) were used to investigate TRPC6 expression. TRPC6 protein was detected in

Dan Yue; Yong Wang; Jian-Ying Xiao; Ping Wang; Chang-Shan Ren

2009-01-01

155

Antisense-mediated inhibition of the bcl-2 gene induces apoptosis in human malignant glioma  

Microsoft Academic Search

BACKGROUNDThe bcl-2 protooncogene represses a number of cellular apoptotic pathways and is known to be expressed in increasing amounts in glial tumors of higher malignancy. We tested whether antisense oligonucleotides to the bcl-2 gene would affect glioma cell viability.METHODSAntisense oligonucleotides directed to the first six codons of the human bcl-2 gene, and nonsense oligonucleotides as a control, were transfected into

Terrence Julien; Bruce Frankel; Sharon Longo; Michele Kyle; Sandra Gibson; Edward Shillitoe; Timothy Ryken

2000-01-01

156

CARBON NANOTUBES INDUCE MALIGNANT TRANSFORMATION AND TUMORIGENESIS OF HUMAN LUNG EPITHELIAL CELLS  

PubMed Central

Carcinogenicity of carbon nanotubes is a major concern but has not been well addressed due to the lack of experimental models. Here, we show that chronic exposure to single-walled carbon nanotubes causes malignant transformation of human lung epithelial cells. The transformed cells induce tumorigenesis in mice and exhibit an apoptosis resistant phenotype characteristic of cancer cells. This study provides new evidence for carbon nanotube-induced carcinogenesis and indicates the potential role of p53 in the process.

Wang, Liying; Luanpitpong, Sudjit; Castranova, Vincent; Tse, William; Lu, Yongju; Pongrakhananon, Varisa; Rojanasakul, Yon

2011-01-01

157

Human Placental Alkaline Phosphatase in Benign and Malignant Ovarian Neoplasia1  

Microsoft Academic Search

In benign and malignant ovarian tumor patients, human pla- cental alkaline phosphatase (HPLAP) was determined in serum and extracts from surgical tumor biopsies using a highly specific enzyme-antigen immunoassay based on a mouse monoclonal antibody (E6) to HPLAP. Serum HPLAP levels ^0.1 unit\\/liter were found in 58% of ovarian cancer patients. Serum carcinoem- bryonic antigen levels were positive (>5.4 ng\\/ml)

Etienne J. Nouwen; Dirk E. Rollet; Jacques B. Schelstraete; Marlene W. Eerdekens; Christian Mansch; Van de Voorde; Marc E. De Broe

158

Pathology of human malignant mesothelioma--preliminary analysis of 1,517 mesothelioma cases.  

PubMed

The author reviewed 1,517 human malignant mesothelioma cases from 1975 through August 2000. These mesothelioma cases were definite or probable in diagnostic certainty. Sources of these cases varied including asbestos insulation workers, UNARCO workers, Cancer and Leukemia B mesothelioma panel cases and random cases. Pathology materials consisted of autopsy, biopsy and rare cytology specimens. 92.3% of these patients were male, and 85.8% were between 50 and 79 years in age. The major primary site of the tumor was the pleura (73.1%). However, in a group of the asbestos insulation workers, the peritoneum was the more common primary site of malignant mesothelioma, compared to the pleura. Histologically, epithelial cell type was the majority (61.1%), followed by biphasic (22.1%) and fibrosarcomatous (16.4%). A double primary tumor (malignant mesothelioma associated with other cancer) was present in 32 of the 1,517 cases. These 32 cancers included lung cancers, renal cell carcinomas, colorectal cancers, pancreatic cancers and a cancer of the larynx, which are known to be at higher risk among asbestos insulation workers. The latency period of the vast majority (98.1%) of these mesothelioma cases were longer than 20 years. It is well accepted that cigarette smoking does not contribute to the induction of malignant mesothelioma. Indeed, the present study confirmed that 19.9% of these mesothelioma patients had never smoked cigarettes. PMID:11341549

Suzuki, Y

2001-04-01

159

Voltage-dependent calcium release in human malignant hyperthermia muscle fibers.  

PubMed Central

Malignant hyperthermia (MH) results from a defect of calcium release control in skeletal muscle that is often caused by point mutations in the ryanodine receptor gene (RYR1). In malignant hyperthermia-susceptible (MHS) muscle, calcium release responds more sensitively to drugs such as halothane and caffeine. In addition, experiments on the porcine homolog of malignant hyperthermia (mutation Arg615Cys in RYR1) indicated a higher sensitivity to membrane depolarization. Here, we investigated depolarization-dependent calcium release under voltage clamp conditions in human MHS muscle. Segments of muscle fibers dissected from biopsies of the vastus lateralis muscle of MHN (malignant hyperthermia negative) and MHS subjects were voltage-clamped in a double vaseline gap system. Free calcium was determined with the fluorescent indicator fura-2 and converted to an estimate of the rate of SR calcium release. Both MHN and MHS fibers showed an initial peak of the release rate, a subsequent decline, and rapid turn-off after repolarization. Neither the kinetics nor the voltage dependence of calcium release showed significant deviations from controls, but the average maximal peak rate of release was about threefold larger in MHS fibers.

Struk, A; Lehmann-Horn, F; Melzer, W

1998-01-01

160

Co-inhibition of epidermal growth factor receptor and insulin-like growth factor receptor 1 enhances radiosensitivity in human breast cancer cells  

PubMed Central

Background Over-expression of epidermal growth factor receptor (EGFR) or insulin-like growth factor-1 receptor (IGF-1R) have been shown to closely correlate with radioresistance of breast cancer cells. This study aimed to investigate the impact of co-inhibition of EGFR and IGF-1R on the radiosensitivity of two breast cancer cells with different profiles of EGFR and IGF-1R expression. Methods The MCF-7 (EGFR +/?, IGF-1R +++) and MDA-MB-468 (EGFR +++, IGF-1R +++) breast cancer cell lines were used. Radiosensitizing effects were determined by colony formation assay. Apoptosis and cell cycle distribution were measured by flow cytometry. Phospho-Akt and phospho-Erk1/2 were quantified by western blot. In vivo studies were conducted using MDA-MB-468 cells xenografted in nu/nu mice. Results In MDA-MB-468 cells, the inhibition of IGF-1R upregulated the p-EGFR expression. Either EGFR (AG1478) or IGF-1R inhibitor (AG1024) radiosensitized MDA-MB-468 cells. In MCF-7 cells, radiosensitivity was enhanced by AG1024, but not by AG1478. Synergistical radiosensitizing effect was observed by co-inhibition of EGFR and IGF-1R only in MDA-MB-468 cells with a DMF10% of 1.90. The co-inhibition plus irradiation significantly induced more apoptosis and arrested the cells at G0/G1 phase in MDA-MB-468 cells. Only co-inhibition of EGFR and IGF-1R synergistically diminished the expression of p-Akt and p-Erk1/2 in MDA-MB-468 cells. In vivo studies further verified the radiosensitizing effects by co-inhibition of both pathways in a MDA-MB-468 xenograft model. Conclusion Our data suggested that co-inhibition of EGFR and IGF-1R synergistically radiosensitized breast cancer cells with both EGFR and IGF-1R high expression. The approach may have an important therapeutic implication in the treatment of breast cancer patients with high expression of EGFR and IGF-1R.

2013-01-01

161

Critical analysis of the potential for targeting STAT3 in human malignancy  

PubMed Central

The signal transducer and activator of transcription (STAT) family of proteins was originally discovered in the context of normal cell biology where they function to transduce intracellular and extracellular signals to the nucleus, ultimately leading to transcription of specific target genes and downstream phenotypic effects. It was quickly appreciated that the STATs, especially STAT3, play a fundamental role in human malignancy. In contrast to normal biology in which transient STAT3 signaling is strictly regulated by a tightly coordinated network of activators and deactivators, STAT3 is constitutively activated in human malignancies. Constitutive STAT3 signaling has been associated with many cancerous phenotypes across nearly all human cancers, including the upregulation of cell growth, proliferation, survival, and motility, among others. Studies involving candidate preclinical STAT3 inhibitors have further demonstrated that the reversal of these phenotypes results from pharmacologic or genetic inhibition of STAT3, suggesting that STAT3 may be a promising target for clinical interventions. Indeed, a Phase 0 clinical trial involving a STAT3 decoy oligonucleotide demonstrated that STAT3 is a drug-gable target in human tumors. Because of the ubiquity of overactive STAT3 in cancer, its role in promoting a wide variety of cancerous phenotypes, and the strong clinical and preclinical studies performed to date, STAT3 represents a promising target for the development of inhibitors for the treatment of human cancers.

Peyser, Noah D; Grandis, Jennifer R

2013-01-01

162

Sequence Homology between the RNA of Mason-Pfizer Monkey Virus and the RNA of Human Malignant Breast Tumors  

Microsoft Academic Search

Radioactive DNA ([3H]cDNA) complementary to the RNA of Mason-Pfizer monkey virus was used in molecular hybridization experiments to demonstrate sequence homology between its viral RNA and RNA of human malignant breast tumors. Hybridization products were analyzed by cesium sulfate equilibrium density centrifugation and hydroxylapatite chromatography. Seven of ten human malignant breast tumors tested contained virus-related RNA when assayed by hydroxylapatite

David Colcher; S. Spiegelman; Jeffrey Schlom

1974-01-01

163

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

164

Bone morphogenetic protein 6 in skeletal metastases from prostate cancer and other common human malignancies.  

PubMed Central

Prostatic adenocarcinoma commonly metastasizes to bone. Unlike most other bony secondaries, the majority of skeletal prostatic metastases are osteoblastic rather than osteolytic in nature. Several growth factors which are known to stimulate bone formation are expressed in benign and malignant prostate cells, but none has been specifically linked to osteosclerotic metastases. Bone morphogenetic proteins (BMPs) induce ectopic bone formation in vivo. We have reported previously that BMP-6 mRNA and protein are expressed in the majority of primary prostatic carcinomas with established skeletal metastases but rarely in clinically organ-confined tumours. This study examines the expression of BMP-6 mRNA in matched prostatic primary and secondary bony lesions and in isolated skeletal metastases from prostatic adenocarcinomas, as well as other common human malignancies, by in situ hybridization. BMP-6 mRNA was detected in 11 out of 13 bone metastases from prostate carcinoma and in three paired samples of primary prostate carcinoma and matching skeletal metastasis. Weak signals for BMP-6 were also present in 5 out of 17 skeletal deposits from non-prostatic malignancies. BMP-6 mRNA appears to be strongly expressed in prostatic adenocarcinomas, both in the primary tumour and in bone metastases. It is also expressed, though less frequently, in skeletal metastases from other human carcinomas. Our findings suggest that BMP-6 may hold potential as an attractive marker and possible mediator of skeletal metastases, particularly in prostate carcinoma. Images Figure 1

Autzen, P.; Robson, C. N.; Bjartell, A.; Malcolm, A. J.; Johnson, M. I.; Neal, D. E.; Hamdy, F. C.

1998-01-01

165

Differentiation of Human T Lymphocytes: II. Phenotypic Difference in Skin and Blood Malignant T-Cells in Cutaneous T-Cell Lymphoma  

Microsoft Academic Search

The cell surface antigen phenotype of circulating and skin malignant T-cells in patients with cutaneous T-cell lymphoma were studied. The mature T-cell antigen phenotype of the malignant T-cells was identical for circulating and skin malignant T-cells. In contrast, skin malignant T-cells expressed the immature human T-cell antigen Thy-1, surface membrane transferrin receptors, and Ia-like determinants while circulating malignant T- cells

Barton F. Haynes; Lucinda L. Hensley; Brian V. Jegasothy

1982-01-01

166

Estrogen metabolism and the malignant potential of human papillomavirus immortalized keratinocytes.  

PubMed

Increased 16alpha-hydroxylation of estradiol has been shown to be associated with heightened cancer risk in estrogen responsive tissue. Certain types of human papillomavirus (HPV) are cofactors for cancer in the cervix, an estrogen sensitive tissue. We have demonstrated that estradiol and 16alpha-hydroxyestrone increased the number of cells positive for proliferating cell nuclear antigen in HPV immortalized keratinocytes, the in vitro correlate of the premalignant keratinocyte. These estrogens caused the abnormal proliferation and anchorage independent growth, which correlates with malignant conversion. Indole-3-carbinol, a phytochemical in cruciferous vegetables known to preferentially induce 2-hydroxylation with minimal effect on 16alpha-hydroxylation, markedly blocked the ability of estradiol to increase anchorage independent growth. The results indicate that 16alpha-hydroxyestrone increases the malignant phenotype of HPV immortalized keratinocytes. However, indole-3-carbinol will block this response. PMID:9492342

Newfield, L; Bradlow, H L; Sepkovic, D W; Auborn, K

1998-03-01

167

Radiosensitization of human cervical cancer cells by inhibiting ribonucleotide reductase: Enhanced radiation response at low-dose-rates  

PubMed Central

Purpose To test whether pharmacologic inhibition of ribonucleotide reductase (RNR) by 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) enhances radiation sensitivity during low-dose-rate ionizing radiation provided by a novel purpose-built iridium-192 cell irradiator. Methods and Materials Cells were exposed to low (11, 23, 37, 67 cGy/hour) dose-rate radiation using a custom-fabricated cell irradiator or to high (330 cGy/min) dose-rate radiation using a conventional cell irradiator. Radiation sensitivity of human cervical (CaSki, C33-a) cancer cells with or without RNR inhibition by 3-AP was evaluated by clonogenic survival and RNR activity assay. Alteration in cell cycle distribution was monitored by flow cytometry. Results Increasing radiation sensitivity of both CaSki and C33-a cells was observed with incremental rise in radiation dose-rates. 3-AP treatment led to enhanced radiation sensitivity in both cell lines, eliminating differences in cell cytotoxicity due to radiation dose rate. RNR blockade by 3-AP during low-dose-rate irradiation was associated with low RNR activity and an extended G1-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.; Colussi, Valdir C.; Pink, John; Radivoyevitch, Tomas; Oleinick, Nancy L.

2011-01-01

168

Human papilloma virus (HPV) is rarely detected in malignant melanomas of sun sheltered mucosal membranes.  

PubMed

Human papillomavirus (HPV) has been associated with some types of human cancer. The aim of this study was to investigate if HPV could be associated with human primary malignant melanoma in non sun-exposed body areas like mucous membranes. Through the Swedish National Cancer Registry, in compliance with the rules of the Human Ethical Committee, histopathological specimens were collected from different pathological laboratories throughout Sweden. The histopathological diagnosis was reviewed, and from 45 primary melanomas, tumour tissue was micro-dissected and analysed further. A protocol for detection of HPV DNA using general HPV primers GP5 + /GP6+ or CPI/IIG, which together identify 36 different HPV subtypes, was developed. This protocol could detect presence of HPV DNA in less than 10 ng of DNA of a control cell that contained 1-2 copies of HPV type 16/cell. Before HPV testing the melanoma samples were examined for amplifiable DNA by a beta-microglobulin PCR and 39 were positive. Thirty-five of these could be evaluated for HPV DNA and no samples were positive according to all five defined criteria for HPV positivity although two were positive according to 4/5 criteria. In conclusion, HPV is rarely detected in primary malignant melanomas of non-sun exposed body areas. PMID:16227159

Dahlgren, Liselotte; Schedvins, Kjell; Kanter-Lewensohn, Lena; Dalianis, Tina; Ragnarsson-Olding, Boel K

2005-01-01

169

Differential expression of two fibroblast growth factor-receptor genes is associated with malignant progression in human astrocytomas  

SciTech Connect

Malignant astrocytomas, which are highly invasive, vascular neoplasms, compose the majority of nervous system tumors in humans. Elevated expression of fibroblast growth factors (FGFs) in astrocytomas has implicated the FGF family of mitogens in the initiation and progression of astrocyte-derived tumors. In this study, the authors demonstrated that human astrocytomas undergo parallel changes in FGF-receptor (FGFR) expression during their progression from a benign to a malignant phenotype. FGFR type 2 (BEK) expression was abundant in normal white matter and in all low-grade astrocytomas but was not seen in malignant astrocytomas. Conversely, FGFR type 1 (FLG) expression was absent or barely detectable in normal white matter but was significantly elevated in malignant astrocytomas. Malignant astrocytomas also expressed an alternatively spliced form of FGFR-1 (FGFR-1[beta]) containing two immunoglobulin-like disulfide loops, whereas normal human adult and fetal brains expressed a receptor form (FGFR-1[alpha]) containing three immunoglobulin-like disulfide loops. Intermediate grades of astrocytic tumors exhibited a gradual loss of FGFR-2 and a shift in expression from FGFR-1[alpha] to FGFR-2 and a shift in expression from FGFR-1[alpha] to FGFR-1[beta] as they progressed from benign to malignant phenotype. These results suggest that differential expression and alternative splicing of FGFRs may be critical in the malignant progression of astrocytic tumors.

Yamaguchi, F.; Saya, H.; Bruner, J.M.; Morrison, R.S. (Univ. of Texas M.D. Anderson Cancer Center, Houston, TX (United States))

1994-01-18

170

ZnO nanoparticles induces cell death in malignant human T98G gliomas, KB and non-malignant HEK cells.  

PubMed

This paper reports the synthesis and characterization of ZnO nanoparticles prepared by soft chemical process. The nanoparticles of ZnO possess wurtzite hexagonal phase and were used for the induction of cell death in malignant human T98G gliomas, KB epithermoids and HEK normal non-malignant kidney cells. By applying ZnO nanoparticles, the cells exhibit that the nanoparticles are more efficacious on T98G cancer cells, moderately effective on KB cells and least toxic on normal human HEK cells. The results demonstrated that the treatment with ZnO nanoparticles sensitize T98G cells by increasing both the mitotic (linked to cytogenetic damage) and interphase (apoptosis) death. The ZnO nanoparticles behave as genotoxic drugs, since they induce a micronucleus formation in cells. The present study could be helpful in designing more potent anticancer agents for the therapeutic uses. PMID:23909132

Wahab, Rizwan; Kaushik, Nagendra Kumar; Kaushik, Neha; Choi, Eun Ha; Umar, Ahmad; Dwivedi, Sourabh; Musarrat, Javed; Al-Khedhairy, Abdulaziz A

2013-07-01

171

Integration of Principles of Systems Biology and Radiation Biology: Toward Development of in silico Models to Optimize IUdR-Mediated Radiosensitization of DNA Mismatch Repair Deficient (Damage Tolerant) Human Cancers  

PubMed Central

Over the last 7?years, we have focused our experimental and computational research efforts on improving our understanding of the biochemical, molecular, and cellular processing of iododeoxyuridine (IUdR) and ionizing radiation (IR) induced DNA base damage by DNA mismatch repair (MMR). These coordinated research efforts, sponsored by the National Cancer Institute Integrative Cancer Biology Program (ICBP), brought together system scientists with expertise in engineering, mathematics, and complex systems theory and translational cancer researchers with expertise in radiation biology. Our overall goal was to begin to develop computational models of IUdR- and/or IR-induced base damage processing by MMR that may provide new clinical strategies to optimize IUdR-mediated radiosensitization in MMR deficient (MMR?) “damage tolerant” human cancers. Using multiple scales of experimental testing, ranging from purified protein systems to in vitro (cellular) and to in vivo (human tumor xenografts in athymic mice) models, we have begun to integrate and interpolate these experimental data with hybrid stochastic biochemical models of MMR damage processing and probabilistic cell cycle regulation models through a systems biology approach. In this article, we highlight the results and current status of our integration of radiation biology approaches and computational modeling to enhance IUdR-mediated radiosensitization in MMR? damage tolerant cancers.

Kinsella, Timothy J.; Gurkan-Cavusoglu, Evren; Du, Weinan; Loparo, Kenneth A.

2011-01-01

172

Radio-sensitization of human leukaemic molt-4 cells by DNA-dependent protein kinase inhibitor, NU7026.  

PubMed

In this paper we describe the influence of NU7026, a specific inhibitor of DNA-dependent protein kinase, phosphoinositide 3-kinase, and ATM-kinase on molecular and cellular mechanisms triggered by ionising irradiation in human T-lymphocyte leukaemic MOLT-4 cells. We studied the effect of this inhibitor (10 1microM) combined with gamma-radiation (1 Gy) leading to DNA damage response and induction of apoptosis. We used methods for apoptosis assessment (cell viability count and flow-cytometric analysis) and cell cycle analysis (DNA content measurement) and we detected expression and post-translational modifications (Western blotting) of proteins involved in DNA repair signalling pathways. Pre-treatment with NU7026 resulted into decreased activation of checkpoint kinase-2 (Thr68), p53 (Ser15 and Ser392), and histone H2A.X (Ser139) 2 hours after irradiation. Subsequently, combination of radiation and inhibitor led to decreased amount of cells in G2-phase arrest and into increased apoptosis after 72 hours. Our results indicate that in leukaemic cells the pre-incubation with inhibitor NU7026 followed by low doses of ionising radiation results in radio-sensitising of MOLT-4 cells via diminished DNA repair and delayed but pronounced apoptosis. This novel approach might offer new strategies in combined treatment of leukaemia diseases. PMID:23101268

Tichý, Ales; Novotná, Eva; Durisová, Kamila; Salovská, Barbora; Sedlaríková, Radka; Pejchal, Jaroslav; Zárybnická, Lenka; Vávrová, Jirina; Sinkorová, Zuzana; Rezácová, Martina

2012-01-01

173

Alterations in oncogene expression and radiosensitivity in the most frequently used SV40-transformed human skin fibroblasts.  

PubMed

In comparison with primary cell cultures, SV40-transformed human skin fibroblasts, either from healthy donors or from patients suffering from ataxia-telangiectasia (AT) or xeroderma pigmentosum, are more resistant to the cytotoxic action of low LET 60cobalt gamma-rays as well as to high LET alpha-particles. Resistance factors calculated from D10's lie between 1.4 and 2.0. Northern blot analysis reveals spontaneous overexpression of the oncogenes c-myc, Ki-ras and c-raf and of the tumour suppressor gene p53 as a consequence of SV40 transformation. For c-myc, the increased expression is due to gene amplification and gene rearrangement. An even further increase in the expression of c-myc has been found for AT cells (AT5BI-VA) after moderate doses of 60cobalt gamma-irradiation. A possible correlation between SV40-induced changes in gene expression and cellular radioresistance is discussed. PMID:7912716

Lücke-Huhle, C

1994-06-01

174

TGF-? synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth  

PubMed Central

Malignant mesothelioma (MM) is an incurable malignancy that is caused by exposure to asbestos and is accompanied by severe fibrosis. Because MM is usually diagnosed at an advanced stage and clinical identification of early lesions is difficult, its molecular pathogenesis has not been completely elucidated. Nearly 75% of MM cases have inactivating mutations in the NF2 (neurofibromatosis type 2; Merlin) gene or in downstream signaling molecules of the Hippo signaling cascade, which negatively regulates the transcription factor Yes-associated protein (YAP). In this study, we demonstrate a functional interaction between the Hippo and TGF-? pathways in regulating connective tissue growth factor (CTGF). Expression of CTGF in MM cells was induced by the formation of a YAP–TEAD4–Smad3–p300 complex on the CTGF promoter. Knocking down CTGF expression in MM cells prolonged the survival of xenografted mice, and a significant association was seen between CTGF expression and extracellular matrix deposition in MM xenografts and in patient tissue specimens. We further suggest that CTGF may influence the malignancy of mesothelioma because of the different histological expression patterns observed in human MM tissues. These data suggest that CTGF is an important modulator of MM growth and pathology and represents a novel therapeutic target for this disease.

Toyoda, Takeshi; Nakanishi, Hayao; Yatabe, Yasushi; Sato, Ayuko; Matsudaira, Yasue; Ito, Hidemi; Murakami, Hideki; Kondo, Yutaka; Kondo, Eisaku; Hida, Toyoaki; Tsujimura, Tohru; Osada, Hirotaka

2012-01-01

175

Elevated expression of notch1 is associated with metastasis of human malignancies.  

PubMed

The expression level of Notch1 has been studied in many primary tumor types, but has not been widely investigated in metastatic lesions from human malignancies. Using immunohistochemistry (IHC), the expression level of Notch1 was evaluated and compared between primary and metastatic tumors in 12 different cancers. The mean IHC score of Notch1 was significantly increased in metastatic hepatocellular carcinoma (HCC; 5.4 ± 0.7) and in metastatic renal cell carcinoma (RCC; 5.0 ± 2.3) compared with primary HCC (3.1 ± 0.7, P = .035) and RCC (1.3 ± 0.6, P = .049), respectively. Similarly, the expression level of Notch1 showed an increasing trend in the metastatic malignancies in the larynx, prostate, and stomach compared with corresponding primary malignancies (P values are .055, .072, and .074, respectively). The results demonstrate elevated expression of Notch1 in some metastatic tumors, suggesting that Notch1 may play an important role in the development or maintenance of metastatic lesions, and targeting of Notch1 might be a therapeutic approach against tumor metastasis. PMID:23883974

Zhu, He; Zhou, Xinchun; Redfield, Samantha; He, Zhi; Lewin, Jack; Miele, Lucio

2013-07-24

176

Enhancement of malignant properties of human osteosarcoma cells with disialyl gangliosides GD2/GD3.  

PubMed

The expression and implications of gangliosides in human osteosarcomas have not been systematically analyzed. In this study, we showed that gangliosides GD3 and GD2 are highly expressed in the majority of human osteosarcoma cell lines derived from oral cavity regions. Introduction of GD3 synthase cDNA into a GD3/GD2-negative (GD3/GD2-) human osteosarcoma subline resulted in the establishment of GD3/GD2+ transfectant cells. They showed increased cell migration and invasion activities in wound healing and Boyden chamber invasion assays, respectively, compared to the control cells. When treated with serum, GD3/GD2+ cells showed stronger tyrosine phosphorylation of p130Cas, focal adhesion kinase, and paxillin than GD3/GD2- cells. In particular, paxillin underwent much stronger phosphorylation, suggesting its role in cell motility. Furthermore, we tried to dissect the roles of GD3 and GD2 in the malignant properties of the transfectant cells by establishing single ganglioside-expressing cells, that is, either GD3 or GD2. Although GD3/GD2+ cells showed the most malignant properties, GD2+ cells showed almost equivalent levels to GD3/GD2+ cells in invasion and migration activities, and in the intensities of tyrosine phosphorylation of paxillin. Among Src family kinases, Lyn was expressed predominantly, and was involved in the invasion and motility of GD3- and/or GD2-expressing transfectants. Furthermore, it was elucidated by gene silencing that Lyn was located in a different pathway from that of FAK to eventually lead paxillin activation. These results suggested that GD2/GD3 are responsible for the enhancement of the malignant features of osteosarcomas, and might be candidate targets in molecular-targeted therapy. PMID:22632091

Shibuya, Hidenobu; Hamamura, Kazunori; Hotta, Hiroshi; Matsumoto, Yasuyuki; Nishida, Yoshihiro; Hattori, Hisashi; Furukawa, Keiko; Ueda, Minoru; Furukawa, Koichi

2012-07-16

177

Synergistic effect of combined treatment with gamma-tocotrienol and statin on human malignant mesothelioma cells.  

PubMed

The present study is the first to demonstrate the synergetic effect of statins (atorvastatin and simvastatin) and gamma-tocotrienol (?-T3) on human malignant mesothelioma (MM). Statin+?-T3 combinations induced greater cell growth inhibition more than each single treatment via inhibition of mevalonate pathway, a well-known target of both ?-T3 and statins. ?-T3 was necessary for endoplasmic reticulum stress markers CHOP and GRP78, whereas an intrinsic apoptotic marker, caspase 3 activation was induced only in the presence of statins. Overall, the combination of ?-T3 and statins could be useful for MM therapy and functions in a complementary style. PMID:23879968

Tuerdi, Guligena; Ichinomiya, Saki; Sato, Hiromi; Siddig, Sana; Suwa, Eriko; Iwata, Hiroki; Yano, Tomohiro; Ueno, Koichi

2013-07-20

178

Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations.  

PubMed

We used CDK4/hTERT-immortalized normal human bronchial epithelial cells (HBEC) from several individuals to study lung cancer pathogenesis by introducing combinations of common lung cancer oncogenic changes (p53, KRAS, and MYC) and followed the stepwise transformation of HBECs to full malignancy. This model showed that: (i) the combination of five genetic alterations (CDK4, hTERT, sh-p53, KRAS(V12), and c-MYC) is sufficient for full tumorigenic conversion of HBECs; (ii) genetically identical clones of transformed HBECs exhibit pronounced differences in tumor growth, histology, and differentiation; (iii) HBECs from different individuals vary in their sensitivity to transformation by these oncogenic manipulations; (iv) high levels of KRAS(V12) are required for full malignant transformation of HBECs, however, prior loss of p53 function is required to prevent oncogene-induced senescence; (v) overexpression of c-MYC greatly enhances malignancy but only in the context of sh-p53+KRAS(V12); (vi) growth of parental HBECs in serum-containing medium induces differentiation, whereas 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); (vii) oncogenic transformation of HBECs leads to increased sensitivity to standard chemotherapy doublets; (viii) an mRNA signature derived by comparing tumorigenic versus nontumorigenic clones was predictive of outcome in patients with lung cancer. Collectively, our findings show that 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, John Michael; Gao, Boning; Xie, Yang; Wistuba, Ignacio I; Gazdar, Adi F; Shay, Jerry W; Minna, John D

2013-02-28

179

Differential Expression of Two Fibroblast Growth Factor-Receptor Genes is Associated with Malignant Progression in Human Astrocytomas  

Microsoft Academic Search

Malignant astrocytomas, which are highly invasive, vascular neoplasms, compose the majority of nervous system tumors in humans. Elevated expression of fibroblast growth factors (FGFs) in astrocytomas has implicated the FGF family of mitogens in the initiation and progression of astrocyte-derived tumors. In this study, we demonstrated that human astrocytomas undergo parallel changes in FGF-receptor (FGFR) expression during their progression from

Fumio Yamaguchi; Hideyuki Saya; Janet M. Bruner; Richard S. Morrison

1994-01-01

180

Anticonvulsant drugs fail to modulate chemotherapy-induced cytotoxicity and growth inhibition of human malignant glioma cells  

Microsoft Academic Search

Adjuvant chemotherapy after cytoreductive surgery and irradiation plays an increasingly important role in the management of human malignant glioma. Here we have examined the effect of three anticonvulsants most commonly administered to glioma patients, carbamazepine, phenytoin and valproic acid, on the cytotoxic and antiproliferative actions in vitro of several cancer chemotherapy drugs currently evaluated for human gliomas. We find that

Marko Ständer; Johannes Dichgans; Michael Weller

1998-01-01

181

BAX frameshift mutations in cell lines derived from human haemopoietic malignancies are associated with resistance to apoptosis and microsatellite instability  

Microsoft Academic Search

Bax suppresses tumorigenesis in a mouse model system and Bax-deficient mice exhibit lymphoid hyperplasia suggesting that BAX functions as a tumour suppressor in human haemopoietic cells. We examined BAX expression in 20 cell lines derived from human haemopoietic malignancies and consistent with a potential tumour suppressor function, identified two cell lines, DG75 (a Burkitt lymphoma cell line) and Jurkat (a

Matthew Brimmell; Rezzeline Mendiola; Jonathan Mangion; Graham Packham

1998-01-01

182

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

Microsoft Academic Search

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:

Ramón García-Escudero; Ana B Martínez-Cruz; Mirentxu Santos; Corina Lorz; Carmen Segrelles; Guillermo Garaulet; Cristina Saiz-Ladera; Clotilde Costa; Águeda Buitrago-Pérez; Marta Dueñas; Jesús M Paramio

2010-01-01

183

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

184

The IL-12R?2 gene functions as a tumor suppressor in human B cell malignancies  

PubMed Central

The IL-12R?2 gene is expressed in human mature B cell subsets but not in transformed B cell lines. Silencing of this gene may be advantageous to neoplastic B cells. Our objective was to investigate the mechanism(s) and the functional consequence(s) of IL-12R?2 gene silencing in primary B cell tumors and transformed B cell lines. Purified tumor cells from 41 patients with different chronic B cell lymphoproliferative disorders, representing the counterparts of the major mature human B cell subsets, tested negative for IL-12R?2 gene expression. Hypermethylation of a CpG island in the noncoding exon 1 was associated with silencing of this gene in malignant B cells. Treatment with the DNA methyltransferase inhibitor 5-Aza-2?-deoxycytidine restored IL-12R?2 mRNA expression in primary neoplastic B cells that underwent apoptosis following exposure to human recombinant IL-12 (hrIL-12). hrIL-12 inhibited proliferation and increased the apoptotic rate of IL-12R?2–transfected B cell lines in vitro. Finally, hrIL-12 strongly reduced the tumorigenicity of IL-12R?2–transfected Burkitt lymphoma RAJI cells in SCID-NOD mice through antiproliferative and proapoptotic effects, coupled with neoangiogenesis inhibition related to human IFN-?–independent induction of hMig/CXCL9. The IL-12R?2 gene acts as tumor suppressor in chronic B cell malignancies, and IL-12 exerts direct antitumor effects on IL-12R?2–expressing neoplastic B cells.

Airoldi, Irma; Di Carlo, Emma; Banelli, Barbara; Moserle, Lidia; Cocco, Claudia; Pezzolo, Annalisa; Sorrentino, Carlo; Rossi, Edoardo; Romani, Massimo; Amadori, Alberto; Pistoia, Vito

2004-01-01

185

Characterization of phosphodiesterase 2A in human malignant melanoma PMP cells.  

PubMed

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

2013-01-31

186

Bromodeoxyuridine-mediated radiosensitization in hum glioma: The effect of concentration, duration, and fluoropyrimidine modulation  

SciTech Connect

To define the relative influence of duration of exposure, concentration, and modulation by fluorodeoxyuridines (FdUrd) on the incorporation of 5-bromo-2-deoxyuridine (BrdUrd) into DNA of human malignant glioma line (D-54) in vitro and in vivo. In vitro studies: an established human malignant glioma line (D-54)was exposed to a clinically achievable concentration of BrdUrd to model intravenous (1 {mu}M BrdUrd) and intraarterial (4 {mu}MBrdUrd) conditions. The influence of modulation was assessed using 1 nM FdUrd. Incorporation of BrdUrd, radiosensitization, and cytotoxicity were determined after 24, 72, and 120 h drug exposures. In Vivo studies: nude mice bearing D-54 xenografts were infused with BrdUrd at 100 mg/kg/day for 7 and 14 days or BrdUrd at 400 mg/kg/day for 5 days. The influence of modulation was assessed by combining 100 mg/kg/day of BrdUrd with 0.1, 0.3 and 1 mg/kg/day FdUrd for 7 days. Incorporation of BrddUrd into the DNA of tumor, gut, and marrow were determined. In Vitro: thymidine replacement and radiosensitization were a function of concentration, and incorporation began to plateau after 2 to 3 population doublings. Modulation with 1 nM FdUrd significantly increased incorporation. Radiosensitization was a linear function of thymidine replacement under all conditions tested. In Vivo: infusion with 400 mg/kg/day for 5 days resulted in greater tumor incorporation (10.3 {plus_minus} 0.4% thymidine replaced) than treatment with 100 mg/kg/day for 14 days (6.0 {plus_minus} 0.6% of thymidine replaced) than treatment with 100 mg/kg/day for 14 days for 14 days (6.0 {plus_minus} 0.6% of thymidine replaced). Infusion of FdUrd with BrdUrd increased normal tissue incorporation of BrdUrd, but failed to increase BrdUrd incorporation in tumor cells. These results suggest that relatively short, high dose rate infusions may be preferable to long, low dose rate infusions. 33 refs., 5 figs., 2 tabs.

McLaughlin, P.W.; Lawrence, T.S.; Seabury, H. [Univ. of Michigan Medical Center, Ann Arbor, MI (United States)] [and others

1994-10-15

187

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.

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

2012-01-01

188

Expression of metalloprotease insulin-degrading enzyme (insulysin) in normal and malignant human tissues  

PubMed Central

Background Insulin-degrading enzyme (IDE, insulysin, insulinase; EC 3.4.22.11), a thiol metalloendopeptidase, is involved in intracellular degradation of insulin, thereby inhibiting its translocation and accumulation to the nucleus. Recently, protein expression of IDE has been demonstrated in the epithelial ducts of normal breast and in breast cancer tissue (Radulescu et al., Int J Oncol 30:73; 2007). Materials and Methods Utilizing four different antibodies generated against different epitopes of the IDE molecule, we performed western blot analysis and immunohistochemical staining on several normal human tissues, on a plethora of tumor cell lines of different tissue origin, and on malignant breast and ovarian tissue. Results Applying the four IDE-directed antibodies, we demonstrate IDE expression at the protein level, both by means of immunoblotting and immunocytochemistry, in all of the tumor cell lines analyzed. Besides, IDE protein expression was found in normal tissues of the kidney, liver, lung, brain, breast and skeletal muscle, as well as in breast and ovarian cancer tissues. Immunohistochemical visualization of IDE indicated cytoplasmic localization of IDE in all of the cell lines and tissues assessed. Conclusions We performed for the first time a wide-ranging survey on IDE protein expression in normal and malignant tissues and cells and thus extend knowledge about cellular and tissue distribution of IDE, an enzyme which so far has mainly been studied in connection with Alzheimer’s disease and diabetes but not in cancer.

Yfanti, Christina; Mengele, Karin; Gkazepis, Apostolos; Weirich, Gregor; Giersig, Cecylia; Kuo, Wen-Liang; Tang, Wei-Jen; Rosner, Marsha; Schmitt, Manfred

2013-01-01

189

Comparison of metabolites in skeletal muscle biopsies from normal humans and those susceptible to malignant hyperthermia.  

PubMed

In earlier work on malignant hyperthermia (MH) susceptible pigs the concentration of muscle metabolites differed from that found in normal control pigs. Therefore, in the present study these metabolites were measured in human muscle biopsies to find out whether normal individuals could be discriminated from MH-susceptible persons. Analysis of skeletal muscle metabolites was performed on skeletal muscle obtained from humans (n = 68) being screened to exclude or confirm susceptibility to MH. Three groups were identified based on the reaction pattern of a skeletal muscle sample exposed in vitro to caffeine or halothane 1% plus caffeine: 1) MH susceptible (MHS; n = 19); 2) normal humans, (controls; n = 31); and 3) intermediate-reaction type (K-type:n = 18). No significant differences were found in metabolite levels of phosphocreatine (normal, MHS, and K-type: 13.20 vs. 13.74 vs. 14.42 nmol/mg wet weight, respectively), creatine (16.30 vs. 16.94 vs. 15.06 nmol/mg wet weight, respectively), adenosine triphospate (3.75 vs. 3.98 vs. 3.89 nmol/mg wet weight, respectively) and lactate (3.73 vs. 3.65 vs. 3.79 nmol/mg wet weight, respectively). It is concluded that analysis of skeletal muscle metabolites cannot be used as a screening test to confirm or exclude MH susceptibility in humans. PMID:3789437

Verburg, M P; Britt, B A; Oerlemans, F T; Scott, B; van Egmond, J; De Bruijn, C H

1986-12-01

190

Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse  

PubMed Central

Genomic studies in human acute lymphoblastic leukemia (ALL) have revealed clonal heterogeneity at diagnosis and clonal evolution at relapse. In this study, we used genome-wide profiling to compare human T cell ALL samples at the time of diagnosis and after engraftment (xenograft) into immunodeficient recipient mice. Compared with paired diagnosis samples, the xenograft leukemia often contained additional genomic lesions in established human oncogenes and/or tumor suppressor genes. Mimicking such genomic lesions by short hairpin RNA–mediated knockdown in diagnosis samples conferred a selective advantage in competitive engraftment experiments, demonstrating that additional lesions can be drivers of increased leukemia-initiating activity. In addition, the xenograft leukemias appeared to arise from minor subclones existing in the patient at diagnosis. Comparison of paired diagnosis and relapse samples showed that, with regard to genetic lesions, xenograft leukemias more frequently more closely resembled relapse samples than bulk diagnosis samples. Moreover, a cell cycle– and mitosis-associated gene expression signature was present in xenograft and relapse samples, and xenograft leukemia exhibited diminished sensitivity to drugs. Thus, the establishment of human leukemia in immunodeficient mice selects and expands a more aggressive malignancy, recapitulating the process of relapse in patients. These findings may contribute to the design of novel strategies to prevent or treat relapse.

Clappier, Emmanuelle; Gerby, Bastien; Sigaux, Francois; Delord, Marc; Touzri, Farah; Hernandez, Lucie; Ballerini, Paola; Baruchel, Andre

2011-01-01

191

Lin28 Enhances Tumorigenesis and is Associated With Advanced Human Malignancies  

PubMed Central

Multiple members of the let-7 family of miRNAs are often repressed in human cancers1,2, thereby promoting oncogenesis by de-repressing the targets K-Ras, c-Myc, and HMGA2 3,4. However, the mechanism by which let-7 miRNAs are coordinately repressed is unclear. The RNA-binding proteins Lin28 and Lin28B block let-7 precursors from being processed to mature miRNAs5–8, suggesting that over-expression of Lin28/Lin28B might promote malignancy via repression of let-7. Here we show that LIN28 and LIN28B are over-expressed in primary human tumors and human cancer cell lines (overall frequency ?15%), and that over-expression is linked to repression of let-7 family miRNAs and de-repression of let-7 targets. Lin28/Lin28B facilitate cellular transformation in vitro, and over-expression is associated with advanced disease across multiple tumor types. Our work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of LIN28/LIN28B with poor clinical prognosis.

Viswanathan, Srinivas R.; Powers, John T.; Einhorn, William; Hoshida, Yujin; Ng, Tony; Toffanin, Sara; O'Sullivan, Maureen; Lu, Jun; Philips, Letha A.; Lockhart, Victoria L.; Shah, Samar P.; Tanwar, Pradeep S.; Mermel, Craig H.; Beroukhim, Rameen; Azam, Mohammad; Teixeira, Jose; Meyerson, Matthew; Hughes, Timothy P.; Llovet, Josep M; Radich, Jerald; Mullighan, Charles G.; Golub, Todd R.; Sorensen, Poul H.; Daley, George Q.

2009-01-01

192

Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy.  

PubMed

Subunits of mammalian SWI/SNF (mSWI/SNF or BAF) complexes have recently been implicated as tumor suppressors in human malignancies. To understand the full extent of their involvement, we conducted a proteomic analysis of endogenous mSWI/SNF complexes, which identified several new dedicated, stable subunits not found in yeast SWI/SNF complexes, including BCL7A, BCL7B and BCL7C, BCL11A and BCL11B, BRD9 and SS18. Incorporating these new members, we determined mSWI/SNF subunit mutation frequency in exome and whole-genome sequencing studies of primary human tumors. Notably, mSWI/SNF subunits are mutated in 19.6% of all human tumors reported in 44 studies. Our analysis suggests that specific subunits protect against cancer in specific tissues. In addition, mutations affecting more than one subunit, defined here as compound heterozygosity, are prevalent in certain cancers. Our studies demonstrate that mSWI/SNF is the most frequently mutated chromatin-regulatory complex (CRC) in human cancer, exhibiting a broad mutation pattern, similar to that of TP53. Thus, proper functioning of polymorphic BAF complexes may constitute a major mechanism of tumor suppression. PMID:23644491

Kadoch, Cigall; Hargreaves, Diana C; Hodges, Courtney; Elias, Laura; Ho, Lena; Ranish, Jeff; Crabtree, Gerald R

2013-05-05

193

Effect of human cell malignancy on activity of DNA polymerase iota.  

PubMed

An increased level of mutagenesis, partially caused by imbalanced activities of error prone DNA polymerases, is a key symptom of cell malignancy. To clarify the possible role of incorrect DNA polymerase iota (Pol iota) function in increased frequency of mutations in mammalian cells, the activity of this enzyme in extracts of cells of different mouse organs and human eye (melanoma) and eyelid (basal-cell skin carcinoma) tumor cells was studied. Both Mg2+, considered as the main activator of the enzyme reaction of in vivo DNA replication, and Mn2+, that activates homogeneous Pol iota preparations in experiments in vitro more efficiently compared to all other bivalent cations, were used as cofactors of the DNA polymerase reaction in these experiments. In the presence of Mg2+, the enzyme was active only in cell extracts of mouse testicles and brain, whereas in the presence of Mn2+ the activity of Pol iota was found in all studied normal mouse organs. It was found that in cell extracts of both types of malignant tumors (basal-cell carcinoma and melanoma) Pol iota activity was observed in the presence of either Mn2+ or Mg2+. Manganese ions activated Pol iota in both cases, though to a different extent. In the presence of Mn2+ the Pol iota activity in the basal-cell carcinoma exceeded 2.5-fold that in control cells (benign tumors from the same eyelid region). In extracts of melanoma cells in the presence of either cation, the level of the enzyme activity was approximately equal to that in extracts of cells of surrounding tumor-free tissues as well as in eyes removed after traumas. The distinctive feature of tissue malignancy (in basal-cell carcinoma and in melanoma) was the change in DNA synthesis revealed as Mn2+-activated continuation of DNA synthesis after incorrect incorporation of dG opposite dT in the template by Pol iota. Among cell extracts of different normal mouse organs, only those of testicles exhibited a similar feature. This similarity can be explained by cell division blocking that occurs in all normal cells except in testicles and in malignant cells. PMID:20673215

Kazakov, A A; Grishina, E E; Tarantul, V Z; Gening, L V

2010-07-01

194

Photodynamic Therapy of Human Malignant Melanoma Xenografts in Athymic Nude Mice,  

National Technical Information Service (NTIS)

While photodynamic therapy (PDT) for cutaneous malignancies including dermal recurrences of breast cancer and basal cell carcinomas has shown great promise, PDT of malignant melanoma has remained incompletely understood. A comparison study of the effects ...

J. S. Nelson J. L. McCullough M. W. Berns

1981-01-01

195

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

196

Understanding the role of NRF2-regulated miRNAs in human malignancies  

PubMed Central

Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a key transcription factor that regulates the expression of over a hundred cytoprotective and antioxidant genes that provide cellular protection from reactive oxygen species. Chemotherapy resistance in several cancers has been linked to dysregulation of the NRF2 signalling pathway, moreover there is growing evidence that NRF2 may contribute to tumorigenesis. MicroRNA (miRNA) are small non-coding RNA sequences that post-transcriptionally regulate mRNA sequences. In cancer pathogenesis, aberrantly expressed miRNAs can act as either tumor suppressor or oncogenic miRNA. Recent evidence has been described that identifies a number of miRNA that can be regulated by NRF2. This review outlines the importance of NRF2 in regulating miRNA, and the functional role this may have in the tumorigenesis of human malignancies and their chemotherapy resistance.

Shah, Niraj M; Rushworth, Stuart A; Murray, Megan Y; Bowles, Kristian M; MacEwan, David J

2013-01-01

197

Cyclin D1 and Cyclin E expression in malignant thyroid cells and in human thyroid carcinomas.  

PubMed

Evidence of the involvement of cyclin gene alterations in human cancer is growing. In this study, we sought to determine the pattern of expression of cyclin D1 and cyclin E in normal and malignant thyroid cells. Quiescent rat thyroid cells in culture, induced to synthesize DNA by thyrotropin (TSH), expressed cyclin D1 gene after 6 hr and cyclin E gene with a peak at 18 hr from the stimulus; K-ras-transformed rat thyroid cells, which grew without addition of hormones necessary for normal cell proliferation, expressed elevated levels of cyclin D1 and cyclin E, compared with normal differentiated thyroid cells. Human benign and malignant thyroid tumors and their relative normal tissues were then analyzed. Neither major genetic alterations nor amplifications for cyclin D1 and cyclin E genes were found by Southern blot analysis in genomic DNAs extracted from all types of thyroid tumors. Moreover, statistical analyses of densitometric values from Northern blots did not show increased levels of cyclin D1 and E mRNAs in the tumor samples, compared with normal thyroid. Immunohistochemical analyses of formalin-fixed paraffin-embedded sections of tissues with specific antibodies revealed a prevalent cytoplasmic cyclin E staining in the thyroid tissues analyzed. Cyclin D1, instead, was present in the cytoplasm of normal thyroids and adenomas, but in 31% of thyroid papillary carcinomas analysed, it was overexpressed, with a localization in the nucleus. Our in vivo observations suggest that unlike cyclin E, elevated nuclear cyclin D1 expression defines a subset of thyroid papillary carcinomas, and might be a contributory factor to thyroid tumorigenesis. PMID:9626345

Lazzereschi, D; Sambuco, L; Carnovale Scalzo, C; Ranieri, A; Mincione, G; Nardi, F; Colletta, G

1998-06-10

198

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.

2010-01-01

199

Investigation of ovarian neoplasia of low malignant potential for human papillomavirus.  

PubMed

Recent in situ hybridization studies have suggested the presence of human papillomavirus type 6 (HPV-6) DNA in ovarian cancer cells. An association between HPV and ovarian neoplasia of low malignant potential (LMP) has not been previously identified. Paraffin-embedded tissue blocks from 24 patients with LMP ovarian tumors were screened for human papillomavirus DNA. The patients ranged in age from 18 to 73 years. Corresponding microscopic slides from each tissue block were reviewed to confirm the histopathologic diagnosis. For identification of HPV genome, deparaffinized sections were subjected to the polymerase chain reaction to achieve amplification of DNAs of HPV types 6, 11, 16, and 18. For each HPV type, a 120-base-pair region of the E6 gene was targeted for amplification. Human papillomaviral DNA was not detected in the tissue specimens subjected to polymerase chain reaction. These results suggest that HPV types 6, 11, 16, and 18 are not likely to play a role in LMP ovarian tumors. These results do not totally exclude possible contributions of other HPV types. PMID:2172118

McLellan, R; Buscema, J; Guerrero, E; Shah, K V; Woodruff, J D; Currie, J L

1990-09-01

200

Two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy  

PubMed Central

Human malignant melanoma has poor prognosis because of resistance to apoptosis and therapy. We describe identification of the expression profile of 1,037 mitochondria-focused genes and 84 survival-apoptosis genes in 21 malignant melanoma cell lines and 3 normal melanocyte controls using recently developed hMitChip3 cDNA micro-arrays. Unsupervised hierarchical clustering analysis of 1,037 informative genes, and 84 survival-apoptosis genes, classified these malignant melanoma cell lines into type A (n = 12) and type B (n = 9). Three hundred fifty-five of 1,037 (34.2%) genes displayed significant (P ? 0.030; false discovery rate ? 3.68%) differences (±?2.0-fold) in average expression, with 197 genes higher and 158 genes lower in type A than in type B. Of 84 genes with known survival-apoptosis functions, 38 (45.2%) displayed the significant (P < 0.001; false discovery rate < 0.15%) difference. Antiapoptotic (BCL2, BCL2A1, PPARD, and RAF1), antioxidant (MT3, PRDX5, PRDX3, GPX4, GLRX2, and GSR), and proapoptotic (BAD, BNIP1, APAF1, BNIP3L, CASP7, CYCS, CASP1, and VDAC1) genes expressed at higher levels in type A than in type B, whereas the different set of antiapoptotic (PSEN1, PPP2CA, API5, PPP2R1B, PPP2R1A, and FIS1), antioxidant (HSPD1, GSS, SOD1, ATOX1, and CAT), and proapoptotic (ENDOG, BAK1, CASP2, CASP4, PDCD5, HTRA2, SEPT4, TNFSF10, and PRODH) genes expressed at lower levels in type A than in type B. Microarray data were validated by quantitative reverse transcription-PCR. These results showed the presence of two types of malignant melanoma, each with a specific set of dysregulated survival-apoptosis genes, which may prove useful for development of new molecular targets for therapeutic intervention and novel diagnostic biomarkers for treatment and prognosis of malignant melanoma.

Su, David M.; Zhang, Qiuyang; Wang, Xuexi; He, Ping; Zhu, Yuelin Jack; Zhao, Jianxiong; Rennert, Owen M.; Su, Yan A.

2011-01-01

201

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

202

Molecular Definition of Chromosome Translocations Involving 10q24 and 19q13 in Human Malignant Glioma Cells  

Microsoft Academic Search

Loss of heterozygosity (LOH) analysis has repeatedly implicated the 10q24–26 region as the site of tumor suppressor genes involved in the development of malignant human gliomas. However, deletions of this kind are generally too big to pinpoint the critical genes involved. On the other hand, chromosome translocations frequently interrupt genes important in the development of the phenotype. We have screened

Olga Chernova; John K. Cowell

1998-01-01

203

Cytotoxic and radiosensitizing effects of misonidazole on hematopoiesis in normal and tumor-bearing mice. [¹³⁷Cs  

Microsoft Academic Search

Misonidazole is a 2-nitroimidazole hypoxic cell radiosensitizing agent currently undergoing clinical trials. Preliminary studies have shown that misonidazole is toxic to human hematopoietic stem cells. A survey of the effects of misonidazole on a variety of murine hematopoietic stemcells was undertaken. No cytotoxicity or radiosensitization could be demonstrated when misonidazole was administered in vivo. Misonidazole was toxic to bone marrow

A. Robert Turner; M. Joan Allalunis; Raul C. Urtasun; John E. Pedersen; Bert E. Meeker

1980-01-01

204

Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma  

PubMed Central

The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth.

Favoni, Roberto E; Daga, Antonio; Malatesta, Paolo; Florio, Tullio

2012-01-01

205

Horizontal transmission and retention of malignancy, as well as functional human genes, after spontaneous fusion of human glioblastoma and hamster host cells in vivo.  

PubMed

Cell fusion in vitro has been used to study cancer, gene mapping and regulation, and the production of antibodies via hybridomas. However, in-vivo heterosynkaryon formation by cell-cell fusion has received less attention. This investigation describes the spontaneous fusion of a human glioblastoma with normal hamster cells after xenogeneic transplantation, resulting in malignant cells that express both human and hamster genes and gene products, and retention of glioblastoma traits with an enhanced ability to metastasize. Three of 7 human genes found showed translation of their proteins during serial propagation in vivo or in vitro for years; namely, CD74, CXCR4 and PLAGL2, each implicated with malignancy or glioblastoma. This supports the thesis that genetic hybridization of cancer and normal cells can transmit malignancy and also, as first described herein, regulatory genes involved in the tumor's organotypic morphology. Evidence also is increasing that even cell-free human cancer DNA can induce malignancy and transfer genetic information to normal cells. Hence, we posit that the transfer of genetic information between tumor and stromal cells, whether by cell-cell fusion or other mechanisms, is implicated in the progression of malignancy, and may further define the crosstalk between cancer cells and their stromal neighbors. PMID:21796629

Goldenberg, David M; Zagzag, David; Heselmeyer-Haddad, Kerstin M; Berroa Garcia, Lissa Y; Ried, Thomas; Loo, Meiyu; Chang, Chien-Hsing; Gold, David V

2011-08-30

206

Distinct patterns of hypoxic expression of carbonic anhydrase IX (CA IX) in human malignant glioma cell lines  

Microsoft Academic Search

The hypoxia-inducible enzyme carbonic anhydrase IX (CA IX) has recently been discussed as a surrogate marker of tumor hypoxia,\\u000a an indicator of prognosis and a potential therapeutic target in malignant glioma. To characterize patterns of expression of\\u000a CA IX in human malignant glioma cells, we studied CA IX protein, CA9 mRNA and hypoxia-inducible factor-1? (HIF-1?) protein\\u000a levels in U87-MG, U251,

Harun M. Said; Adrian Staab; Carsten Hagemann; Giles H. Vince; Astrid Katzer; Michael Flentje; Dirk Vordermark

2007-01-01

207

Lack of Decorin Expression by Human Bladder Cancer Cells Offers New Tools in the Therapy of Urothelial Malignancies  

PubMed Central

Decorin, a multifunctional small leucine-rich extracellular matrix proteoglycan, has been shown to possess potent antitumour activity. However, there is some uncertainty whether different cancer cells express decorin in addition to non-malignant stromal cells. In this study we clarified decorin expression by human bladder cancer cells both in vivo and in vitro. In addition, the effect of adenovirus-mediated decorin expression on human bladder cancer cells in vitro was examined. We first demonstrated using the publicly available GeneSapiens databank that decorin gene expression is present in both normal and malignant human bladder tissues. However, when we applied in situ hybridization with digoxigenin-labeled RNA probes for decorin on human bladder carcinoma tissue samples derived from a large radical cystectomy patient cohort (n?=?199), we unambiguously demonstrated that invasive and non-invasive bladder carcinoma cells completely lack decorin mRNA. The cancer cells were also negative for decorin immunoreactivity. Instead, decorin expression was localized solely to original non-malignant stromal areas of bladder tissue. In accordance with the aforementioned results, human bladder cancer cells in vitro were also negative for decorin expression as shown by RT-qPCR analyses. The lack of decorin expression by bladder cancer cells was shown not to be due to the methylation of the proximal promoter region of the decorin gene. When bladder cancer cells were transfected with a decorin adenoviral vector, their proliferation was significantly decreased. In conclusion, we have shown that human bladder cancer cells are totally devoid of decorin expression. We have also shown that adenovirus-mediated decorin gene transduction of human bladder cancer cell lines markedly inhibits their proliferation. Thus, decorin gene delivery offers new potential therapeutic tools in urothelial malignancies.

Lund, Riikka; Vuorikoski, Sanna; Bostrom, Pia; Laato, Matti; Bostrom, Peter J.; Jarvelainen, Hannu

2013-01-01

208

Diagnosis and origin determination of malignant pleural effusions through the use of the breast cancer marker human mammaglobin.  

PubMed

As was reported that human mammaglobin (hMAM) may be expressed in malignant pleural effusions (PEs), we investigated the relevance of hMAM reverse-transcriptase polymerase chain reaction (RT-PCR) for their diagnosis and determination of primary origin. Two hundred and twenty-eight malignant (132 male, 96 female) and 185 benign (132 male, 53 female) PEs were investigated. Statistical analyses evaluated the diagnostic performance parameters in all PEs and in cytologically negative malignant PEs, the association between hMAM and benign or malignant status by the direct index of correlation [diagnostic odds ratio (DOR)], chi test, and P value (P). In addition, the discriminative diagnostic power of hMAM expression, independently in breast cancer, lung cancer (LC), malignant mesothelioma (MM), and other cancers was evaluated. In the entire patient population, hMAM was detected in 45.6% and 5.4% of malignant and benign PEs, respectively, in the male group in 41.7% and 4.5% and in the female group in 51.0% and 7.5% of malignant and benign PEs, respectively. A statistically significant correlation between hMAM and malignancy was found in the entire population (DOR=14.68, P<0.001) and in the male (DOR=15.00, P<0.001) or female (DOR=12.77, P<0.001) groups. hMAM RT-PCR increased the diagnostic rate of malignant PEs as it allowed us to detect as malignant 32.1% of cytologically negative PEs. In female patients the positivity of hMAM indicated with higher probability (50.8%) the origin of PEs from breast cancer but lower probability from LC (17%), MM (9.4%), or other cancers (15.1%), whereas in male patients it indicated with similar probability (about 40%) the origin from LC or MM. Our results suggest that hMAM RT-PCR may provide information both in the diagnosis of PE and in the search for the primary site of neoplasia, either in male or female patients. PMID:20502186

Roncella, Silvio; Ferro, Paola; Franceschini, Maria Cristiana; Bacigalupo, Bartolomeo; Dessanti, Paolo; Sivori, Massimiliano; Carletti, Anna Maria; Fontana, Vincenzo; Canessa, Pier Aldo; Pistillo, Maria Pia; Fedeli, Franco

2010-06-01

209

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.

Sandfort, Veit; Eke, Iris; Cordes, Nils

2010-01-01

210

The role of the focal adhesion protein PINCH1 for the radiosensitivity of adhesion and suspension cell cultures.  

PubMed

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 PINCH1(fl/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, p130(CAS), 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

2010-09-28

211

Human T-cell lymphotropic virus type 1 (HTLV-1) and lymphoid malignancies in Dominica: a seroprevalence study.  

PubMed

Human T-cell lymphotropic virus type 1 (HTLV-1) is endemic in certain regions of the world where it is associated with lymphoid malignancies. Herein we aim to describe the seroprevalence of HTLV-1 in lymphoid malignancies in Dominica. We carried out a 10-year retrospective study of histologically proven hematologic malignancies and HTLV-1 seropositivity at the Princess Margaret Hospital, Dominica. Ninety-eight cases were reviewed (59% males, 41% females), ranging in age from 3 to 91 years. HTLV-1 was seropositive in 38.6% (31/80) of all hematologic malignancies. Three of 6 cases of Hodgkin disease (50%), 16 of 36 (44.4%) of non-Hodgkin lymphoma, and 3 out of 8 unclassified lymphomas (37.5%) were seropositive; all 6 cases (100%) of acute adult T-cell leukemia/lymphoma (ATLL) were seropositive. One case each of chronic lymphocytic leukemia and myeloproliferative disorder was seropositive. HTLV-1-seropositive lymphomas presented at a younger age than did seronegative cases. Thus, HTLV-1 is significantly associated with lymphoid malignancies in Dominica, and further studies are needed before a causal relationship with Hodgkin disease can be established. PMID:15551358

Adedayo, Olayinka A; Shehu, Sani M

2004-12-01

212

The heritability of G2 chromosomal radiosensitivity and its association with cancer in Danish cancer survivors and their offspring  

PubMed Central

Purpose To investigate the relationship between chromosomal radiosensitivity and early-onset cancer under age 35 years and to examine the heritability of chromosomal radiosensitivity. Materials and methods Peripheral blood lymphocytes were cultured for 72 hours prior to being irradiated with 0.5 Gy, 300 kV X-rays. Colcemid was added to cultures 30 minutes post-irradiation. Cultures were harvested 90 minutes post-irradiation and analysed for chromatid gaps and breaks. Heritability was estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR) software and by segregation analysis. Results Elevated radiosensitivity was seen for 7 out of 29 (24.1%) cancer survivors, 3 out of 29 (10.3%) partners and 10 out of 53 (20.8%) offspring. Although the proportion of individuals displaying enhanced radiosensitivity was twice as high in both the cancer survivor and offspring groups than the partner controls, neither reached statistical significance. Heritability analysis of the radiosensitive phenotype suggested 57.9 – 78.0% of the variance could be attributed to genetic factors. Conclusions An association between G2 chromosomal radiosensitivity and childhood and young adult cancer is suggested but was not statistically significant. In contrast, there is strong evidence for heritability of the radiosensitive phenotype. The cancer survivors included a broad range of malignancies and future studies should focus on specific cancers with known or likely faults in deoxyribonucleic acid (DNA) damage recognition and repair mechanisms.

Curwen, Gillian B.; Cadwell, Kevin K.; Winther, Jeanette F.; Tawn, E. Janet; Rees, Gwen S.; Olsen, J?rgen H.; Rechnitzer, Catherine; Schroeder, Henrik; Guldberg, Per; Cordell, Heather J.; Boice, John D.

2013-01-01

213

Androgen metabolism and biotransformation in nontumoral and malignant human liver tissues and cells.  

PubMed

There is indirect multiple evidence that hints at a potential role of sex steroids in development and progression of human hepatocellular carcinoma (HCC). In the present study, we have investigated androgen metabolism in a panel of human liver cancer cell lines (HA22T, Huh7, HepG2) and in normal, cirrhotic and malignant human liver tissues aiming to dissect the potential impact of individual enzyme activities and their products in normal and diseased human liver, both in vivo and in vitro. Using our intact cell analysis we were able to assess rates and pathways of androgen metabolism in living conditions. Overall, incubation of cultured cells or tissue minces with either testosterone (T) or androstenedione (Ad) used as precursor resulted in a large extent of 17betaoxidation of T to Ad (cells: 28-77%; tissues: 35-50%). In malignant liver cell lines, both HA22T and Huh7 cells showed consistent amounts of the 5alpha-reductase enzyme products (18% and 15%, respectively), while 5beta-reductase activity was more pronounced in Huh7 cells (18%) than in HA22T cells (1.8%). Interestingly, a significant extent of estrogen formation could be observed in Huh7 cells (5.4-11.5%), while no aromatase activity could be detected in HA22T cells. In HepG2 cells, along with a relatively high proportion of Ad, estrogens represented the most prominent (50-55%) end product of androgen metabolism, regardless of the precursor used. In liver tissues, equivalent results could be obtained, with a consistent proportion of 17betaoxidation of T to Ad (35-50%) being observed in the majority of samples. However, while normal liver tissue samples exhibited a minor proportion of bioactive androgens (3.4%) with no aromatase products, HCC tissues showed a significant extent of aromatase activity (nearly 20%) with estrogen representing the most prominent metabolic product after 24h incubation with either T or Ad. HCV and alcoholic cirrhotic tissues displayed different patterns of androgen metabolism. The former produced limited amounts of bioactive androgens (5.3%) and considerable levels of the intermediate aromatase product 19OH-Ad (up to 28%), the latter exhibited a prevalence of androgen degradation through the 5beta-reductase pathway (9.8%) and a significant extent of aromatase activity (16% as a whole). In conclusion, three major metabolic states could be depicted, depending on prevalent pathways of androgen metabolism and steroid receptor status: estrogenic, androgenic, and mixed. This model supports the idea that local estrogen biosynthesis may be implicated in human HCC and provides a basis for the exploitation of aromatase inhibitors and/or ER antagonists or selective estrogen receptor modulators (SERMs) as a new therapeutic strategy in HCC patients. PMID:19429435

Granata, Orazia M; Cocciadifero, Letizia; Campisi, Ildegarda; Miceli, Vitale; Montalto, Giuseppe; Polito, Lucia M; Agostara, Biagio; Carruba, Giuseppe

2009-02-07

214

The Involvement of Xanthohumol in the Expression of Annexin in Human Malignant Glioblastoma Cells  

PubMed Central

Glioblastoma multiforme (GBM) is the most common malignant and resistant tumor of the central nervous system in humans and new therapeutic strategies are urgently required. Recently, we have shown that the potential chemotherapeutic polyphenol xanthohumol (XH), isolated from Humulus Lupulus, induces apoptosis of human T98G glioblastoma cells by increasing reactive oxygen species and activating MAPK pathways. Then we have found, by western blotting and microscopic analysis, that XH up-regulates cytosolic levels of ANXA1 and induces translocation of the protein on the cell membrane of T98G cells in a time-dependent manner with significant effects observed after 24 h. On the basis of the above evidence, the aim of this work was to investigate the role of intracellular and cell membrane localized ANXA1 in GBM cells. RT-PCR analysis has shown that XH up-regulates mRNA levels of ANXA1 after 16 h treatment. To demonstrate the involvement of ANXA1 in apoptosis of GBM cells we down-regulated ANXA1 expression with small interfering RNA (siRNA) and then analysed apoptosis in the presence and absence of apoptotic stimuli. Importantly, apoptosis induced by XH was reduced in siRNA-ANXA1 transfected cells where western blot analysis shows a significant reduction of ANXA1 protein levels. To investigate the role of ANXA1 expression on the cell membrane of T98G cells as potential “eat-me” signal we studied phagocytosis of apoptotic cells by human macrophages. We incubated apoptotic T98G cells with human blood monocyte derived macrophages (M=). After co-incubation period we analysed the percentage of M= phagocytosing the apoptotic cells by cytofluorimetric FACS analysis and by confocal microscopy. Our results show that XH induces phagocytosis of apoptotic T98G cells by human M= in a concentration-effect manner, a processes that is dependent on caspase mediated apoptosis. ANXA1 acts as an “eat-me” signal on the cell membrane of T98G cells, and interestingly, apoptotic siRNA-ANXA1 transfected cells are not completely ingested by M=. These results were confirmed by incubating apoptotic cells with a neutralizing anti-ANXA1 antiboby and ANXA1 membrane depletion by EDTA washing. ANXA1 was also detected in supernatants of apoptotic cells and the incubation of enriched supernatants enhanced the percentage of phagocytosis by M=. These results demonstrated that ANXA1 is involved both in the apoptosis and phagocytosis of glioblastoma cells. This study shows a possible role of ANXA1 in maintenance of brain homeostasis and may lead to novel therapeutic approaches for neuro-inflammatory diseases and chemotherapy targets in the treatment of glioblastoma multiforme.

Festa, M; Caputo, M; Cipolla, C; D'Acunto, CW; Rossi, AG; Tecce, MF; Capasso, A

2013-01-01

215

Comparative analysis of cell death induction by Taurolidine in different malignant human cancer cell lines  

Microsoft Academic Search

BACKGROUND: Taurolidine (TRD) represents an anti-infective substance with anti-neoplastic activity in many malignant cell lines. So far, the knowledge about the cell death inducing mechanisms and pathways activated by TRD is limited. The aim of this study was therefore, to perform a comparative analysis of cell death induction by TRD simultaneously in different malignant cell lines. MATERIALS AND METHODS: Five

Ansgar M Chromik; Adrien Daigeler; Daniel Bulut; Annegret Flier; Christina May; Kamran Harati; Jan Roschinsky; Dominique Sülberg; Peter R Ritter; Ulrich Mittelkötter; Stephan A Hahn; Waldemar Uhl

2010-01-01

216

Differential expression of Bcl2 in human plasma cell disorders according to proliferation status and malignancy  

Microsoft Academic Search

Multiple myeloma (MM) is a malignancy characterized by a very slow proliferation of malignant plasma cells leading to their accumulation within the bone marrow. This suggests that resistance to apoptosis may play a critical role both in the pathogenesis and resistance to treatment of MM. Bcl-2 is a key protein for the regulation of apoptosis. However, it has been shown

D Puthier; C Pellat-Deceunynck; S Barillé; N Robillard; M-J Rapp; N Juge-Morineau; J-L Harousseau; R Bataille; M Amiot

1999-01-01

217

Monoclonal antibody localization of A and B isoantigens in normal and malignant fixed human tissues.  

PubMed Central

The expression of human blood group A and B isoantigens in normal and malignant tissues from stomach, colon, and pancreas was analyzed in an immunoperoxidase assay using monoclonal antibodies specific for these isoantigens. Appropriate isoantigen expression was demonstrated in the normal epithelium from the stomach, pancreas, and proximal but not distal colon of blood group A, AB, or B patients. Half of all gastric carcinomas and of proximal colon carcinomas showed complete loss of isoantigen, whereas the adjacent mucosa in these cases continued to express appropriate isoantigen. Isoantigen expression was completely lost in only 13% of pancreatic carcinomas tested. Neither A nor B isoantigen was detected in normal epithelium from the distal colon. By contrast, 85% of carcinomas derived from this site showed reexpression of isoantigen. Inappropriate expression of A isoantigen was detected in pancreatic carcinomas (2/5) but not in gastric or colon carcinomas (0/21). Inappropriate expression of B substance was not detected in any tissue (0/38). Interestingly, differential binding of antibodies to Type 1 versus Type 2 and/or difucosyl versus monofucosyl blood group B substances was manifested by differences in intensity of staining for endothelium and red blood cells. Images Figure 2 Figure 1 Figure 3 Figure 4 Figure 5

Ernst, C.; Thurin, J.; Atkinson, B.; Wurzel, H.; Herlyn, M.; Stromberg, N.; Civin, C.; Koprowski, H.

1984-01-01

218

ERK2 is Essential for the Growth of Human Epithelioid Malignant Mesotheliomas  

PubMed Central

Members of the extracellular signal-regulated kinase (ERK) family may have distinct roles in the development of cell injury and repair, differentiation and carcinogenesis. Here we show, using a synthetic small molecule MEK1/2 inhibitor (U0126) and RNA silencing of ERK1 and 2, comparatively, that ERK2 is critical to transformation and homeostasis of human epithelioid malignant mesotheliomas (MMs), asbestos-induced tumors with a poor prognosis. Whereas MM cell (HMESO) lines stably transfected with shERK1 or shERK2 both exhibited significant decreases in cell proliferation in vitro, injection of shERK2 cells, and not shERK1 cells, into immunocompromised SCID mice showed significant attenuated tumor growth in comparison to shControl cells. Inhibition of migration, invasion, and colony formation occurred in shERK2 MM cells in vitro, suggesting multiple roles of ERK2 in neoplasia. Microarray and qRT-PCR analyses revealed gene expression that was significantly increased (CASP1, TRAF1, FAS) or decreased (SEMA3E, RPS6KA2, EGF, BCL2L1) in shERK2-transfected MM cells in contrast to shControl-transfected MM cells. Most striking decreases were observed in mRNA levels of Semaphorin 3 (SEMA3E), a candidate tumor suppressor gene linked to inhibition of angiogenesis. These studies demonstrate a key role of ERK2 in novel gene expression critical to the development of epithelioid MMs. After injection of sarcomatoid human MM (PPMMill) cells into SCID mice, both shERK1 and shERK2 lines showed significant decreased tumor growth, suggesting heterogeneous effects of ERKs in individual MMs.

Shukla, Arti; Hillegass, Jedd M.; MacPherson, Maximilian B.; Beuschel, Stacie L.; Vacek, Pamela M.; Butnor, Kelly J.; Pass, Harvey I.; Carbone, Michele; Testa, Joseph R.; Heintz, Nicholas H.; Mossman, Brooke T.

2010-01-01

219

Malignant mesothelioma  

PubMed Central

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 malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational "environmental" exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis.

Moore, Alastair J; Parker, Robert J; Wiggins, John

2008-01-01

220

Assessment of protein conformation in human benign and malignant astrocytomas by reflectance Fourier transform infrared microspectroscopy.  

PubMed

The secondary structure and composition of protein in the tissues of benign and malignant astrocytomas were determined by reflectance Fourier-transform infrared (FT-IR) microspectroscopy. The peak maximum of IR spectra of the tissues from recurrent malignant astrocytoma markedly appeared at higher frequency (1655 or 1663 cm(-1)), which was significantly different from that of the tissues from benign astrocytoma at 1651 cm(-1) and tissues from malignant astrocytoma at 1652 cm(-1). Malignant astrocytoma indicated slightly different compositions in the protein secondary structure from benign astrocytoma. However, a significant increase in beta-turn structure but a marked decrease in beta-sheet and random coil structures were observed in the protein secondary structure of the recurrent malignant astrocytoma. The phenomenon was more pronounced in recurrent malignant astrocytoma pretreated with radiation and chemotherapy. The rapid cell proliferation and cell differentiation of malignant astrocytoma with or without recurrence might be the possible explanations for the different compositions of protein conformational structures. PMID:9613454

Lee, L S; Chi, C W; Liu, H C; Cheng, C L; Li, M J; Lin, S Y

1998-01-01

221

The Scatter Factor\\/Hepatocyte Growth Factor: c-Met Pathway in Human Embryonal Central Nervous System Tumor Malignancy  

Microsoft Academic Search

Embryonal central nervous system (CNS) tumors, which comprise medulloblastoma, are the most common malignant brain tumors in children. The role of the growth factor scat- ter factor\\/hepatocyte growth factor (SF\\/HGF) and its tyro- sine kinase receptor c-Met in these tumors has been until now completely unknown. In the present study, we show that human embryonal CNS tumor cell lines and

Yunqing Li; Bachchu Lal; Sherwin Kwon; Xing Fan; Usha Saldanha; Thomas E. Reznik; Eric B. Kuchner; Charles Eberhart; John Laterra; Roger Abounader

2005-01-01

222

ZINGIPAIN, A CYSTEINE PROTEASE FROM Zingiber ottensii VALETON RHIZOMES WITH ANTIPROLIFERATIVE ACTIVITIES AGAINST FUNGI AND HUMAN MALIGNANT CELL LINES  

Microsoft Academic Search

The objective of this study was to investigate the activity of a protein identified as cysteine protease, purified from Zingiber ottensii Valeton rhizomes, in terms of antiproliferation against fungi, bacteria, and human malignant cell lines. By means of buffer extraction followed by (NH4)2SO4 precipitation and ion-exchange chromatography, the obtained dominant protein (designated F50) was submitted to non-denaturing and reducing sodium

Aphichart Karnchanatat; Nathachai Tiengburanatam; Apaporn Boonmee; Songchan Puthong; Polkit Sangvanich

2011-01-01

223

A novel lipoxygenase inhibitor Nordy attenuates malignant human glioma cell responses to chemotactic and growth stimulating factors  

Microsoft Academic Search

Nordy is a chiral compound synthesized based on the structure of a natural lipoxygenase (LO) inhibitor nordihydroguaiaretic\\u000a acid (NDGA) from plants. The aim of the present study is to investigate the effect of Nordy on malignant human glioma cell\\u000a responses to chemoattractants and growth promoting signals. We found that Nordy, in a non-cytotoxic concentration range, potently\\u000a inhibited the chemotaxis and

Jian-hong Chen; Xiao-hong Yao; Wanghua Gong; Jinyue Hu; Xiang-dong Zhou; Keqiang Chen; Hong Liu; Yi-fang Ping; Ji Ming Wang; Xiu-wu Bian

2007-01-01

224

A quantitative investigation of immunocytochemically stained blood vessels in normal, benign, premalignant and malignant human oral cheek epithelium  

Microsoft Academic Search

The present study was designed to determine whether increased vascularity occurs during malignant transformation of human oral cheek epithelium. Nine normal (N) samples were taken from the resection margins of benign lesions; the pathological lesions were classified as chronic inflammation (CI; n=11), fibrous hyperplasia (FH; n=12), lichen planus (LIP; n=8), dysplasia (DYS; n=5), squamous cell carcinoma (SCC; n=25; well differentiated

G. L. Tipoe; F. H. White; Y. Jin; L. Yang

1995-01-01

225

300. Adenoviral Delivery of the Gene Encoding Secretable Trimeric TRAIL Induces Apoptosis and Suppresses Human Malignant Glioma In Vivo  

Microsoft Academic Search

Malignant gliomas are most common human primary brain tumors. Despite of intensive research, current treatments have not significantly improved patient survival over last three decades. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a wide range of tumor cells without fatal effect on normal cells. In previous study, we designed a replication deficient adenovirus (Ad) to encode secretable trimeric TRAIL (stTRAIL).

Moonsup Jeong; In-Ho Kwon; Chae-Young Kim; Dai-Wu Seol; Paul D. Robbins; Byong-Moon Kim

2005-01-01

226

Inhibitory effect of 1-O (2 methoxy) hexadecyl glycerol and phenylbutyrate on the malignant properties of human prostate cancer cells  

Microsoft Academic Search

The ability of the naturally occurring ether lipid, 1-O (2 methoxy) hexadecyl glycerol (MHG), and phenylbutyrate (BP) to inhibit\\u000a cellular proliferation, anchorage-independent growth and cellular invasion in the human prostate cancer LnCap and DU145 cells\\u000a was determined. Both MHG and PB inhibited the malignant properties of these prostate cancer cells. The concentrations required\\u000a to achieve similar inhibitory effect, however, were

Sharon Reynolds; Hokan Cederberg; Subhas Chakrabarty

2000-01-01

227

1H NMR Investigations of Tumor Spheroids Grown from a Human Glioma Biopsy or from a Human Malignant Glioma Cell Line  

Microsoft Academic Search

Three-dimensional spherical aggregates of cells, grown from a permanent human malignant glioma cell line (multicellular GaMG spheroids) and from a human glioma biopsy (fragment spheroids), were investigated by 1H NMR spectroscopy. In addition, 1H NMR spectra of biopsy specimens immediately after explantation and of cell monolayers from primary passage and passage 5 were acquired and compared to those of fragment

K. Kotitschke; J. C. Tonn; R. Goldbrunner; U. Bogdahn; A. Haase

1995-01-01

228

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

229

[The 3-dimensional organization of the nucleoli of benign and malignant tumor cells from different human organs].  

PubMed

The method of ultrathin serial sections was used to perform a comparative ultrastructural and 3-dimensional analysis of nucleoli for the following variants of human tumours: benign (fibroadenoma) and malignant (infiltrating ductal carcinoma) tumours of one organ (mammary gland); malignant tumours of epidermal genesis in different organs (squamous cell carcinomas of skin, larynx, lung, gullet, uterus); two forms of malignant tumours (squamous cell and small cell carcinomas) of one organ (lung). The spatial models of nucleoli in these tumour cells are given. The specific signs in architecture of tumour nucleoli was found. Nucleoli of fibroadenomas have well pronounced 1-4 fibrillar centres forming a united system with a lacunar component and intranucleolar chromatin. Unlike benign tumour cells, nucleoli of infiltrating ductal carcinomas are characterized by large, prominent nucleoli containing giant, multiform fibrillar centres with a complicated surface, a well developed granular component and an unusually organized lacunar system. In squamous cell carcinomas of various localization, active, hypertrophied nucleoli with pseudonucleolonemal organization were found. The small cell carcinoma of lung differs from the squamous cell cancer of the same organ by dense, fibrillar nucleoli with a small amount of granular component located on the periphery of the nucleolar body. Nucleolar type reflecting the functional state of malignization process may serve as an additional diagnostic criterion for tumour identification. PMID:1665610

Chelidze, P V; Todriia, T V; Agladze, A G; Topuriia, I V; Silagadze, D G; Piradashvili, K N

1991-01-01

230

In the absence of IGF-1 signaling, IFN-gamma suppresses human malignant T-cell growth.  

PubMed

Several approaches to target insulin-like growth factor-1 (IGF-1) signaling have resulted in the inhibition of the growth of a broad range of tumor cells. Malignant T cells are insensitive to the antiproliferative effects of the interferon-gamma (IFN-gamma)/signal transducer and activator of transcription 1 (STAT1) pathway because of the IGF-1-dependent internalization of the IFN-gammaR2 signaling chain. Here we show that human malignant T cells are also resistant to the growth inhibitory effect of both the IGF-1 receptor-specific inhibitor picropodophyllin (PPP) and retrovirus-mediated gene transfer of a dominant negative IGF-1 receptor. However, blockade of IGF-1 receptor perturbs IFN-gammaR2 internalization and induces its cell surface accumulation in malignant T cells. This allows the reinstatement of the IFN-gamma-induced STAT1 activation, a high expression of proapoptotic molecules, and the suppression of malignant T-cell growth both in vitro and in vivo in a severe combined immunodeficiency (SCID) mouse model. These data indicate that the inhibition of IGF-1 signaling combined with IFN-gamma administration could be a promising approach to suppress the growth of neoplastic T cells resistant to each treatment on its own. PMID:17148586

Conti, Laura; Regis, Gabriella; Longo, Angela; Bernabei, Paola; Chiarle, Roberto; Giovarelli, Mirella; Novelli, Francesco

2006-12-05

231

Inhibition of Cellular Proliferation and Induction of Apoptosis by Curcumin in Human Malignant Astrocytoma Cell Lines  

Microsoft Academic Search

Summary Nuclear factor (NF)-?B is known to control cellular proliferation and apoptosis. In malignant astrocytoma cells, it was reported that NF-?B was activated aberrantly and promoted their proliferation. Thus, inhibition of NF-?B activity is considered to be a promising therapeutic strategy for malignant astrocytoma. Recently, curcumin, the major constituent of turmeric, was reported to inhibit NF-?B activity. In this study,

Shoichi Nagai; Masanori Kurimoto; Kazuo Washiyama; Yutaka Hirashima; Toshiro Kumanishi; Shunro Endo

2005-01-01

232

p53 mutations in human lymphoid malignancies: Association with Burkitt lymphoma and chronic lymphocytic leukemia  

SciTech Connect

The authors have investigated the frequency of p53 mutations in B- and T-cell human lymphoid malignancies, including acute lymphoblastic leukemia, the major subtypes of non-Hodgkin lymphoma, and chronic lymphocytic leukemia. p53 exons 5-9 were studied by using genomic DNA from 197 primary tumors and 27 cell lines by single-strand conformation polymorphism analysis and by direst sequencing of PCR-amplified fragments. Mutations were found associated with (i) Burkitt lymphoma (9/27 biopsoes; 17/27 cell lines) and its leukemic counterpart L{sub 3}-type B-cell acute lymphoblastic leukemia (5/9), both of which also carry activated c-myc oncogenes, and (ii) B-cell chronic lymphocytic leukemia (6/40) and, in particular, its stage of progression known as Richter's transformation (3/7). Mutations were not found at any significant frequency in other types of non-Hodgkin lymphoma or acute lymphoblastic leukemia. In many cases, only the mutated allele was detectable, implying loss of the normal allele. These results suggest that (1) significant differences in the frequency of p53 mutations are present among subtypes of neoplasms derived from the same tissue; (2) p53 may play a role in tumor progression in B-cell chronic lymphocytic leukemia; (3) the presence of both p53 loss/inactivation and c-myc oncogene activation may be important in the pathogenesis of Burkitt lymphoma and its leukemia form L{sub 3}-type B-cell acute lymphoblastic leukemia.

Gaidano, G.; Ballerini, P.; Gong, J.Z.; Inghirami, G.; Knowles, D.M.; Dalla-Favera, R. (Columbia Univ., New York, NY (United States)); Neri, A, (Columbia Univ., New York, NY (United States) Centro Malattie del Sangue G. Marcora, Milan (Italy)); Newcomb, E.W. (New York Univ. School of Medicine, New York (United States)); Magrath, I.T. (National Cancer Institute, Bethesda, MD (United States))

1991-06-15

233

The Biology of Human Lymphoid Malignancies Revealed by Gene Expression Profiling  

PubMed Central

Gene expression profiling provides a quantitative molecular framework for the study of human lymphomas. This genomic technology has revealed that existing diagnostic categories are comprised of multiple molecularly and clinically distinct diseases. Diffuse large B cell lymphoma (DLBCL), for example, consists of three gene expression subgroups, termed germinal center B cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal be cell lymphoma (PMBL). These DLBCL subgroups arise from different stages of normal B cell differentiation, utilize distinct oncogenic mechanisms, and differ in their ability to be cured by chemotherapy. Key regulatory factors and their target genes are differentially expressed among these subgroups, including BCL-6, Blimp-1, and XBP1. ABC DLBCL and PMBL depend upon constitutive activation of the NF-?B pathway for their survival but GCB DLBCL does not, demonstrating that this pathway is a potential therapeutic target for certain DLBCL subgroups. In DLBCL, mantle cell lymphoma, and follicular lymphoma, gene expression profiling has also been used to create gene expression-based models of survival, which have identified the biological characteristics of the tumors that influence their clinical behavior. In mantle cell lymphoma, the length of survival following diagnosis is primarily influenced by the tumor proliferation rate, which can be quantitatively measured by a proliferation gene expression “signature”. Based on this accurate measure, the proliferation rate can now be viewed as an integration of several oncogenic lesions that each increase progression from G1 to S phase of the cell cycle. In DLBCL and follicular lymphoma, gene expression profiling has revealed that the molecular characteristics of non-malignant tumor-infiltrating immune cells have a major influence on the length of survival. The implications of these insights for the diagnosis and treatment of non-Hodgkin lymphomas are discussed.

Dave, Sandeep

2005-01-01

234

Recombinant Human Endostatin Endostar Suppresses Angiogenesis and Lymphangiogenesis of Malignant Pleural Effusion in Mice  

PubMed Central

Background Malignant pleural effusion (MPE) is a common complication of lung cancer. One widely used treatment for MPE is Endostar, a recombined humanized endostatin based treatment. However, the mechanism of this treatment is still unclear. The aim of this study was to investigate the effects of Endostar in mice with MPE. Methods and Materials Lewis lung carcinoma (LLC) cell line expressing enhanced green fluorescent protein (EGFP) was injected into pleural cavity to establish MPE mice model. Mice were randomly divided into four groups. High dose of Endostar (30 mg/kg), low dose of Endostar (8 mg/kg), normal saline, or Bevacizumab (5 mg/kg) was respectively injected into pleural cavity three times with 3-day interval in each group. Transverse computed tomography (CT) was performed to observe pleural fluid formation 14 days after LLC cells injection. Mice were anesthetized and sacrificed 3 days after final administration. The volume of pleural effusion n was measured using 1 ml syringe. Micro blood vessel density (MVD), Lymphatic micro vessel density (LMVD), the expression level of vascular endothelial growth factor A (VEGF-A) and VEGF-C were observed by immunohistochemistry (IHC) staining. Results The volume of pleural effusion as well as the number of pleural tumor foci, MVD and the expression of VEGF-A were significantly reduced in high dose of Endostar treat group. More importantly, LMVD and the expression of VEGF-C were markedly lower in treat group than those in the other three control groups. Conclusion Our work demonstrated that Endostar played an efficient anti-cancer role in MPE through its suppressive effect on angiogenesis and lymphangiogenesis, which provided a certain theoretical basis for the effectiveness of Endostar on the MPE treatment.

Yuan, Dongmei; Liu, Hongbing; Wang, Shouju; Zhou, Changsheng; Song, Yong

2012-01-01

235

The effect of antisense inhibition of urokinase receptor in human squamous cell carcinoma on malignancy.  

PubMed Central

Concomitant expression of urokinase type plasminogen activator (uPA) and its surface receptor (uPAR) has been shown to correlate strongly with a more invasive tumor cell phenotype. A highly malignant human epidermoid carcinoma cell line (HEp3) was transfected with a vector capable of expressing an antisense transcript complementary to 300 bases of the 5' end of uPAR, including the ATG codon. Six stably transfected antisense (AS-2, 3, 5, 9, 10, 12) and eight control clones were characterized. All clones produced high levels of uPA activity. Examination of collagenase production and doubling time showed that all of the clones tested produced similar activities. The antisense clones showed a 20-74% reduction in the uPAR sites; the uPAR mRNA level was also reduced. A test of the invasive ability of all clones in a modified chorioallantoic membrane (CAM) showed that invasiveness of the antisense-inhibited clones was directly proportional to the density of surface uPAR. The AS-2 clone, which expressed the lowest number of uPARs showed a significantly reduced level of invasion. The invasiveness of additional AS-inhibited clones was also reduced. Seven control and four AS-inhibited clones were tested for tumorigenicity on CAMs of chick embryos. Inoculation of control cells produced large tumors, while the As clones were non-tumorigenic. AS-2 did not produce tumors even if kept in vivo for up to 10 weeks.(ABSTRACT TRUNCATED AT 250 WORDS) Images

Kook, Y H; Adamski, J; Zelent, A; Ossowski, L

1994-01-01

236

Protective Role of Hsp27 Protein Against Gamma Radiation-Induced Apoptosis and Radiosensitization Effects of Hsp27 Gene Silencing in Different Human Tumor Cells  

SciTech Connect

Purpose: The ability of heat shock protein 27 (Hsp27) to protect cells from stressful stimuli and its increased levels in tumors resistant to anticancer therapeutics suggest that it may represent a target for sensitization to radiotherapy. In this study, we investigate the protective role of Hsp27 against radiation-induced apoptosis and the effect of its attenuation in highly expressing radioresistant cancer cell lines. Methods and Materials: We examined clonogenic death and the kinetics of apoptotic events in different tumor cell lines overexpressing or underexpressing Hsp27 protein irradiated with photons. The radiosensitive Jurkat cell line, which does not express Hsp27 constitutively or in response to {gamma}-rays, was stably transfected with Hsp27 complementary DNA. Attenuation of Hsp27 expression was accomplished by antisense or RNAi (interfering RNA) strategies in SQ20B head-and-neck squamous carcinoma, PC3 prostate cancer, and U87 glioblastoma radioresistant cells. Results: We measured concentration-dependent protection against the cytotoxic effects of radiation in Jurkat-Hsp27 cells, which led to a 50% decrease in apoptotic cells at 48 hours in the highest expressing cells. Underlying mechanisms leading to radiation resistance involved a significant increase in glutathione levels associated with detoxification of reactive oxygen species, a delay in mitochondrial collapse, and caspase activation. Conversely, attenuation of Hsp27 in SQ20B cells, characterized by their resistance to apoptosis, sensitizes cells to irradiation. This was emphasized by increased apoptosis, decreased glutathione basal level, and clonogenic cell death. Sensitization to irradiation was confirmed in PC3 and U87 radioresistant cells. Conclusion: Hsp27 gene therapy offers a potential adjuvant to radiation-based therapy of resistant tumors.

Aloy, Marie-Therese [Universite de Lyon 1, Laboratoire de Radiobiologie Cellulaire et Moleculaire, Faculte de Medecine Lyon-Sud, Oullins (France); Hospices Civils de Lyon, Service de Radiotherapie, Centre Hospitalier Lyon-Sud, Pierre-Benite (France)], E-mail: marie-therese.aloy@sante.univ-lyon1.fr; Hadchity, Elie; Bionda, Clara [Universite de Lyon 1, Laboratoire de Radiobiologie Cellulaire et Moleculaire, Faculte de Medecine Lyon-Sud, Oullins (France); Diaz-Latoud, Chantal [Universite de Lyon 1, UMR-CNRS-5534, Centre de Genetique Moleculaire et Cellulaire, Villeurbanne (France); Claude, Line; Rousson, Robert [Universite de Lyon 1, Laboratoire de Radiobiologie Cellulaire et Moleculaire, Faculte de Medecine Lyon-Sud, Oullins (France); Arrigo, Andre-Patrick [Universite de Lyon 1, UMR-CNRS-5534, Centre de Genetique Moleculaire et Cellulaire, Villeurbanne (France); Rodriguez-Lafrasse, Claire [Universite de Lyon 1, Laboratoire de Radiobiologie Cellulaire et Moleculaire, Faculte de Medecine Lyon-Sud, Oullins (France)

2008-02-01

237

AYA Monograph Malignant Melanoma  

Cancer.gov

Chapter 5 Malignant Melanoma ??????? ??????? ????????????? ?? ??????????????? ?? ??????????????? ??? ??????????? ???????? ?? ? ??????? ??? ?????? ??????? ??? ??????? ????????? ??? ??????????? ???????? ?? ?????????? ?? ??????????? ?????????????? ?? ????? ?? ????????????

238

Mitochondrial aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues  

PubMed Central

Background In prostate cancer, normal citrate-producing glandular secretory epithelial cells undergo a metabolic transformation to malignant citrate-oxidizing cells. m-Aconitase is the critical step involved in this altered citrate metabolism that is essential to prostate malignancy. The limiting m-aconitase activity in prostate epithelial cells could be the result of a decreased level of m-aconitase enzyme and/or the inhibition of existing m-aconitase. Earlier studies identified zinc as an inhibitor of m-aconitase activity in prostate cells; and that the depletion of zinc in malignant cells is an important factor in this metabolic transformation. However, a possibility remains that an altered expression and level of m-aconitase enzyme might also be involved in this metabolic transformation. To address this issue, the in situ level of m-aconitase enzyme was determined by immunohistochemical analysis of prostate cancer tissue sections and malignant prostate cell lines. Results The immunocytochemical procedure successfully identified the presence of m-aconitase localized in the mitochondrial compartment in PC-3, LNCaP, and DU-145 malignant prostate cell lines. The examination of prostate tissue sections from prostate cancer subjects demonstrated that m-aconitase enzyme is present in the glandular epithelium of normal glands, hyperplastic glands, adenocrcinomatous glands, and prostatic intraepithelial neoplastic foci. Quantitative analysis of the relative level of m-aconitase in the glandular epithelium of citrate-producing adenomatous glands versus the citrate-oxidizing adenocarcinomatous glands revealed no significant difference in m-aconitase enzyme levels. This is in contrast to the down-regulation of ZIP1 zinc transporter in the malignant glands versus hyperplastic glands that exists in the same tissue samples. Conclusion The results demonstrate the existence of m-aconitase enzyme in the citrate-producing glandular epithelial cells; so that deficient m-aconitase enzyme is not associated with the limiting m-aconitase activity that prevents citrate oxidation in these cells. The level of m-aconitase is maintained in the malignant cells; so that an altered enzyme level is not associated with the increased m-aconitase activity. Consequently, the elevated zinc level that inhibits m-aconitase enzyme is responsible for the impaired citrate oxidation in normal and hyperplastic prostate glandular epithelial cells. Moreover, the down-regulation of ZIP1 zinc transporter and corresponding depletion of zinc results in the increase in the activity of the existing m-aconitase activity in the malignant prostate cells. The studies now define the mechanism for the metabolic transformation that characterizes the essential transition of normal citrate-producing epithelial cells to malignant citrate-oxidizing cells.

Singh, Keshav K; Desouki, Mohamed M; Franklin, Renty B; Costello, Leslie C

2006-01-01

239

ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome  

PubMed Central

Application of stem cell biology to breast cancer research has been limited by the lack of simple methods for identification and isolation of normal and malignant stem cells. Utilizing in vitro and in vivo experimental systems, we show that normal and cancer human mammary epithelial cells with increased aldehyde dehydrogenase activity (ALDH) have stem/progenitor properties. These cells contain the subpopulation of normal breast epithelium with the broadest lineage differentiation potential and greatest growth capacity in a xenotransplant model. In breast carcinomas, high ALDH activity identifies the tumorigenic cell fraction, capable of self-renewal and of generating tumors which recapitulate the heterogeneity of the parental tumor. In a series of 577 breast carcinomas, expression of ALDH1 detected by immunostaining correlated with poor prognosis. These findings offer an important new tool for the study of normal and malignant breast stem cells and facilitate the clinical application of stem cell concepts.

Ginestier, Christophe; Hur, Min Hee; Charafe-Jauffret, Emmanuelle; Monville, Florence; Dutcher, Julie; Brown, Marty; Jacquemier, Jocelyne; Viens, Patrice; Kleer, Celina; Liu, Suling; Schott, Anne; Hayes, Dan; Birnbaum, Daniel; Wicha, Max S.; Dontu, Gabriela

2008-01-01

240

Improving Outcome in Malignant Pleural Mesothelioma (MPM) Using Pulsed- Protracted External Beam Radiation (PERT) and Intrapleural Delivery of Stem Cells.  

National Technical Information Service (NTIS)

Malignant Pleural Mesothelioma (MPM) survival remains poor despite multidisciplinary treatment involving aggressive surgery, chemotherapy and adjuvant radiotherapy (RT). The large RT treatment volume, and concerns about the proximity of radiosensitive nor...

B. Marples

2012-01-01

241

Celecoxib enhances radiosensitivity of hypoxic glioblastoma cells through endoplasmic reticulum stress.  

PubMed

Background Refractoriness of glioblastoma multiforme (GBM) largely depends on its radioresistance. We investigated the radiosensitizing effects of celecoxib on GBM cell lines under both normoxic and hypoxic conditions. Methods Two human GBM cell lines, U87MG and U251MG, and a mouse GBM cell line, GL261, were treated with celecoxib or ?-irradiation either alone or in combination under normoxic and hypoxic conditions. Radiosensitizing effects were analyzed by clonogenic survival assays and cell growth assays and by assessing apoptosis and autophagy. Expression of apoptosis-, autophagy-, and endoplasmic reticulum (ER) stress-related genes was analyzed by immunoblotting. Results Celecoxib significantly enhanced the radiosensitivity of GBM cells under both normoxic and hypoxic conditions. In addition, combined treatment with celecoxib and ?-irradiation induced marked autophagy, particularly in hypoxic cells. The mechanism underlying the radiosensitizing effect of celecoxib was determined to be ER stress loading on GBM cells. Conclusion Celecoxib enhances the radiosensitivity of GBM cells by a mechanism that is different from cyclooxygenase-2 inhibition. Our results indicate that celecoxib may be a promising radiosensitizing drug for clinical use in patients with GBM. PMID:23658321

Suzuki, Kenshi; Gerelchuluun, Ariungerel; Hong, Zhengshan; Sun, Lue; Zenkoh, Junko; Moritake, Takashi; Tsuboi, Koji

2013-05-07

242

Intra-arterial bromodeoxyuridine radiosensitization of malignant gliomas  

Microsoft Academic Search

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

T. J. Hegarty; A. F. Thornton; R. F. Diaz; W. F. Chandler; W. D. Ensminger; L. Junck; M. A. Page; S. S. Gebarski; T. W. Hood; P. L. Stetson

1990-01-01

243

Analysis of the expression profile of Dickkopf-1 gene in human glioma and the association with tumor malignancy  

PubMed Central

Background Gliomas represent the most common primary malignant brain tumors, yet little is known about the molecular pathogenesis of these tumors. The highly-regulated Wnt signal transduction pathway is essential for normal developmental processes, and defects in the pathway are closely linked to oncogenesis. Dickkopf-1 (DKK-1) is a secreted protein that acts as a potent inhibitor of the Wnt pathway. The aim of this study was to examine the expression profile of DKK-1 gene in human glioma and its association with tumor malignancy. Methods We determined the expression levels of DKK-1 transcript and protein in 12 glioblastoma cell lines, medulloblastoma cells, low-grade glioma cells, and human astrocyte cells by semiquantitative RT-PCR and ELISA. A total of 47 tumor biopsy specimens and 11 normal brain tissue samples from patients with cerebral trauma internal decompression were embedded in paraffin blocks and used for immunostaining. Twenty-six primary tumors and 7 corresponding brain samples were stored in liquid nitrogen and used for RT-PCR. We further examined serologic concentrations and cerebral fluid levels of DKK-1 in patients with tumors. Results DKK-1 could only be detected in 12 human glioblastoma cell lines, not in a panel of other tumor and normal cell lines. The difference between glioma patients and healthy individuals was significant. Kendall's tau-c association analysis also revealed the increased DKK-1 protein expression in tumor tissues of higher pathologic classification. The levels of cerebral fluid DKK-1 protein were significantly higher in glioma patients than in healthy donors or in neuronal benign tumor patients, suggesting that the DKK-1 molecule in cerebral fluids can be applicable to detect the presence of glioma and be developed as a novel prognostic treatment. Conclusion The Wnt antagonist DKK-1 gene may have important roles in glioma tumorigenesis and act as a novel biomarker in human malignant glioblastoma.

2010-01-01

244

Polymorphisms in the syntaxin 17 gene are not associated with human cutaneous malignant melanoma  

Microsoft Academic Search

The prevalence of cutaneous malignant melanoma (CMM) has increased significantly in most Caucasian populations in recent decades. Both genetic and environmental risk factors are involved in the development of CMM. A germline mutation in the syntaxin 17 (STX17) gene of horses was recently identified, which causes premature hair graying and is associated with susceptibility to melanoma. We hypothesized that common

Zhen Zhen Zhao; David L. Duffy; Shane A. Thomas; Nicholas G. Martin; Nicholas K. Hayward; Grant W. Montgomery

2009-01-01

245

Activation of an alpha-fetoprotein/receptor pathway in human normal and malignant peripheral blood mononuclear cells.  

PubMed

Alpha-fetoprotein (AFP) is mainly synthesized by the fetal liver and the yolk sac with minor contributions of several non-hepatic fetal tissues, variable according to the species considered. Most fetal cells, whatever their origin, possess the ability to bind and to endocytose the protein. This property, which is considered to be lost in differentiated cells of the adult, may be resumed in tumoral cells and is due to the expression of specific AFP receptors at the cell surface. Cytochemical and immunological approaches, combined with in situ hybridization, were used to investigate the specific uptake and synthesis of human AFP in several classes of peripheral blood mononuclear cells (PBMC) and in several malignant cell lines of hematopoietic origin. With the exception of quiescent T lymphocytes, all cells investigated specifically bound AFP. Both normal and malignant blood mononuclear cells expressed mRNA transcripts of AFP which were translated into the protein during a well established period of cellular growth. These results suggest that an AFP/receptor autocrine system might operate in normal and malignant blood mononuclear cells. Its physiological role is discussed in relation to recent work from our laboratory--providing experimental evidence that AFP, throughout its interaction with specific cell receptors, regulates and facilitates the entry of fatty acids into living cells undergoing growth and differentiation. PMID:7694005

Esteban, C; Trojan, J; Macho, A; Mishal, Z; Lafarge-Frayssinet, C; Uriel, J

1993-11-01

246

MED12 alterations in both human benign and malignant uterine soft tissue tumors.  

PubMed

The relationship between benign uterine leiomyomas and their malignant counterparts, i.e. leiomyosarcomas and smooth muscle tumors of uncertain malignant potential (STUMP), is still poorly understood. The idea that a leiomyosarcoma could derive from a leiomyoma is still controversial. Recently MED12 mutations have been reported in uterine leiomyomas. In this study we asked whether such mutations could also be involved in leiomyosarcomas and STUMP oncogenesis. For this purpose we examined 33 uterine mesenchymal tumors by sequencing the hot-spot mutation region of MED12. We determined that MED12 is altered in 66.6% of typical leiomyomas as previously reported but also in 11% of STUMP and 20% of leiomyosarcomas. The mutated allele is predominantly expressed in leiomyomas and STUMP. Interestingly all classical leiomyomas exhibit MED12 protein expression while 40% of atypical leiomyomas, 50% of STUMP and 80% of leiomyosarcomas (among them the two mutated ones) do not express MED12. All these tumors without protein expression exhibit complex genomic profiles. No mutations and no expression loss were identified in an additional series of 38 non-uterine leiomyosarcomas. MED12 mutations are not exclusive to leiomyomas but seem to be specific to uterine malignancies. A previous study has suggested that MED12 mutations in leiomyomas could lead to Wnt/?-catenin pathway activation however our immunohistochemistry results show that there is no association between MED12 status and ?-catenin nuclear/cytoplasmic localization. Collectively, our results show that subgroups of benign and malignant tumors share a common genetics. We propose here that MED12 alterations could be implicated in the development of smooth muscle tumor and that its expression could be inhibited in malignant tumors. PMID:22768200

Pérot, Gaëlle; Croce, Sabrina; Ribeiro, Agnès; Lagarde, Pauline; Velasco, Valérie; Neuville, Agnès; Coindre, Jean-Michel; Stoeckle, Eberhard; Floquet, Anne; MacGrogan, Gaëtan; Chibon, Frédéric

2012-06-29

247

Mechanism of radiosensitization by porphyrins.  

PubMed

According to our previous data, hematoporphyrin dimethyl ether (HPde) at concentrations useful for photodynamic therapy can radiosensitize aggressive Ehrlich ascite carcinoma (EAT) to 2Gy irradiation inducing total tumour growth inhibition. The aim of this study was to further investigate the possible mechanism of radiosensitization of EAT by dicarboxylic porphyrin-HPde. Our results reveal that HPde is inducing several rearrangements in the EAT cells: 1.2 x 10-6 M of the photosensitizer diminishes the number of cells in mitosis by a factor of 3, increases the number of cells in the S phase of the cell cycle, modifies the activities of antioxidant enzymes glutation S-transferase (GST) and DT-diaphorase (DTD), and eventually induces slight apoptosis. Moreover, it was shown that HPde is a ligand of peripheral benzodiazepine receptor (PBR). Named "house keeper," PBR is usually responsible for all these perturbations, which, in our case, act in concert with the following ionizing radiation, producing the interaction of two antiproliferative/destructive factors. PMID:16566725

Luksiene, Zivile; Labeikyte, Danute; Juodka, Benediktas; Moan, Johan

2006-01-01

248

Gemcitabine uptake in glioblastoma multiforme: potential as a radiosensitizer.  

PubMed

Glioblastoma multiforme (GBM), the most frequent malignant brain tumor, has a poor prognosis, but is relatively sensitive to radiation. Both gemcitabine and its metabolite difluorodeoxyuridine (dFdU) are potent radiosensitizers. The aim of this phase 0 study was to investigate whether gemcitabine passes the blood-tumor barrier, and is phosphorylated in the tumor by deoxycytidine kinase (dCK) to gemcitabine nucleotides in order to enable radiosensitization, and whether it is deaminated by deoxycytidine deaminase (dCDA) to dFdU. Gemcitabine was administered at 500 or 1000 mg/m(2) just before surgery to 10 GBM patients, who were biopsied after 1-4 h. Plasma gemcitabine and dFdU levels varied between 0.9 and 9.2 microM and 24.9 and 72.6 microM, respectively. Tumor gemcitabine and dFdU levels varied from 60 to 3580 pmol/g tissue and from 29 to 72 nmol/g tissue, respectively. The gene expression of dCK (beta-actin ratio) varied between 0.44 and 2.56. The dCK and dCDA activities varied from 1.06 to 2.32 nmol/h/mg protein and from 1.51 to 5.50 nmol/h/mg protein, respectively. These enzyme levels were sufficient to enable gemcitabine phosphorylation, leading to 130-3083 pmol gemcitabine nucleotides/g tissue. These data demonstrate for the first time that gemcitabine passes the blood-tumor barrier in GBM patients. In tumor samples, both gemcitabine and dFdU concentrations are high enough to enable radiosensitization, which warrants clinical studies using gemcitabine in combination with radiation. PMID:18701427

Sigmond, J; Honeywell, R J; Postma, T J; Dirven, C M F; de Lange, S M; van der Born, K; Laan, A C; Baayen, J C A; Van Groeningen, C J; Bergman, A M; Giaccone, G; Peters, G J

2008-08-12

249

Preclinical evaluation of radiosensitizing activity of Pluronic block copolymers.  

PubMed

Abstract Purpose: Pluronic block copolymers are non-ionic surfactants with demonstrated sensitizing activity in chemotherapy and hyperthermia in various tumor cell lines. In the current study we investigated the potential activity of Pluronic as a radiosensitizing agent. Materials and methods: As a possible mechanism, the effect of Pluronic on Hsp70 and Hsp90 was examined. Gli36 human glioma cells were treated with radiation alone as well as with a combination treatment of Pluronic and radiation. Results: Clonogenic cell survival assays show that Pluronic has an elevated effect on radiosensitization (50% high, p < 0.01), even with radiation doses as low as 2 Gy. The Hsp90 level was reduced 24 h after the combined treatment in both in vitro and in vivo. Similarly, Hsp70 levels were also decreased 24 h post treatment. When Gli36 cells were exposed to Pluronic before and during irradiation, DNA DSB: double-strand breaks repair was reduced, and elevated apoptosis was also seen in tumor xenografts. Conclusion: Data suggest the potential use of L10 as a radiosensitizer. While the mechanism of sensitization requires additional investigation, the presented results indicate that the effect may be due, in part, to a decrease in Hsp90 and 70 levels and increased DNA damage. PMID:23631609

Perera, Reshani H; Patel, Ravi; Wu, Hanping; Gangolli, Mihika; Traughber, Bryan; Oleinick, Nancy; Exner, Agata A

2013-06-03

250

Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies  

PubMed Central

The Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway was discovered 20 years ago as a mediator of cytokine signaling. Since this time, more than 2,500 articles have been published demonstrating the importance of this pathway in virtually all malignancies. Although there are dozens of cytokines and cytokine receptors, four Jaks, and seven Stats, it seems that interleukin-6–mediated activation of Stat3 is a principal pathway implicated in promoting tumorigenesis. This transcription factor regulates the expression of numerous critical mediators of tumor formation and metastatic progression. This review will examine the relative importance and function of this pathway in nonmalignant conditions as well as malignancies (including tumor intrinsic and extrinsic), the influence of other Stats, the development of inhibitors to this pathway, and the potential role of inhibitors in controlling or eradicating cancers.

Sansone, Pasquale; Bromberg, Jacqueline

2012-01-01

251

Radiosensitization of head and neck squamous cell carcinoma by a SMAC-mimetic compound, SM-164, requires activation of caspases  

PubMed Central

Chemoradiation is the treatment of choice for locally advanced head and neck squamous cell carcinoma (HNSCC). However, radioresistance, which contributes to local recurrence, remains a significant therapeutic problem. In this study, we characterized SM-164, a small SMAC mimetic compound that promotes degradation of cIAP-1 (also known as BIRC2) and releases active caspases from XIAP inhibitory binding, as a radiosensitizing agent in HNSCC cells. We found that SM-164 at nanomolar concentrations induced radiosensitization in some HNSCC cell lines in a manner dependent on intrinsic sensitivity to caspase activation and apoptosis induction. Blockage of caspase activation via siRNA knockdown or a pan-caspase inhibitor, z-VAD-fmk largely abrogated SM-164 radiosensitization. On the other hand, the resistant lines with a high level of BCL-2 that blocks caspase activation and apoptosis induction became sensitive to radiation upon BCL-2 knockdown. Mechanistic studies revealed that SM-164 radiosensitization in sensitive cells was associated with NF?B activation and TNF? secretion, followed by activation of caspases-8 and -9, leading to enhanced apoptosis. Finally, SM-164 also radiosensitized human tumor xenograft, while causing minimal toxicity. Thus, SM-164 is a potent radiosensitizer via a mechanism involving caspase activation and holds promise for future clinical development as a novel class of radiosensitizer for the treatment of a subset of head and neck cancer patients.

Yang, Jie; McEachern, Donna; Li, Wenyan; Davis, Mary A.; Li, Hua; Morgan, Meredith A.; Bai, Longchuan; Sebolt, Jonathan T.; Sun, Haiying; Lawrence, Theodore S.; Wang, Shaomeng; Sun, Yi

2011-01-01

252

Characterization of malignant mesenchymal cell line (UISO-RS-3) derived from a human rhabdomyosarcoma and inhibition by pharmacologic doses of estrogen  

Microsoft Academic Search

Summary  A new tumor cell line has been established from a malignant pleural effusion in a 28-yr-old female patient with a primary\\u000a alveolar rhabdomyosarcoma of the left buttock. The in vitro and in vivo growth characteristics, morphologic features, abnormal\\u000a karyotype, and immunohistochemical staining pattern indicate that this cell line is comprised of primitive malignant mesenchymal\\u000a cells derived from a human rhabdomyosarcoma.

Walter E. Madsen; Michael J. Walker; Elizabeth A. Shaughnessy; John M. Brown; Tapas K. Das Gupta

1990-01-01

253

Oncolysis of malignant human melanoma tumors by Coxsackieviruses A13, A15 and A18  

PubMed Central

Many RNA viruses are displaying great promise in the field of oncolytic virotherapy. Previously, we reported that the picornavirus Coxsackievirus A21 (CVA21) possessed potent oncolytic activity against cultured malignant melanoma cells and melanoma xenografts in mice. In the present study, we demonstrate that three additional Group A Coxsackieviruses; Coxsackievirus A13 (CVA13), Coxsackievirus A15 (CVA15) and Coxsackievirus A18 (CVA18), also have similar oncolytic activity against malignant melanoma. Each of the viruses grew quickly to high titers in cancer cells expressing ICAM-1 and intratumoral injection of preformed subcutaneous SK-Mel-28 xenografts in mice with CVA13, CVA15 and CVA18 resulted in significant tumor volume reduction. As preexisting immunity could potentially hinder oncolytic virotherapy, sera from stage IV melanoma patients and normal controls were tested for levels of protective antibody against the panel of oncolytic Coxsackieviruses. Serum neutralization assays revealed that 3 of 21 subjects possessed low levels of anti-CVA21 antibodies, while protective antibodies for CVA13, CVA15 and CVA18 were not detected in any sample. Serum from individuals who were seropositive for CVA21 failed to exhibit cross-neutralization of CVA13, CVA15 and CVA18. From these studies it can be concluded that the administration of CVA13, CVA15 or CVA18 could be employed as a potential multivalent oncolytic therapy against malignant melanoma.

2011-01-01

254

FT-IR Spectroscopic Analysis of Normal and Malignant Human Oral Tissues  

NASA Astrophysics Data System (ADS)

FT-IR spectroscopy has been used to explore the changes in the vibrational bands of normal and oral squamous cell carcinoma (OSCC) tissues in the region 4000-400 cm-1. Significant changes in the spectral features were observed. The spectral changes were the results of characteristics structural alterations at the molecular level in the malignant tissues. These alterations include structural changes of proteins and possible increase of its content, an increase in the nucleic-to-cytoplasm ratio, an increase in the relative amount of DNA, an increase in the rate of phosphorylation process induced by carcinogenesis, a loss of hydrogen bonding of the C-OH groups in the amino acid residues of proteins, a decrease in the relative amount of lipids compared to normal epithelial oral tissues. The results of the present study demonstrate that the FT-IR technique has the feasibility of discriminating malignant from normal tissues and other pathological states in a short period of time and may detect malignant transformation earlier than the standard histological examination stage.

Krishnakumar, N.; Madhavan, R. Nirmal; Sumesh, P.; Palaniappan, Pl. Rm.; Venkatachalam, P.; Ramachandran, C. R.

2008-11-01

255

AIDS-Related Malignancies  

Microsoft Academic Search

OVERVIEW OF MALIGNANCY IN PATIENTS WITH AIDS Despite the advent of highly active antiretroviral therapy, the incidence of human immunodeficiency virus (HIV)-asso- ciated malignancies has not decreased. The United States Centers for Disease Control (CDC) has determined that Kaposi's sarcoma, non-Hodgkin's lymphoma (including pri- mary central nervous system lymphoma), and cervical carci- noma define the acquired immune deficiency syndrome (AIDS).

G. MICHAEL WOOL

256

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.

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

2010-01-01

257

Radiosensitivity Enhancement by Celecoxib, a Cyclooxygenase (COX)-2 Selective Inhibitor, via COX2Dependent Cell Cycle Regulation on Human Cancer Cells Expressing Differential COX2 Levels  

Microsoft Academic Search

To characterize the radiation-enhancing effects on human cancer cells and underlying mechanisms of celecoxib, a cyclooxygenase (COX)-2 selective inhibitor, and to ascertain whether its effects are COX-2 dependent. Clonogenic cytotox- icity assays and radiation survival assays after treatment with celecoxib F radiation were done on four human cancer cell lines that expressed differential COX-2 levels. Stably COX-2 knocked down or

You Keun Shin; Ji Sun Park; Hyun Seok Kim; Hyun Jung Jun; Gwi Eon Kim; Chang Ok Suh; Yeon Sook Yun; Hongryull Pyo

258

An Antibody-based Multifaceted Approach Targeting the Human Transferrin Receptor for the Treatment of B-cell Malignancies  

PubMed Central

Summary We previously developed an antibody-avidin fusion protein (ch128.1Av) targeting the human transferrin receptor 1 (TfR1, also known as CD71), which demonstrates direct in vitro cytotoxicity against malignant hematopoietic cells. This cytotoxicity is attributed to its ability to decrease the level of TfR1 leading to lethal iron deprivation. We now report that ch128.1Av shows the ability to bind the Fc ? receptors and the complement component C1q, suggesting that it is capable of eliciting Fcmediated effector functions such as antibody-dependent cellmediated cytotoxicity and complement-mediated cytotoxicity. In addition, in 2 disseminated multiple myeloma xenograft mouse models, we show that a single dose of ch128.1Av results in significant antitumor activity, including long-term survival. It is interesting to note that the parental antibody without avidin (ch128.1) also shows remarkable in vivo anticancer activity despite its limited in vitro cytotoxicity. Finally, we demonstrate that ch128.1Av is not toxic to pluripotent hematopoietic progenitor cells using the long-term cell-initiating culture assay suggesting that these important progenitors would be preserved in different therapeutic approaches, including the in vitro purging of cancer cells for autologous transplantation and in vivo passive immunotherapy. Our results suggest that ch128.1Av and ch128.1 may be effective in the therapy of human multiple myeloma and potentially other hematopoietic malignancies.

Daniels, Tracy R.; Ortiz-Sanchez, Elizabeth; Luria-Perez, Rosendo; Quintero, Rafaela; Helguera, Gustavo; Bonavida, Benjamin; Martinez-Maza, Otoniel; Penichet, Manuel L.

2013-01-01

259

Detection by a human monoclonal antibody of a glycoprotein associated with malignant proliferation of mammary epithelial cells.  

PubMed Central

A tumour-associated antigen (TAA.62) with an apparent mol. wt. of 62 kd, identified by a human monoclonal antibody (IgG2, kappa-light chain), was found to be expressed at elevated levels in the cytoplasmic compartment of malignant as compared with normal mammary epithelial cells in both tissues and cultured cells. Increased levels of cytoplasmic expression of the antigen were also observed in malignant cells of cervix, colon, kidney, lung, and stomach. The patterns of expression of TAA.62 in cultured cells mirrored those of tissues and the antigen was expressed at elevated levels in the established breast cancer lines or oncogenically transformed mammary carcinoma cell line (tumourigenic) compared with the immortalised mammary epithelial cell line (non-tumourigenic). Aliquots of TAA.62 were purified to homogeneity from the conditioned-medium of malignant and immortalised breast cells by immunoaffinity chromatography using immobilised anti-TAA.62 antibody, and gel filtration. Both preparations of TAA.62 yielded a single band with an apparent molecular weight of 62 kd under reducing condition on sodium dodecyl sulphate-polyacrylamide gel electrophoresis, and both were identical in terms of size and immunoreactivity to anti-TAA.62 antibody. However, TAA.62(T) isolated from tumourigenic cell lines itself interacted with a cell surface molecule having an apparent molecular weight of 160 kd on both the malignant and immortalised cells: TAA.62(I) isolated from immortalized cell lines, showed no comparable interaction. Scatchard analysis of the concentration-dependent binding of TAA.62(T) to 160 kd-receptor molecule revealed a 2.6 x 10(4) binding sites per cell. The association constant of such binding was determined to be approximately 16.6 nM. Finally, addition of anti-TAA.62 antibody to culture medium resulted in the inhibition of proliferation of the malignant cells, but showed no effect on the normal cells. The results suggest that TAA.62 may interact as a ligand with its 160 kd cell surface receptor with a possible growth related function. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 10

Imam, S. A.; Mills, L. A.; Taylor, C. R.

1991-01-01

260

Generation of cytotoxic responses in mice and human individuals against hematological malignancies using survivin-RNA-transfected dendritic cells.  

PubMed

Survivin is a member of the inhibitors of apoptosis family and is overexpressed in many types of human cancers, making it an attractive target for T cell-based immunotherapeutic strategies. Recently, HLA-A2-binding peptides derived from the survivin protein were identified as capable of inducing specific T cell responses in cancer patients. Here we demonstrate that human survivin-specific CTLs generated from PBMC by stimulation with autologous dendritic cells transfected with survivin-RNA were cytotoxic for a range of hemopoietic malignant cell lines and primary tumor cells isolated from patients with acute myeloid leukemia. We also show that vaccination of mice with survivin-RNA-transfected dendritic cells leads to long term resistance to challenge by a survivin-expressing lymphoma, demonstrating the potential of survivin as a tumor rejection Ag. Our data provide evidence for the use of survivin as a target structure for immunotherapeutic strategies against hematological neoplasms. PMID:12759413

Zeis, Matthias; Siegel, Sandra; Wagner, Andreas; Schmitz, Marc; Marget, Matthias; Kühl-Burmeister, Rita; Adamzik, Ilse; Kabelitz, Dieter; Dreger, Peter; Schmitz, Norbert; Heiser, Axel

2003-06-01

261

A Gene Expression Model of Intrinsic Tumor Radiosensitivity: Prediction of Response and Prognosis After Chemoradiation  

SciTech Connect

Purpose: Development of a radiosensitivity predictive assay is a central goal of radiation oncology. We reasoned a gene expression model could be developed to predict intrinsic radiosensitivity and treatment response in patients. Methods and Materials: Radiosensitivity (determined by survival fraction at 2 Gy) was modeled as a function of gene expression, tissue of origin, ras status (mut/wt), and p53 status (mut/wt) in 48 human cancer cell lines. Ten genes were identified and used to build a rank-based linear regression algorithm to predict an intrinsic radiosensitivity index (RSI, high index = radioresistance). This model was applied to three independent cohorts treated with concurrent chemoradiation: head-and-neck cancer (HNC, n = 92); rectal cancer (n = 14); and esophageal cancer (n = 12). Results: Predicted RSI was significantly different in responders (R) vs. nonresponders (NR) in the rectal (RSI R vs. NR 0.32 vs. 0.46, p = 0.03), esophageal (RSI R vs. NR 0.37 vs. 0.50, p = 0.05) and combined rectal/esophageal (RSI R vs. NR 0.34 vs. 0.48, p = 0.001511) cohorts. Using a threshold RSI of 0.46, the model has a sensitivity of 80%, specificity of 82%, and positive predictive value of 86%. Finally, we evaluated the model as a prognostic marker in HNC. There was an improved 2-year locoregional control (LRC) in the predicted radiosensitive group (2-year LRC 86% vs. 61%, p = 0.05). Conclusions: We validate a robust multigene expression model of intrinsic tumor radiosensitivity in three independent cohorts totaling 118 patients. To our knowledge, this is the first time that a systems biology-based radiosensitivity model is validated in multiple independent clinical datasets.

Eschrich, Steven A. [H Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States); Pramana, Jimmy [Netherlands Cancer Institute, Amsterdam (Netherlands); Zhang Hongling; Zhao Haiyan; Boulware, David; Lee, Ji-Hyun; Bloom, Gregory [H Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States); Rocha-Lima, Caio [Department of Medicine, University of Miami, Miami, FL (United States); Kelley, Scott; Calvin, Douglas P.; Yeatman, Timothy J. [H Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States); Begg, Adrian C. [Netherlands Cancer Institute, Amsterdam (Netherlands); Torres-Roca, Javier F. [H Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States)], E-mail: Javier.Torresroca@moffitt.org

2009-10-01

262

A GENE EXPRESSION MODEL OF INTRINSIC TUMOR RADIOSENSITIVITY: PREDICTION OF RESPONSE AND PROGNOSIS AFTER CHEMORADIATION  

PubMed Central

Purpose Development of a radiosensitivity predictive assay is a central goal of radiation oncology. We reasoned a gene expression model could be developed to predict intrinsic radiosensitivity and treatment response in patients. Methods and Materials Radiosensitivity (determined by survival fraction at 2 Gy) was modeled as a function of gene expression, tissue of origin, ras status (mut/wt), and p53 status (mut/wt) in 48 human cancer cell lines. Ten genes were identified and used to build a rank-based linear regression algorithm to predict an intrinsic radiosensitivity index (RSI, high index = radioresistance). This model was applied to three independent cohorts treated with concurrent chemoradiation: head-and-neck cancer (HNC, n = 92); rectal cancer (n = 14); and esophageal cancer (n = 12). Results Predicted RSI was significantly different in responders (R) vs. nonresponders (NR) in the rectal (RSI R vs. NR 0.32 vs. 0.46, p = 0.03), esophageal (RSI R vs. NR 0.37 vs. 0.50, p = 0.05) and combined rectal/esophageal (RSI R vs. NR 0.34 vs. 0.48, p = 0.001511) cohorts. Using a threshold RSI of 0.46, the model has a sensitivity of 80%, specificity of 82%, and positive predictive value of 86%. Finally, we evaluated the model as a prognostic marker in HNC. There was an improved 2-year locoregional control (LRC) in the predicted radiosensitive group (2-year LRC 86% vs. 61%, p = 0.05). Conclusions We validate a robust multigene expression model of intrinsic tumor radiosensitivity in three independent cohorts totaling 118 patients. To our knowledge, this is the first time that a systems biology-based radiosensitivity model is validated in multiple independent clinical datasets.

Eschrich, Steven A.; Pramana, Jimmy; Zhang, Hongling; Zhao, Haiyan; Boulware, David; Lee, Ji-Hyun; Bloom, Gregory; Rocha-Lima, Caio; Kelley, Scott; Calvin, Douglas P.; Yeatman, Timothy J.; Begg, Adrian C.; Torres-Roca, Javier F.

2011-01-01

263

Proteomic and Bioinformatic Analysis of mSWI/SNF (BAF) Complexes Reveals Extensive Roles in Human Malignancy  

PubMed Central

Subunits of mammalian SWI/SNF (mSWI/SNF, also called BAF) complexes have recently been implicated as tumor suppressors in a number of human malignancies. To understand the full extent of their involvement, we conducted a proteomic analysis of purified endogenous mSWI/SNF complexes. Our studies revealed several new dedicated, stable subunits not found in the yeast SWI/SNF complex including Bcl7a, b and c, Bcl11a and b, Brd9 and SS18. Incorporating these novel members, we determined the frequency of mSWI/SNF subunit mutations in recent exome- and whole-genome sequencing studies of primary human tumors. Surprisingly, mSWI/SNF subunits are mutated in 19.6% of all human tumors reported in 44 exome sequencing studies. Our analysis suggests that specific subunits protect against cancer in specific tissues. In addition, we find that mutations to more than one subunit, which we define as a type of compound heterozygosity, are prevalent in certain cancers. Our studies demonstrate that mSWI/SNF is the most frequently mutated chromatin-regulatory complex (CRC) in human cancer and that in contrast to other known tumor suppressors and oncogenes surveyed, mSWI/SNF is broadly mutated, similar to TP53. Thus, proper functioning of these polymorphic chromatin regulatory complexes may constitute a major mechanism of human tumor suppression.

Kadoch, Cigall; Hargreaves, Diana C.; Hodges, Courtney; Elias, Laura; Ho, Lena; Ranish, Jeff; Crabtree, Gerald R.

2013-01-01

264

Overexpression of Yin Yang 1 in the pathogenesis of human hematopoietic malignancies.  

PubMed

The transcription factor Yin Yang (YY) 1 has been reported to be overexpressed in several tumor types and plays a role in both the progression of the disease as well as the maintenance of tumor cell resistance to cell death by cytotoxic drugs. YY1 also has been reported to be a prognostic factor for several cancers and was proposed to be a therapeutic target. The expression, function, and role of YY1 in the pathogenesis of hematologic malignancies are summarized briefly herein. Data are represented for B non-Hodgkin lymphoma, AIDS-related lymphoma, multiple myeloma, and children's acute lymphocytic leukemia. PMID:22248059

Bonavida, B; Huerta-Yepez, S; Baritaki, S; Vega, M; Liu, H; Chen, H; Berenson, J

2011-01-01

265

DNA Cross-Linking Responses of Human Malignant Glioma Cell Strains to Chloroethylnitrosoureas, Cisplatin, and Diaziquone  

Microsoft Academic Search

Cell strains derived by culture of malignant glioma (astrocytoma grade III IV) surgical specimens were tested for the production of DNA interstrand cross-links (ISC) and DNA-protein cross-links following treatment in vitro with l-(2-ch!oroethyl)-l-nitrosourea, l,3-bis(2-chlo- roethylH-nitrosourea (BCNU, carmustine), l-(2-chloroethyl)-3-{2,6- dioxo-l-piperidyl)-l-nitrosourea (PCNU), c\\/s-dichlorodiamminepla- tinum(II) (cisplatin), and 3,6-diaziridinyl-2,5-bis(carboethoxyamino)- 1,4-benzoquinone (diaziquone). ISC and DNA-protein crosslinks were measured by means of the DNA alkaline elution

Eric Sariban; Kurt W. Kohn; Chana Zlotogorski; Guy Laurent; Mauricio D'Incaici; Rufus Day III; Barry H. Smith; Paul L. Kornblith; Leonard C. Erickson

1987-01-01

266

A dimeric mutant of human pancreatic ribonuclease with selective cytotoxicity toward malignant cells  

PubMed Central

Monomeric human pancreatic RNase, devoid of any biological activity other than its RNA degrading ability, was engineered into a dimeric protein with a cytotoxic action on mouse and human tumor cells, but lacking any appreciable toxicity on mouse and human normal cells. This dimeric variant of human pancreas RNase selectively sensitizes to apoptotic death cells derived from a human thyroid tumor. Because of its selectivity for tumor cells, and because of its human origin, this protein represents a potentially very attractive, novel tool for anticancer therapy.

Piccoli, Renata; Di Gaetano, Sonia; De Lorenzo, Claudia; Grauso, Michela; Monaco, Carmen; Spalletti-Cernia, Daniela; Laccetti, Paolo; Cinatl, Jaroslav; Matousek, Josef; D'Alessio, Giuseppe

1999-01-01

267

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

268

Selective cytotoxicity of /sup 125/I-labeled monoclonal antibody T101 in human malignant T cell lines  

SciTech Connect

The radiolabeled anti-T cell antibody T/sup 101/ can be used for specific tumor localization, but unlabeled T/sup 101/ produces limited cytotoxicity in patients. We studied the in vitro cytotoxic effects of T/sup 101/ labeled with /sup 125/I, a radionuclide known for its short-range, high-linear-energy electrons. We showed that /sup 125/I-T/sup 101/ could be readily prepared at high specific activity with high immunoreactivity. Human malignant T cell lines HUT 102, MOLT-4, and HUT 78 were found to differ in the number of T65 determinants (the antigen recognized by T/sup 101/) and the sensitivity to external x-ray radiation, which were of significance for the cytotoxicity of /sup 125/I-T/sup 101/ in vitro. The cytotoxic effects of /sup 125/I-T/sup 101/ were also found to be dose dependent and increased with exposure time under frozen conditions. As controls, unlabeled T/sup 101/ had no cytotoxic effect, while free Na /sup 125/I or the /sup 125/I-labeled irrelevant antibody 9.2.27 exerted minor cytotoxicity. In HUT 102 and MOLT-4, more than 3 logs cell killing was achieved within four weeks. Because considerable cytotoxicity was demonstrated in vitro by /sup 125/I-T/sup 101/ on T65-positive malignant cells, and because low-dose /sup 111/In-T/sup 101/ can be used successfully for tumor localization, future trials using /sup 125/I-T/sup 101/ at high specific radioactivity may improve therapeutic results in patients with T65-positive malignancies.

Boven, E.; Lindmo, T.; Mitchell, J.B.; Bunn, P.A. Jr.

1986-02-01

269

Central Role of c-Myc during Malignant Conversion in Human Hepatocarcinogenesis  

PubMed Central

Hepatocarcinogenesis is a multi-stage process in which precursor lesions progress into early hepatocellular carcinomas (eHCC) by sequential accumulation of multiple genetic and epigenetic alterations. To decode the molecular events during early stages of liver carcinogenesis, we performed gene expression profiling on cirrhotic (regenerative) and dysplastic nodules (DN) as well as eHCC. Although considerable heterogeneity was observed at the regenerative and dysplastic stages, overall 460 differentially expressed genes were detected between DN and eHCC. Functional analysis of the significant gene set identified the MYC oncogene as a plausible driver gene for malignant conversion of the dysplastic nodules. In addition, gene set enrichment analysis (GSEA) revealed global activation of the MYC up-regulated gene set in eHCC versus dysplasia. Presence of the MYC signature significantly correlated with increased expression of CSN5 as well as with higher overall transcription rate of genes located in the 8q chromosome region. Furthermore, a classifier constructed from MYC target genes could robustly discriminate eHCC from high- and low-grade dysplastic nodules. In conclusion, our study identified unique expression patterns associated with the transition of high-grade dysplastic nodules into early HCC and demonstrated that activation of the MYC transcription signature is strongly associated with the malignant conversion of pre-neoplastic liver lesions.

Kaposi-Novak, Pal; Libbrecht, Louis; Woo, Hyun-Goo; Lee, Yun-Han; Sears, Nathaniel C.; Conner, Elizabeth A.; Factor, Valentina M.; Roskams, Tania; Thorgeirsson, Snorri S.

2009-01-01

270

Hypoxia-induced Up-Regulation of Angiogenin in Human Malignant Melanoma  

Microsoft Academic Search

Angiogenesis is essential for tumor progression and metastasis, how- ever, the angiogenesis regulators that are biologically relevant for human melanoma are still unknown. In this study, we analyzed the expression of the potent angiogenic factor angiogenin (ANG) in human melanoma in vitro and in vivo. Four different human melanoma cell lines and two normal melanocytes were kept either under normoxic

Anke Hartmann; Manfred Kunz; Sebastian Kostlin; Reinhard Gillitzer; Atiye Toksoy; C. Eberhard Klein

1999-01-01

271

Abrogation of p53 function by HPV16 E6 gene delays apoptosis and enhances mutagenesis but does not alter radiosensitivity in TK6 human lymphoblast cells  

Microsoft Academic Search

In order to gain a better understanding of the role of p53 in radiation-induced mitotic failure, apoptosis and mutagenesis, we introduced the HPV16 E6 gene via a retroviral vector into the TK6 human lymphoblast cell line which expresses wild type p53. Abrogation of p53 function by E6 resulted in a delayed and reduced apoptotic response and a moderate increase in

Yongjia Yu; Chuan-Yuan Li; John B Little

1997-01-01

272

Prostate cancer radiosensitization through poly(ADP-Ribose) polymerase-1 hyperactivation.  

PubMed

The clinical experimental agent, ?-lapachone (?-lap; Arq 501), can act as a potent radiosensitizer in vitro through an unknown mechanism. In this study, we analyzed the mechanism to determine whether ?-lap may warrant clinical evaluation as a radiosensitizer. ?-Lap killed prostate cancer cells by NAD(P)H:quinone oxidoreductase 1 (NQO1) metabolic bioactivation, triggering a massive induction of reactive oxygen species, irreversible DNA single-strand breaks (SSB), poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation, NAD(+)/ATP depletion, and ?-calpain-induced programmed necrosis. In combination with ionizing radiation (IR), ?-lap radiosensitized NQO1(+) prostate cancer cells under conditions where nontoxic doses of either agent alone achieved threshold levels of SSBs required for hyperactivation of PARP-1. Combination therapy significantly elevated SSB level, ?-H2AX foci formation, and poly(ADP-ribosylation) of PARP-1, which were associated with ATP loss and induction of ?-calpain-induced programmed cell death. Radiosensitization by ?-lap was blocked by the NQO1 inhibitor dicoumarol or the PARP-1 inhibitor DPQ. In a mouse xenograft model of prostate cancer, ?-lap synergized with IR to promote antitumor efficacy. NQO1 levels were elevated in ?60% of human prostate tumors evaluated relative to adjacent normal tissue, where ?-lap might be efficacious alone or in combination with radiation. Our findings offer a rationale for the clinical utilization of ?-lap (Arq 501) as a radiosensitizer in prostate cancers that overexpress NQO1, offering a potentially synergistic targeting strategy to exploit PARP-1 hyperactivation. PMID:20940411

Dong, Ying; Bey, Erik A; Li, Long-Shan; Kabbani, Wareef; Yan, Jingsheng; Xie, Xian-Jin; Hsieh, Jer-Tsong; Gao, Jinming; Boothman, David A

2010-10-12

273

EGFR antisense RNA blocks expression of the epidermal growth factor receptor and partially reverse the malignant phenotype of human breast cancer MDA-MB-231 cells  

Microsoft Academic Search

The effects of human EGFR to the malignant phenotype of human breast cancer cell line MDA-MB-231 were investigated experimentally. A retroviral vector containing a 5'1350bp fragment of the human EGFR cDNA in the antisense orientation was transfected into targeted cells by lipofectamine. The effects on cell proliferation, cell cycle and adherent ability to extracellular matrix (ECM) components were studied after

Wen Hong Fan; Ying Lin Lu; Fan Deng; Xue Ming Ge; Shuang Liu; Pie-Hesin Tang; Pei-Hesin Tang

1998-01-01

274

Horizontal transmission of malignancy: in-vivo fusion of human lymphomas with hamster stroma produces tumors retaining human genes and lymphoid pathology.  

PubMed

We report the in-vivo fusion of two Hodgkin lymphomas with golden hamster cheek pouch cells, resulting in serially-transplanted (over 5-6 years) GW-532 and GW-584 heterosynkaryon tumor cells displaying both human and hamster DNA (by FISH), lymphoma-like morphology, aggressive metastasis, and retention of 7 human genes (CD74, CXCR4, CD19, CD20, CD71, CD79b, and VIM) out of 24 tested by PCR. The prevalence of B-cell restricted genes (CD19, CD20, and CD79b) suggests that this uniform population may be the clonal initiating (malignant) cells of Hodgkin lymphoma, despite their not showing translation to their respective proteins by immunohistochemical analysis. This is believed to be the first report of in-vivo cell-cell fusion of human lymphoma and rodent host cells, and may be a method to disclose genes regulating both organoid and metastasis signatures, suggesting that the horizontal transfer of tumor DNA to adjacent stromal cells may be implicated in tumor heterogeneity and progression. The B-cell gene signature of the hybrid xenografts suggests that Hodgkin lymphoma, or its initiating cells, is a B-cell malignancy. PMID:23405135

Goldenberg, David M; Gold, David V; Loo, Meiyu; Liu, Donglin; Chang, Chien-Hsing; Jaffe, Elaine S

2013-02-06

275

Horizontal Transmission of Malignancy: In-Vivo Fusion of Human Lymphomas with Hamster Stroma Produces Tumors Retaining Human Genes and Lymphoid Pathology  

PubMed Central

We report the in-vivo fusion of two Hodgkin lymphomas with golden hamster cheek pouch cells, resulting in serially-transplanted (over 5–6 years) GW-532 and GW-584 heterosynkaryon tumor cells displaying both human and hamster DNA (by FISH), lymphoma-like morphology, aggressive metastasis, and retention of 7 human genes (CD74, CXCR4, CD19, CD20, CD71, CD79b, and VIM) out of 24 tested by PCR. The prevalence of B-cell restricted genes (CD19, CD20, and CD79b) suggests that this uniform population may be the clonal initiating (malignant) cells of Hodgkin lymphoma, despite their not showing translation to their respective proteins by immunohistochemical analysis. This is believed to be the first report of in-vivo cell-cell fusion of human lymphoma and rodent host cells, and may be a method to disclose genes regulating both organoid and metastasis signatures, suggesting that the horizontal transfer of tumor DNA to adjacent stromal cells may be implicated in tumor heterogeneity and progression. The B-cell gene signature of the hybrid xenografts suggests that Hodgkin lymphoma, or its initiating cells, is a B-cell malignancy.

Goldenberg, David M.; Gold, David V.; Loo, Meiyu; Liu, Donglin; Chang, Chien-Hsing; Jaffe, Elaine S.

2013-01-01

276

Large-scale molecular comparison of human schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues.  

PubMed

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 and exhibit diverse alterations in expression of pRb, p53, p14(Arf), and p16(INK4a) proteins. All MPNST cell lines express the epidermal growth factor receptor and lack S100beta protein. Global gene expression profiling using Affymetrix oligonucleotide microarrays identified a 159-gene molecular signature distinguishing MPNST cell lines from normal Schwann cells, which was validated in Affymetrix microarray data generated from 45 primary MPNSTs. Expression of Schwann cell differentiation markers (SOX10, CNP, PMP22, and NGFR) was down-regulated in MPNSTs whereas neural crest stem cell markers, SOX9 and TWIST1, were overexpressed in MPNSTs. Previous studies have implicated TWIST1 in apoptosis inhibition, resistance to chemotherapy, and metastasis. Reducing TWIST1 expression in MPNST cells using small interfering RNA did not affect apoptosis or chemoresistance but inhibited cell chemotaxis. Our results highlight the use of gene expression profiling in identifying genes and molecular pathways that are potential biomarkers and/or therapeutic targets for treatment of MPNST and support the use of the MPNST cell lines as a primary analytic tool. PMID:16510576

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

2006-03-01

277

In vitro response to Corynebacterium parvum of human effusion lymphocytes isolated from patients with malignant and benign disease.  

PubMed

Non-adherent effusion cells (EC), mostly lymphocytes, were isolated from the pleural effusions of 8 patients with malignant and 7 patients with benign disease. Corynebacterium parvum (Cp) induced increased methyl-3H-thymidine (methyl-3H-TdR) incorporation in EC cultures, but the response was lower than that usually found with autologous or allogeneic normal human blood lymphocytes. Experiments with highly purified effusion lymphocytes indicated that the response to CP was influenced by the presence of adherent cells, probably macrophages. Normal human monocytes incubated in vitro with supernatants of unstimulated EC cultures expressed slightly increased ability to suppress methyl-3H-TdR-incorporation in a human tumour cell line. Supernatants of Cp-stimulated EC induced a further increase in monocyte-mediated cytostatic activity. Cell-free effusion fluid from 8 patients were largely inactive when tested for induction of monocyte-mediated cytostatic activity in the same system, and the effusion fluid reduced monocyte methyl-3H-TdR-incorporation in vitro. Thus, Cp seems to be able to induce DNA-synthesis and release of mononuclear phagocyte-activating lymphokines in human effusion lymphocytes. PMID:7446130

Hammerstrøm, J

1980-08-01

278

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

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

2000-01-01

279

[Standardized recall antigen testing in patients with malignant melanoma, endogenous eczema patients and healthy humans].  

PubMed

By means of a new test kit (Multitest), intracutaneous tests have been performed on several groups of patients in order to evaluate the degree of cellular immunity. This test system affords the simultaneous application of seven quantitatively and qualitatively standardized antigens. In comparison to healthy people, patients suffering from malignant melanoma showed a slightly higher immunity reaction whereas patients with atopic dermatitis revealed a significantly lesser degree of reactivity to the recall-antigens. Chemotherapy with Dacarbazine did not change the amount of reactivity to the Multitest. This paper discusses the advantages of the new test kit as well as the difficulties of recall-antigen testing with regard to the evaluation of cellular immunity. PMID:6845797

Stenger, D; Delbrück, H; Krumrey, K; Zaun, H

1983-03-01

280

Inhibition of transient receptor potential canonical channels impairs cytokinesis in human malignant gliomas  

PubMed Central

Objectives Glial-derived primary brain tumours, gliomas, are among the fastest growing malignancies and present a huge clinical challenge. Research suggests an important, yet poorly understood, role of ion channels in growth control of normal and malignant cells. In this study, we sought to functionally characterize Transient Receptor Potential Canoncial (TRPC) channels in glioma cell proliferation. TRPC channels form non-selective cation channels that have been suggested to represent a Ca2+ influx pathway impacting cellular growth. Materials and Methods Employing a combination of molecular, biochemical and biophysical techniques, we characterized TRPC channels in glioma cells. Results We showed consistent expression of four channel family members (TRPC-1, -3, -5, -6) in glioma cell lines and acute patient-derived tissues. These channels gave rise to small, non-voltage-dependent cation currents that were blocked by the TRPC inhibitors GdCl3, 2-APB, or SKF96365. Importantly, TRPC channels contributed to the resting conductance of glioma cells and their acute pharmacological inhibition caused an ~10 mV hyperpolarization of the cells’ resting potential. Additionally, chronic application of the TRPC inhibitor SKF96365 caused near complete growth arrest. A detailed analysis, by fluorescence-activated cell sorting and time-lapse microscopy, showed that growth inhibition occurred at the G2 + M phase of the cell cycle with cytokinesis defects. Cells underwent incomplete cell divisions and became multinucleate, enlarged cells. Conclusions Nuclear atypia and enlarged cells are histopathological hallmarks for glioblastoma multiforme, the highest grade glioma, suggesting that a defect in TRPC channel function may contribute to cellular abnormalities in these tumours.

Bomben, V. C.; Sontheimer, H. W.

2009-01-01

281

Radiosensitivity and TP53, EGFR Amplification and LOH10 Analysis of Primary Glioma Cell Cultures  

Microsoft Academic Search

Aim: Determination of in-vitro radiosensitivity and genetic alterations of cell cultures derived from human glioma biopsy tissue and established glioma cell lines. Material and Methods: Fresh brain tumor specimens of six patients were processed to early passage cell cultures. In addition the cell lines D 384 and Gli 6 were used. Cell cultures were irradiated with doses from 2 to

Bärbel Gerlach; Anna H. Harder; Theo J. M. Hulsebos; Sieger Leenstra; Berend J. Slotman; W. Peter Vandertop; Karl-Axel Hartmann; Peter Sminia

2002-01-01

282

Anogenital malignancies and pre-malignancies.  

PubMed

Anogenital pre-malignancies and malignancies are frequently encountered. Aetiopathogenetically, human papillomavirus (HPV) infection plays a critical role. However, there is a variable degree of association of HPV infection with the development of anogenital malignancies. In this context, the high level of clinically unapparent HPV infection should be considered. Therefore, the question arises if the association with HPV is always causative. Besides HPV, pre-existent lichen sclerosus is also an important aetiopathologic factor in the development of anogenital malignancies. Common anogenital pre-malignancies comprise Bowen's disease (BD), Bowenoid papulosis (BP) and erythroplasia of Queyrat (EQ). From a clinical point of view, these are clearly different entities, but from a histopathological point of view, BD, BP and EQ are indistinguishable. They all represent forms of squamous intraepithelial neoplasia (IN). Intraepithelial neoplasia (IN) is not only restricted to squamous variants, but also includes non-squamous IN, Paget's disease (PD) and melanoma in situ. The risk of developing anogenital (pre)malignancies or other tumours is higher in immunocompromised and immunodeficient patients, in particular those suffering from human immunodeficiency virus (HIV) infection. Such risk factors will affect treatment and follow-up modalities. Regarding prophylactic measures, a relatively recent but very important development is the availability of HPV vaccination on a large scale. Momentarily, the effects of such vaccination, on a population-based scale, are not yet clear but will become apparent in the near future. Management of anogenital pre-malignancies and malignancies should be tailor-made and may be organized in a multidisciplinary fashion. PMID:21272092

Henquet, C J M

2011-01-28

283

Identification of expressed genes linked to malignancy of human colorectal carcinoma by parametric clustering of quantitative expression data  

PubMed Central

Background Individual human carcinomas have distinct biological and clinical properties: gene-expression profiling is expected to unveil the underlying molecular features. Particular interest has been focused on potential diagnostic and therapeutic applications. Solid tumors, such as colorectal carcinoma, present additional obstacles for experimental and data analysis. Results We analyzed the expression levels of 1,536 genes in 100 colorectal cancer and 11 normal tissues using adaptor-tagged competitive PCR, a high-throughput reverse transcription-PCR technique. A parametric clustering method using the Gaussian mixture model and the Bayes inference revealed three groups of expressed genes. Two contained large numbers of genes. One of these groups correlated well with both the differences between tumor and normal tissues and the presence or absence of distant metastasis, whereas the other correlated only with the tumor/normal difference. The third group comprised a small number of genes. Approximately half showed an identical expression pattern, and cancer tissues were classified into two groups by their expression levels. The high-expression group had strong correlation with distant metastasis, and a poorer survival rate than the low-expression group, indicating possible clinical applications of these genes. In addition to c-yes, a homolog of a viral oncogene, prognostic indicators included genes specific to glial cells, which gives a new link between malignancy and ectopic gene expression. Conclusions The malignancy of human colorectal carcinoma is correlated with a unique expression pattern of a specific group of genes, allowing the classification of tumor tissues into two clinically distinct groups.

Muro, Shizuko; Takemasa, Ichiro; Oba, Shigeyuki; Matoba, Ryo; Ueno, Noriko; Maruyama, Chiyuri; Yamashita, Riu; Sekimoto, Mitsugu; Yamamoto, Hirofumi; Nakamori, Shoji; Monden, Morito; Ishii, Shin; Kato, Kikuya

2003-01-01

284

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

285

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, 12C6+ and 36Ar18+ 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-112C6+ ions, and 2.9 for both of the two cell lines of 512 keV?m-136Ar18+ 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

286

Effects of the protein kinase inhibitors wortmannin and KN62 on cellular radiosensitivity and radiation-activated S phase and G1/S checkpoints in normal human fibroblasts  

PubMed Central

Wortmannin is a potent inhibitor of phosphatidylinositol (PI) 3-kinase and PI 3-kinase-related proteins (e.g. ATM), but it does not inhibit the activity of purified calmodulin-dependent protein kinase II (CaMKII). In the present study, we compared the effects of wortmannin and the CaMKII inhibitor KN62 on the response of normal human dermal fibroblast cultures to ? radiation. We demonstrate that wortmannin confers a phenotype on normal fibroblasts remarkably similar to that characteristic of cells homozygous for the ATM mutation. Thus wortmannin-treated normal fibroblasts exhibit increased sensitivity to radiation-induced cell killing, lack of temporary block in transition from G1 to S phase following irradiation (i.e. impaired G1/S checkpoint), and radioresistant DNA synthesis (i.e. impaired S phase checkpoint). Wortmannin-treated cultures display a diminished capacity for radiation-induced up-regulation of p53 protein and expression of p21WAF1, a p53-regulated gene involved in cell cycle arrest at the G1/S border; the treated cultures also exhibit decreased capacity for enhancement of CaMKII activity post-irradiation, known to be necessary for triggering the S phase checkpoint. We further demonstrate that KN62 confers a radioresistant DNA synthesis phenotype on normal fibroblasts and moderately potentiates their sensitivity to killing by ? rays, without modulating G1/S checkpoint, p53 up-regulation and p21WAF1 expression following radiation exposure. We conclude that CaMKII is involved in the radiation responsive signalling pathway mediating S phase checkpoint but not in the p53-dependent pathway controlling G1/S checkpoint, and that a wortmannin-sensitive kinase functions upstream in both pathways. © 1999 Cancer Research Campaign

Enns, L; Murray, D; Mirzayans, R

1999-01-01

287

Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells.  

PubMed

The heregulins are a family of ligands with ability to induce phosphorylation of the p185HER-2/neu receptor. Various investigators have reported a variety of responses of mouse and human breast and ovarian cells to this family of ligands including growth stimulation, growth inhibition, apoptosis and induction of differentiation in cells expressing the HER-2/neu receptor. Some of the disparity in the literature has been attributed to variations in the cell lines studied, ligand dose applied, methodologies utilized or model system evaluated (i.e. in vitro or in vivo). To evaluate the effects of heregulin on normal and malignant human breast and ovarian epithelial cells expressing known levels of the HER-2/neu receptor, this report presents the use of several different assays, performed both in vitro and in vivo, in vitro proliferation assays, direct cell counts, clonogenicity under anchorage-dependent and anchorage-independent conditions, as well as the in vivo effects of heregulin on human cells growing in nude mice to address heregulin activity. Using a total of five different biologic assays in nine different cell lines, across two different epithelia and over a one log heregulin dose range, we obtained results that clearly indicate a growth-stimulatory role for this ligand in human breast and ovarian epithelial cells. We find no evidence that heregulin has any growth-inhibitory effects in human epithelial cells. We also quantitated the amount of each member of the type I receptor tyrosine kinase family (RTK I, i.e. HER-1, HER-2, HER-3 and HER-4) in the cell lines employed and correlated this to their respective heregulin responses. These data demonstrate that HER-2/neu overexpression itself affects the expression of other RTK I members and that cells expressing the highest levels of HER-2/neu have the greatest response to HRG. PMID:10557094

Aguilar, Z; Akita, R W; Finn, R S; Ramos, B L; Pegram, M D; Kabbinavar, F F; Pietras, R J; Pisacane, P; Sliwkowski, M X; Slamon, D J

1999-10-28

288

Fully human, HLA-DR-specific monoclonal antibodies efficiently induce programmed death of malignant lymphoid cells  

Microsoft Academic Search

The Human Combinatorial Antibody Library (HuCAL) was screened for antibodies specific to human leukocyte antigen-DR (HLA-DR) that induce programmed death of lymphoma\\/leukemia cells expressing the target antigen. The active Fab fragments were affinity-matured, and engineered to IgG4 antibodies of sub-nanomolar affinity. The antibodies exhibited potent in vitro tumoricidal activity on several lymphoma and leukemia cell lines and on chronic lymphocytic

Bernd Hubner; Corinna Löhning; Robert Rauchenberger; Silke Reiffert; Elisabeth Thomassen-Wolf; Stefan Zahn; Sigmar Leyer; Eva M. Schier; Angelika Zahradnik; Christoph Brunner; Kurt Lobenwein; Benno Rattel; Michael Stanglmaier; Michael Hallek; Mark Wing; Steve Anderson; Matt Dunn; Titus Kretzschmar; Michael Tesar; Zoltan A. Nagy

2002-01-01

289

RNA interference against SPARC promotes the growth of U-87MG human malignant glioma cells  

PubMed Central

Malignant glioma is a highly invasive brain tumor resistant to conventional therapies. Secreted protein acidic and rich in cysteine (SPARC) has been shown to facilitate glioma invasion. However, the effects of SPARC on cell growth have yet to be adequately elucidated. In this study, we constructed a plasmid expressing shRNA against SPARC, evaluated the effect of SPARCshRNA on SPARC expression and then assessed its effect on cell growth in U-87MG cells. Using plasmid-delivered shRNA, we effectively suppressed SPARC expression in U-87MG cells. Cell growth curves and colony formation assay suggested that the introduction of SPARCshRNA resulted in an increase of cell growth and colony formation. We also showed that knockdown of SPARC expression was capable of promoting the cell cycle progression from the G1 to S phase. However, no difference was found in the level of apoptosis. A molecular analysis of signal mediators indicated that the inhibition of p-c-Raf (Ser259) and accumulation of p-GSK-3? (Ser9) and p-AKT (Ser473) may be connected with the growth promotion by SPARC shRNA. Our study may provide an insight into the biological function of SPARC in glioma.

Liu, Haiyan; Xu, Yuanyuan; Chen, Yun; Zhang, Haowen; Fan, Saijun; Feng, Shuang; Liu, Fenju

2011-01-01

290

Potential for cripto-1 in defining stem cell-like characteristics in human malignant melanoma.  

PubMed

The diagnosis of melanoma is becoming ever more frequent. Although surgical excision of early lesions is associated with relatively significant high cure rates, treatment modalities are largely unsuccessful for advanced disease. Characteristics such as cellular heterogeneity and plasticity, expression of certain molecules such as the multidrug resistance protein-1 (MDR1) or the aberrant expression of embryonic signaling molecules and morphogens like Nodal, important for self renewal and pluripotency, suggest that a stem cell-like population may reside in aggressive melanomas. This perspective focuses on preliminary findings obtained in our laboratory which indicate that the expression of the Nodal coreceptor, Cripto-1, in a subset of malignant melanoma cells may be exploited to identify possible melanoma stem cells (MSC). In fact, the use of anti-Cripto-1 antibodies to cell sort Cripto-1-positive cells in the metastatic melanoma cell line C8161 has identified a slow growing, sphere forming subpopulation that expresses increased levels of Oct4, Nanog and MDR1. If current in vivo studies confirm the self renewal and tumorigenic characteristics of these cells, the expression of Cripto-1 may represent a useful marker to identify cancer stem cells in melanoma, and possibly other aggressive tumors as well. PMID:18604175

Strizzi, Luigi; Abbott, Daniel E; Salomon, David S; Hendrix, Mary J C

2008-05-05

291

Hypoxia-induced cell death in human malignant glioma cells: energy deprivation promotes decoupling of mitochondrial cytochrome c release from caspase processing and necrotic cell death  

Microsoft Academic Search

Hypoxia induces apoptosis in primary and transformed cells and in various tumor cell lines in vitro. In contrast, there is little apoptosis and predominant necrosis despite extensive hypoxia in human glioblastomas in vivo. We here characterize ultrastructural and biochemical features of cell death in LN-229, LN-18 and U87MG malignant glioma cells in a paradigm of hypoxia with partial glucose deprivation

J P Steinbach; H Wolburg; A Klumpp; H Probst; M Weller

2003-01-01

292

Long-Term Survival of Dogs with Advanced Malignant Melanoma after DNA Vaccination with Xenogeneic Human Tyrosinase: A Phase I Trial1  

Microsoft Academic Search

Purpose: Canine malignant melanoma (CMM) is a spontaneous, aggressive, and metastatic neoplasm. Preclin- ical mouse studies have shown that xenogeneic DNA vacci- nation with genes encoding tyrosinase family members can induce antibody and cytotoxic T-cell responses, resulting in tumor rejection. These studies provided the rationale for a trial of xenogeneic DNA vaccination in CMM using the human tyrosinase gene. Experimental

Philip J. Bergman; Joanne McKnight; Andrew Novosad; Sarah Charney; John Farrelly; Diane Craft; Michelle Wulderk; Yusuf Jeffers; Michel Sadelain; Ann E. Hohenhaus; Neil Segal; Polly Gregor; Manuel Engelhorn; Isabelle Riviere; Alan N. Houghton; Jedd D. Wolchok

2003-01-01

293

Modulation of oxygen consumption rate and vascular endothelial growth factor mRNA expression in human malignant glioma cells by hypoxia  

Microsoft Academic Search

Cellular responses to hypoxia include modulation of respiration rate and up-regulation of genes which encode for angiogenesis factors. We tested whether human malignant glioma cells vary in their response to hypoxic stress over the range of oxygen concentrations which exist in tumours. In five cell lines tested, decreased oxygen availability resulted in decreased rates of oxygen utilization, however substantial differences

M J Allalunis-Turner; A J Franko; M B Parliament

1999-01-01

294

Major improvement of the reference method of the French drug resistance network for P-glycoprotein detection in human haematological malignancies  

Microsoft Academic Search

The aim of this study was to improve significantly the sensitivity and specificity of the flow cytometric assay of P-glycoprotein (Pgp) implemented and validated by the laboratories of the French Drug Resistance Network [Huet S, Marie JP, Gualde N, Robert J. Reference method for detection of Pgp mediated multidrug resistance in human hematological malignancies: a method validated by the laboratories

Sylvie Huet; Jean-Pierre Marie; Armelle Laurand; Jacques Robert

2005-01-01

295

[Primary malignant bone tumors].  

PubMed

Among human neoplasms, primary malignant bone tumors are fairly rare. They present an incidence rate of roughly 10 cases per 1 million inhabitants per year. During childhood (<15 years), the percentage of malignant bone tumors amounts to 6% of all infantile malignancies. Only leukemia and lymphoma show a higher incidence in adolescence. Of all primary malignant bone tumors, 60% affect patients younger than 45 years and the peak incidence of all bone tumors occurs between 15 and 19 years. The most common primary malignant bone tumors are osteosarcoma (35%), chondrosarcoma (25%), and Ewing's sarcoma (16%). Less frequently (??5%) occurring tumors are chordoma, malignant fibrous histiocytoma of bone, and fibrosarcoma of bone. Vascular primary malignant tumors of bone and adamantinoma are very rare. Staging of the lesion is essential for systemic therapeutic decision-making and includes complete imaging and histo-pathological confirmation of the suspected entity. In most cases, this is established by open- or image-guided biopsy. Based on this information, an interdisciplinary tumor board will determine the individual therapeutic approach. Endoprosthetic or biological reconstruction following wide tumor resection is the most common surgical therapy for primary malignant bone tumors. There is vital importance in a thorough postoperative follow-up and continous after-care by a competent tumor center which is permanentely in charge of therapy. PMID:22130624

von Eisenhart-Rothe, R; Toepfer, A; Salzmann, M; Schauwecker, J; Gollwitzer, H; Rechl, H

2011-12-01

296

Malignant transformation of immortalized human bronchial epithelial cells by asbestos fibers.  

PubMed

Although asbestos is a well-established lung carcinogen, there currently is no suitable human cell model in which to examine the underlying cellular and molecular changes associated with fiber-mediated bronchial carcinogenesis. Using a recently established transformation model based on a human papillomavirus-immortalized human bronchial epithelial cell line, we successfully transformed these BEP2D cells after a single, 7-day treatment with a 20-microgram/ml (4 micrograms per cm2 area) dose of Union Internationale Contre le Cancer (UICC) Rhodesian chrysotile fibers. Asbestos treatment resulted in a surviving fraction of 0.18 compared to control cells. Transformed cells developed through a series of sequential steps, including altered growth kinetics, resistance to serum-induced terminal differentiation, and anchorage-independent growth, before becoming tumorigenic to form progressively growing tumors in nude mice. Seven tumorigenic cell lines were isolated and determined to be of human epithelial origin based on immunofluorescent staining of keratin and isozyme analysis. Analysis of tumor DNA revealed no mutations at either codon 12 or 13 in any the ras oncogenes. An independent role for K-ras mutation in fiber carcinogenesis, therefore, cannot be confirmed. This model provides a unique opportunity to study the cellular and molecular changes at the various stages in fiber-mediated neoplastic transformation of human bronchial epithelial cells. PMID:9400704

Hei, T K; Wu, L J; Piao, C Q

1997-09-01

297

The endothelin axis as therapeutic target in human malignancies: present and future.  

PubMed

To assure their growth advantage cancer cells require the appropriation of key pathways, such as those controlled by G-protein coupled receptor (GPCR), that influence cell growth, migration, and death, as well as the expansion of vascular networks. Accumulating molecular and in vivo evidences demonstrate that the activation of the endothelin-1 (ET-1) axis elicites pleiotropic effects on tumour cells and on the tumour microenvironment as well, modulating epithelial to mesenchymal transition, chemoresistance, and other tumourassociated processes. As ET-1 axis blockade has been shown to reduce tumor growth in preclinical models, several small molecule antagonists of ET-1 receptors are currently undergoing clinical trial as novel agents in cancer therapy. To fully appreciate the potential hegemony of the ET-1 axis in cancer, here we review emerging preclinical and clinical data outlining the spectrum of cellular activities triggered by ET-1 signaling and the challenges facing molecular targeted therapy. Because scaffold proteins, such as ?-arrestin, create signalling platforms that drive cellular transformation upon GPCR activation, mechanisms mediated by ?-arrestin in ET-1 signalling are discussed. Deeper understanding of molecular mechanisms activated by ET-1 receptor, as well as of how pathway crosstalk can influence ET-1 signalling outcome in cancer, is of paramount translational relevance in the study of ET-1 receptor-targeted therapy. The improved knowledge of the interconnected molecular mechanism promoted by ET-1 axis in cancer will certainly result in more effective and durable mechanism-guided combinations of ET-1 receptor antagonists with cytotoxic drugs or other targeted agents in the clinical management of ET-1 axis-dependent malignancies. PMID:22390759

Bagnato, Anna

2012-01-01

298

Effects of curcumin on bleomycin-induced apoptosis in human malignant testicular germ cells.  

PubMed

Testicular cancer is the most common cancer among young men of reproductive age. Bleomycin is a frequently used drug for the treatment of several malignancies and is part of the chemotherapy protocols in testicular cancer. Bleomycin causes an increase in oxidative stress which has been shown to induce apoptosis in cancer cells. Curcumin (diferuloylmethane), an active component of the spice turmeric, has attracted interest because of its anti-inflammatory and chemopreventive activities. However, no study has been carried out so far to elucidate its interaction with bleomycin in testicular cancer cells. In this study, we investigated the effects of curcumin and bleomycin on apoptosis signalling pathways and compared the effects of bleomycin with H2O2 which directly produces reactive oxygen species. We measured apoptosis markers such as caspase-3, caspase-8, and caspase-9 activities and Bcl-2, Bax, and Cyt-c levels in NCCIT cells incubated with curcumin (5 ?M), bleomycin (120 ?g/ml), bleomycin + curcumin, H2O2 (35 ?M), and H2O2 + curcumin for 72 h. Curcumin, bleomycin, and H2O2 caused apoptosis indicated as increases in caspase-3, caspase-8, and caspase-9 activities and Bax and cytoplasmic Cyt-c levels and a decrease in Bcl-2 level. Concurrent use of curcumin with bleomycin decreased caspase activities and Bax and Cyt-c levels compared to their separate effects in NCCIT cells. Our findings suggest that concurrent use of curcumin during chemotherapy in testis cancer should be avoided due to the inhibitory effect of curcumin on bleomycin-induced apoptosis. PMID:23001851

Cort, Aysegul; Timur, Mujgan; Ozdemir, Evrim; Ozben, Tomris

2012-09-23

299

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

PubMed

As compared with peptide- or protein-based vaccines, naked DNA vectors and even traditional attenuated or inactivated virus vaccines, virus-like particles (VLPs) are an attractive vaccine platform, as 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, HPV vaccines based on VLP production by recombinant expression of major capsid antigen L1 in yeast (Gardasil(®), Merck & Co., NJ, USA) or insect cells (Cervarix(®), GlaxoSmithKline, London, UK) have been licensed for the prevention of cervical and anogenital infection and disease associated with the genotypes targeted by each vaccine. However, these HPV vaccines 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. In this article, the authors 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

2013-02-01

300

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

301

Telomerase-immortalized non-malignant human prostate epithelial cells retain the properties of multipotent stem cells  

SciTech Connect

Understanding prostate stem cells may provide insight into the origin of prostate cancer. Primary cells have been cultured from human prostate tissue but they usually survive only 15-20 population doublings before undergoing senescence. We report here that RC-170N/h/clone 7 cells, a clonal cell line from hTERT-immortalized primary non-malignant tissue-derived human prostate epithelial cell line (RC170N/h), retain multipotent stem cell properties. The RC-170N/h/clone 7 cells expressed a human embryonic stem cell marker, Oct-4, and potential prostate epithelial stem cell markers, CD133, integrin {alpha}2{beta}1{sup hi} and CD44. The RC-170N/h/clone 7 cells proliferated in KGM and Dulbecco's Modified Eagle Medium with 10% fetal bovine serum and 5 {mu}g/ml insulin (DMEM + 10% FBS + Ins.) medium, and differentiated into epithelial stem cells that expressed epithelial cell markers, including CK5/14, CD44, p63 and cytokeratin 18 (CK18); as well as the mesenchymal cell markers, vimentin, desmin; the neuron and neuroendocrine cell marker, chromogranin A. Furthermore the RC170 N/h/clone 7 cells differentiated into multi tissues when transplanted into the sub-renal capsule and subcutaneously of NOD-SCID mice. The results indicate that RC170N/h/clone 7 cells retain the properties of multipotent stem cells and will be useful as a novel cell model for studying the mechanisms of human prostate stem cell differentiation and transformation.

Li Hongzhen [Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD 20814 (United States); Zhou Jianjun [Dermatology Branch, National Cancer Institute, NIH, Bethesda, MD 20892 (United States); Miki, Jun [Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD 20814 (United States); Furusato, Bungo [Department of Genitourinary Pathology, Armed Forces Institutes of Pathology, Washington, DC 20307 (United States); Gu Yongpeng; Srivastava, Shiv; McLeod, David G. [Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD 20814 (United States); Vogel, Jonathan C. [Dermatology Branch, National Cancer Institute, NIH, Bethesda, MD 20892 (United States); Rhim, Johng S. [Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD 20814 (United States)], E-mail: jrhim@cpdr.org

2008-01-01

302

Differential expression of neurotensin and specific receptors, NTSR1 and NTSR2, in normal and malignant human B lymphocytes.  

PubMed

Neurotensin, a neuropeptide growth factor, and its two specific neurotensin receptors, NTSR1 and NTSR2, were shown to be expressed by human B cell lines. Another NTSR, sortilin, which is common to neurotensin and neurotrophins, was also detected as we have previously described. Neurotensin was functional in B cell lines; it induced their proliferation and inhibited apoptosis induced by serum deprivation or Fas activation. Quantitative study of gene expression in two malignant B cell diseases showed that NTSR2 was overexpressed, NTSR1 decreased, and neurotensin was unexpressed in B cell leukemia patient's cells, as compared with healthy B cells. However, these expressions did not significantly change in large diffuse B cell lymphoma lymph nodes compared with benign ones. This study points out that neurotensin and its two specific receptors are expressed in human B lymphocytes. Such expressions were not described, and their relationship in B cell diseases, especially in chronic B cell leukemia, needs to be considered further in regard to these findings. PMID:23109725

Saada, Sofiane; Marget, Pierre; Fauchais, Anne-Laure; Lise, Marie-Claude; Chemin, Guillaume; Sindou, Philippe; Martel, Clothilde; Delpy, Laurent; Vidal, Elisabeth; Jaccard, Arnaud; Troutaud, Danielle; Lalloué, Fabrice; Jauberteau, Marie-Odile

2012-10-29

303

Growth-inhibitory effects of coumarin (1,2-benzopyrone) and 7-hydroxycoumarin on human malignant cell lines in vitro.  

PubMed

Coumarin (1,2-benzopyrone) is a natural substance that has shown antitumor activity in vivo. The major human metabolite of coumarin, 7-hydroxycoumarin (7-HC), is the active form of the drug. While the exact mechanism(s) of action of coumarin is unknown, it has been shown previously that this drug possesses immunomodulatory activity in vitro and in vivo. The present investigations examined the direct (non-immunological) antitumor effects of coumarin and 7-HC in vitro. Both coumarin and 7-HC were found to be growth-inhibitory (cytostatic) for the following human malignant cell lines: A549, ACHN, Caki-2, Dakiki, HS-Sultan, H727, HCT-15, HL-60, K562, LNCaP, PC-3, Du 145 COLO-232, MCF-7 and RP-1788. The growth inhibition was dependent on dose and time and was reversible upon removal of cells from medium containing the drug. Coumarin and 7-HC inhibited [3H]thymidine, [3H]uridine and [3H]leucine incorporation. In a similar fashion, coumarin and 7-HC inhibited the intracellular production of prostate-specific antigen by LNCaP cells. Coumarin and 7-HC stimulated apoptosis in HL-60 cells but not in other cell lines tested. It is concluded that coumarin and 7-HC have direct antitumor (cytostatic) activity as well as immunomodulatory activity. Further information is needed in order to determine which activities are responsible for antitumor activity in vivo. PMID:7510710

Marshall, M E; Kervin, K; Benefield, C; Umerani, A; Albainy-Jenei, S; Zhao, Q; Khazaeli, M B

1994-01-01

304

A rapid and simple assay for human blood malignancy engraftment, homing and chemotherapy treatment using fluorescent imaging of avian embryos.  

PubMed

Detection of grafted human cells in mice using fluorescence is a rapid and simple technique whose use is continually expanding. Robust engraftment of human hematological malignancy (HHM) lines and patient cells into the naturally immunodeficient turkey embryo has recently been demonstrated by polymerase chain reaction (PCR), fluorescence activated cell sorting (FACS) and histology. We demonstrate here that fluorescence imaging is a rapid and simple technique for detecting engraftment and homing of cells derived from HHM in turkey embryos. Raji lymphoma cells expressing a far-red fluorescent protein were injected intravascularly into turkey embryos and fluorescence was detected 8 days later in their limbs and skulls. Much stronger signals were obtained after removal of the bones from the limbs. Unlabeled Raji cells did not give a fluorescent signal. Treatment with doxorubicin dramatically reduced the fluorescent signal. Intravenously injected HL-60 leukemia cells labeled with infrared-fluorescing dye were detected in the bone marrow after 16 h. Homing was active, although some non-specific fluorescence was present. Use of fluorescence imaging of HHM in turkey embryos is therefore feasible and reduces the time, effort and expense for detecting engraftment. This technique has potential to become a high-throughput xenograft system for hematological chemotherapy development and testing, and for study of hematological cell homing. PMID:21895546

Grinberg, Igor; Dukhovny, Anna; Goldstein, Ronald S

2011-11-15

305

Xenotransplantation of human lymphoid malignancies is optimized in mice with multiple immunologic defects  

Microsoft Academic Search

While it is known that mice with genetic immune defects are useful for establishing durable engraftment of human tumor xenografts, the relative role of components of host innate and adoptive immunity in engraftment has not been determined. We directly compared the ability of four strains of genetically immunodeficient mice (NOD\\/SCID, SCID, Nude and Rag-1-deficient) to successfully engraft and support the

WA Hudson; Q Li; C Le; JH Kersey

1998-01-01

306

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.

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

2013-01-01

307

Malignant Melanoma  

PubMed Central

The diagnosis of malignant melanoma does not necessarily imply a grave prognosis. If the tumor is superficial, the chances of surgical cure may be good. Virtually all malignant melanoma arise from junctional nevi. Most nevi of the palms, soles, and genitalia are junctional nevi, therefore prophylactic excision of these nevi is recommended. The surgical treatment of malignant melanoma involves a wide excision and usually skin graft reconstruction. Chemotherapy and immunotherapy are used as adjuncts in the treatment of disseminated disease.

Birdsell, D. S.

1974-01-01

308

Glucose Metabolism Heterogeneity in Human and Mouse Malignant Glioma Cell Lines  

Microsoft Academic Search

Summary The current study examined specific bioenergetic markers associated with the metabolic phenotype of several human and mouse glioma cell lines. Based on preliminary studies, we hypothesized that glioma cells would express one of at least two different metabolic phenotypes, possibly acquired through progression. The D-54MG and GL261 glioma cell lines displayed an oxidative phosphorylation (OXPHOS)-dependent phenotype, characterized by extremely

Corinne E. Griguer; Claudia R. Oliva; G. Yancey Gillespie

2005-01-01

309

Expression of gap junction protein Cx43 in cultured human normal and malignant lung cells  

Microsoft Academic Search

Gap junctional intercellular communication-exchange of small molecules and ions between contiguous cells through membranous\\u000a gap junctional channels-is essential for growth control and tissue homeostasis. This work concerns the functional expression\\u000a of gap junction protein connexin 43 (Cx43) in normal human lung cells and the changes in lung carcinoma cells. By using Northern\\u000a blot hybridization analysis and Cx43 immunocytochemical methods, it

Zhiqian Zhang; Zhongxiang Lin; Youyong Lu; Songniang Meng; Yaling Han; Parker B. Antin

1994-01-01

310

Modulation of human V?24+V?11+ NKT cells by age, malignancy and conventional anticancer therapies  

Microsoft Academic Search

Immunotherapy strategies aimed at increasing human V?24+V?11+ natural killer T (NKT) cell numbers are currently a major focus. To provide further information towards the goal of NKT cell-based immunotherapy, we assessed the effects of age, cancer status and prior anticancer treatment on NKT cell numbers and their expansion capacity following ?-galactosylceramide (?-GalCer) stimulation. The percentage and absolute number of peripheral

T Crough; D M Purdie; M Okai; A Maksoud; M Nieda; A J Nicol

2004-01-01

311

Immune cytolysis of human malignant melanoma by antibody to oncofetal antigen-I (OFA-I)  

Microsoft Academic Search

IgG anti-OFA-I found in melanoma patients was tested for its ability to lyse human tumor cells in antibody-dependent cell-mediated cytotoxicity (ADCC). Sera from 89 stage II melanoma patients which contained non-HLA-related IgG antibody to an OFA-I-positive melanoma cell line (M14) as tested by indirect membrane immunofluorescence (IMI) were originally chosen as possible sources of IgG anti-OFA-I. Of those tested for

Neil Sidell; Reiko F. Irie; S. David Nathanson; Donald L. Morton

1980-01-01

312

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

313

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

PubMed

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

2012-03-13

314

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

315

S-allylcysteine modulates the expression of E-cadherin and inhibits the malignant progression of human oral cancer.  

PubMed

Oral cancer is a prevalent type of cancer in Asian countries. Several studies indicated that garlic extracts such as diallyl disulfide (DADS) and diallyl trisulfide (DATS) have anticancer effects. However, the inhibitory effects of water soluble garlic extracts, S-allylcysteine (SAC), on the malignant progression of oral cancer have not been studied well yet. Thus, the purpose of this study was to investigate the inhibitory effects of SAC on the proliferation and progression of human oral squamous cancer CAL-27 cells. In the present study, we demonstrated that SAC dose dependently inhibited the growth of human oral squamous cancer cells. Our results showed that SAC induced the expression of E-cadherin adhesion molecule. Immunocytochemical staining result also revealed that SAC could restore the distribution of E-cadherin molecule on cell membrane. We further demonstrated that SAC stabilized the adherent junction complex of E-cadherin/beta-catenin in oral cancer cells. Treatment with the MAPK/MEK specific inhibitor, PD098059, could up-regulate the expression of E-cadherin molecule. Furthermore, SAC significantly inhibited the activation of MAPK/ERK signaling pathway. These findings were associated with the down-regulation of the SLUG repressor protein. In conclusion, our results indicated that SAC effectively inhibited the proliferation, up-regulated the expression of E-cadherin molecule and stabilized the E-cadherin/beta-catenin adherent junction complex in human oral squamous cancer cells. The mechanism of action was in part through the suppression of MAPK/ERK signaling pathway and down-regulation of the SLUG repressor protein. PMID:19157822

Tang, Feng-Yao; Chiang, En-Pei Isabel; Chung, Jing-Gung; Lee, Hong-Zin; Hsu, Chia-Yun

2009-01-20

316

Transcutaneous Application of Carbon Dioxide (CO2) Induces Mitochondrial Apoptosis in Human Malignant Fibrous Histiocytoma In Vivo  

PubMed Central

Mitochondria play an essential role in cellular energy metabolism and apoptosis. Previous studies have demonstrated that decreased mitochondrial biogenesis is associated with cancer progression. In mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1?) regulates the activities of multiple nuclear receptors and transcription factors involved in mitochondrial proliferation. Previously, we showed that overexpression of PGC-1? leads to mitochondrial proliferation and induces apoptosis in human malignant fibrous histiocytoma (MFH) cells in vitro. We also demonstrated that transcutaneous application of carbon dioxide (CO2) to rat skeletal muscle induces PGC-1? expression and causes an increase in mitochondrial proliferation. In this study, we utilized a murine model of human MFH to determine the effect of transcutaneous CO2 exposure on PGC-1? expression, mitochondrial proliferation and cellular apoptosis. PGC-1? expression was evaluated by quantitative real-time PCR, while mitochondrial proliferation was assessed by immunofluorescence staining and the relative copy number of mitochondrial DNA (mtDNA) was assessed by real-time PCR. Immunofluorescence staining and DNA fragmentation assays were used to examine mitochondrial apoptosis. We also evaluated the expression of mitochondrial apoptosis related proteins, such as caspases, cytochorome c and Bax, by immunoblot analysis. We show that transcutaneous application of CO2 induces PGC-1? expression, and increases mitochondrial proliferation and apoptosis of tumor cells, significantly reducing tumor volume. Proteins involved in the mitochondrial apoptotic cascade, including caspase 3 and caspase 9, were elevated in CO2 treated tumors compared to control. We also observed an enrichment of cytochrome c in the cytoplasmic fraction and Bax protein in the mitochondrial fraction of CO2 treated tumors, highlighting the involvement of mitochondria in apoptosis. These data indicate that transcutaneous application of CO2 may represent a novel therapeutic tool in the treatment of human MFH.

Onishi, Yasuo; Kawamoto, Teruya; Ueha, Takeshi; Kishimoto, Kenta; Hara, Hitomi; Fukase, Naomasa; Toda, Mitsunori; Harada, Risa; Minoda, Masaya; Sakai, Yoshitada; Miwa, Masahiko; Kurosaka, Masahiro; Akisue, Toshihiro

2012-01-01

317

Analysis of Mammalian Septin Expression in Human Malignant Brain Tumors1  

PubMed Central

Abstract Septins are a highly conserved subfamily of GTPases that play an important role in the process of cytokinesis. To increase our understanding of the expression and localization of the different mammalian septins in human brain tumors, we used antibodies against septins 2, 3, 4, 5, 6, 7, 9, and 11 in immunofluorescence and Western blot analyses of astrocytomas and medulloblastomas. We then characterized the expression and subcellular distribution of the SEPT2 protein in aphidicolin-synchronized U373 MG astrocytoma cells by immunofluorescence and fluorescence-activated cell sorter analysis. To determine the role of SEPT2 in astrocytoma cytokinesis, we inducibly expressed a dominant-negative (DN) SEPT2 mutant in U373 MG astrocytoma cells. We show variable levels and expression patterns of the different septins in brain tissue, brain tumor specimens, and human brain tumor cell lines. SEPT2 was abundantly expressed in all brain tumor samples and cell lines studied. SEPT3 was expressed in medulloblastoma specimens and cell lines, but not in astrocytoma specimens or cell lines. SEPT2 expression was cell cycle-related, with maximal levels in G2-M. Immunocytochemical analysis showed endogenous levels of the different septins within the perinuclear and peripheral cytoplasmic regions. In mitosis, SEPT2 was concentrated at the cleavage furrow. By immunocytochemistry and flow cytometry, we show that a DN SEPT2 mutant inhibits the completion of cell division and results in the accumulation of multinucleated cells. These results suggest that septins are variably expressed in human brain tumors. Stable expression of the DN SEPT2 mutant leads to a G2-M cell cycle block in astrocytoma cells.

Kim, Dong-Seok; Hubbard, Sherri-Lynn; Peraud, Aurelia; Salhia, Bodour; Sakai, Keiichi; Rutka, James T

2004-01-01

318

Overexpression of GPR39 contributes to malignant development of human esophageal squamous cell carcinoma  

Microsoft Academic Search

Background  By using cDNA microarray analysis, we identified a G protein-coupled receptor, GPR39, that is significantly up-regulated in ESCC. The aim of this study is to investigate the role of GPR39 in human esophageal\\u000a cancer development, and to examine the prevalence and clinical significance of GPR39 overexpression in ESCC.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  The mRNA expression level of GPR39 was analyzed in 9 ESCC cell

Fajun Xie; Haibo Liu; Ying-Hui Zhu; Yan-Ru Qin; Yongdong Dai; Tingting Zeng; Leilei Chen; Changjun Nie; Hong Tang; Yan Li; Li Fu; Xin-Yuan Guan

2011-01-01

319

Distinct host cell fates for human malignant melanoma targeted by oncolytic rodent parvoviruses.  

PubMed

The rodent parvoviruses are known to be oncoselective, and lytically infect many transformed human cells. Because current therapeutic regimens for metastatic melanoma have low response rates and have little effect on improving survival, this disease is a prime candidate for novel approaches to therapy, including oncolytic parvoviruses. Screening of low-passage, patient-derived melanoma cell lines for multiplicity-dependent killing by a panel of five rodent parvoviruses identified LuIII as the most melanoma-lytic. This property was mapped to the LuIII capsid gene, and an efficiently melanoma tropic chimeric virus shown to undergo three types of interaction with primary human melanoma cells: (1) complete lysis of cultures infected at very low multiplicities; (2) acute killing resulting from viral protein synthesis and DNA replication, without concomitant expansion of the infection, due to failure to export progeny virions efficiently; or (3) complete resistance that operates at an intracellular step following virion uptake, but preceding viral transcription. PMID:24074565

Vollmers, Ellen M; Tattersall, Peter

2013-08-09

320

ROR1 and ROR2 in Human Malignancies: Potentials for Targeted Therapy  

PubMed Central

Targeted therapies require cellular protein expression that meets specific requirements that will maximize effectiveness, minimize off-target toxicities, and provide an opportunity for a therapeutic effect. The receptor tyrosine kinase-like orphan receptors (ROR) are possible targets for therapy that may meet such requirements. RORs are transmembrane proteins that are part of the receptor tyrosine kinase (RTK) family. The RORs have been shown to play a role in tumor-like behavior, such as cell migration and cell invasiveness and are normally not expressed in normal adult tissue. As part of the large effort in target discovery, ROR proteins have recently been found to be expressed in human cancers. Their unique expression profiles may provide a novel class of therapeutic targets for small molecules against the kinase or for antibody-based therapies against these receptors. Being restricted on tumor cells and not on most normal tissues, RORs are excellent targets for the treatment of minimal residual disease, the final hurdle in the curative approach to many cancers, including solid tumors such as neuroblastoma. In this review, we summarize the biology of RORs as they relate to human cancer, and highlight the therapeutic approaches directed toward them.

Rebagay, Guilly; Yan, Su; Liu, Cheng; Cheung, Nai-Kong

2012-01-01

321

The Zfx gene is expressed in human gliomas and is important in the proliferation and apoptosis of the human malignant glioma cell line U251  

PubMed Central

Background Zfx is a zinc finger protein of the Zfy family, whose members are highly conserved in vertebrates. Zfx is a shared transcriptional regulator of both embryonic stem cells (ESC) and hematopoietic stem cells (HSC), which suggests a common genetic basis of self-renewal in embryonic and adult stem cells. The level of Zfx expression correlates with aggressiveness and severity in many cancer types, including prostate cancer, breast cancer, and leukemia. However, the importance of Zfx in human glioma is largely unknown. In the present study, we examined the role of Zfx in human glioma. Methods We detected expression levels of Zfx mRNA in U251 cells, U87 cells, U373 cells, and A172 cells by semi-quantitative RT-PCR. To analyze the expression of Zfx mRNA in glioma tissues, we performed real-time quantitative PCR on 35 pathologically confirmed glioma samples (Grade I-4cases, Grade II-13cases, Grade III-11cases, and Grade IV-7cases) and on 5 noncancerous brain tissue samples. We used lentivirus-mediated small interfering RNAs (siRNAs) to knock down Zfx expression in the human malignant glioma cell line U251. Changes in Zfx target gene expression were determined by real-time RT-PCR. Cell proliferation was examined by a High Content Screening assay. DNA synthesis in proliferating cells was determined by BrdU incorporation. Cell cycle distribution and apoptosis were detected by flowcytometric analysis. Results We discovered that Zfx mRNA was expressed in U251 cells, U87 cells, U373 cells, and A172 cells. The expression level of Zfx is significantly higher in gliomas compared to noncancerous brain tissue. Using a lentivirus-based RNAi approach, Zfx expression was significantly inhibited in human glioblastoma U251 cells. The effects of Zfx knockdown on cell proliferation, cell cycle distribution, and apoptosis were assessed. Inhibition of Zfx expression in U251 cells by RNAi significantly impaired cell proliferation, increased apoptosis, and arrested cells in S phase. Conclusions The results of our study demonstrate that the Zfx gene is highly expressed in glioma tissue and in glioma cell lines. Furthermore, Zfx may play a critical role in cell proliferation, cell cycle distribution, and apoptosis of human malignant glioma cells.

2011-01-01

322

SU5416 and EGCG Work Synergistically and Inhibit Angiogenic and Survival Factors and Induce Cell Cycle Arrest to Promote Apoptosis in Human Malignant Neuroblastoma SH-SY5Y and SK-N-BE2 Cells  

Microsoft Academic Search

Malignant neuroblastomas are solid tumors in children. Available therapeutic agents are not highly effective for treatment\\u000a of malignant neuroblastomas. Therefore, new treatment strategies are urgently needed. We tested the efficacy of combination\\u000a of SU5416 (SU), an inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR-2), and (?)-epigallocatechin-3-gallate\\u000a (EGCG), a polyphenolic compound from green tea, for controlling growth of human malignant

Nishant Mohan; Surajit Karmakar; Naren L. Banik; Swapan K. Ray

323

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

324

Characterization of 17beta-hydroxysteroid dehydrogenase isoenzyme expression in benign and malignant human prostate.  

PubMed

In the present study, expressions of 17beta-hydroxysteroid dehydrogenase (17HSD) types 1, 2, and 3, 5alpha-reductase type 2 and human androgen receptor mRNAs were determined in 12 benign prostatic hyperplasia and 17 prostatic carcinoma specimens. 17HSD type 2 was found to be the principle isoenzyme expressed in the prostate. Significantly higher expressions of 17HSD type 2 and 5alpha-reductase type 2 were detected in benign prostatic hyperplasia compared with the carcinoma specimens. Expression of the androgen receptor in the 2 groups was not significantly different. 17HSD type 3 mRNA was not detected in any of the specimens investigated. Only low constructive expression of the 2.3 kb mRNA of 17HSD type 1 was seen. Immunohistochemical analysis indicated that this did not lead to significant enzyme expression, only faint staining for the enzyme protein being detected, mainly in uroepithelial cells. No significant correlation was found between any of the mRNAs analysed, but the data on 5alpha-reductase type 2 mRNA support the presence of an increased proportion of 5alpha-dihydrotesterone in the hyperplastic prostate. In cultured PC-3 prostatic cancer cells and in the transiently transfected human embryonic kidney 293 cells, 17HSD type 2 was found exclusively to convert 5alpha-dihydrotestosterone and testosterone into the less potent 17-keto compounds 5alpha-androstanedione and 4-androstenedione, respectively. We suggest that the 17HSD type 2 isoenzyme plays a part in the metabolic pathway, resulting in the inactivation of testosterone and 5alpha-dihydrotestosterone locally in the prostate. The enzyme expressed in the prostate could, therefore, protect cells from excessive androgen action. PMID:8608963

Elo, J P; Akinola, L A; Poutanen, M; Vihko, P; Kyllönen, A P; Lukkarinen, O; Vihko, R

1996-03-28

325

Radiation-induced autophosphorylation of epidermal growth factor receptor in human malignant mammary and squamous epithelial cells  

SciTech Connect

In an effort to identify events initiating up-regulation of epidermal growth factor receptor after single and repeated radiation exposures, we investigated the role of epidermal growth factor receptor, a receptor protein tyrosine kinase, in radiation-induced signal transduction. Human malignant mammary, MCF-7, and squamous, A431, cells showed low baseline phospho-tyrosine levels of epidermal growth factor receptor, permitting reproducible dose-dependent stimulation of epidermal growth factor receptor autophosphorylation after exposure to epidermal growth factor. MCF-7 cells exhibited a mean 2.3-fold increase (95% confidence interval: 1.91, 2.65; P < 0.0001) in levels of epidermal growth factor phosphorylation in response to exposures of 2 Gy, which was substantially less than the epidermal growth factor receptor Y phosphorylation induced by epidermal growth factor. A quantitatively similar radiation response was seen in A431 cells. In the dose range of 1 to 4 Gy, no clear dose response was seen. There was a rapid induction of radiation-induced epidermal growth factor receptor Y phosphorylation, starting within 2 min, with maximum values between 0.5 and 5 min after radiation exposure followed by a slower decline to baseline levels after 20 min. The data presented identify the epidermal growth factor receptor protein tyrosine kinase associated with the plasma membrane as one target for ionizing radiation in the dose range used in radiotherapy. 20 refs., 4 figs.

Schmidt-Ullrich, R.K.; Valerie, K.; Fogleman, P.B.; Walters, J. [Virginia Commonwealth Univ., Richmond, VA (United States)

1996-01-01

326

Comparative genomic hybridization of human malignant gliomas reveals multiple amplification sites and nonrandom chromosomal gains and losses.  

PubMed

Nine human malignant gliomas (2 astrocytomas grade III and 7 glioblastomas) were analyzed using comparative genomic hybridization (CGH). In addition to the amplification of the EGFR gene at 7p12 in 4 of 9 cases, six new amplification sites were mapped to 1q32, 4q12, 7q21.1, 7q21.2-3, 12p, and 22q12. Nonrandom chromosomal gains and losses were identified with overrepresentation of chromosome 7 and underrepresentation of chromosome 10 as the most frequent events (1 of 2 astrocytomas, 7 of 7 glioblastomas). Gain of a part or the whole chromosome 19 and losses of chromosome bands 9pter-23 and 22q13 were detected each in five cases. Loss of chromosome band 17p13 and gain of chromosome 20 were revealed each in three cases. The validity of the CGH data was confirmed using interphase cytogenetics with YAC clones, chromosome painting in tumor metaphase spreads, and DNA fingerprinting. A comparison of CGH data with the results of chromosome banding analyses indicates that metaphase spreads accessible in primary tumor cell cultures may not represent the clones predominant in the tumor tissue. PMID:8203461

Schröck, E; Thiel, G; Lozanova, T; du Manoir, S; Meffert, M C; Jauch, A; Speicher, M R; Nürnberg, P; Vogel, S; Jänisch, W

1994-06-01

327

Dynamic cell adhesion and viscoelastic signatures distinguish normal from malignant human mammary cells using quartz crystal microbalance.  

PubMed

During transformation of a normal cell to a cell capable of forming a cancerous growth, cellular morphology, the cytoskeleton, and focal contacts undergo significant changes. These changes should be capable of being characterized via real-time monitoring of the dynamic cell adhesion process and viscoelastic properties of cells. Here, we describe use of the quartz crystal microbalance (QCM) to distinguish the dynamic cell adhesion signatures of human normal (HMEC) versus malignant (MCF-7) mammary epithelial cells. The significantly reduced QCM responses (changes in frequency [?f] and motional resistance ?R) of MCF-7 cells compared with those of HMECs mirror the cancer cells' morphological features as observed via optical microscope. We analyzed the initial 2-h cell adhesion kinetics, suggesting cell-cell cooperativity for HMECs and no or weak cell-cell interactions for MCF-7 cells. We propose that changes of the ?R/?f ratio, which we term the cell viscoelastic index (CVI), reflect the establishment of cytoskeleton structure and dynamic viscoelastic properties of living cells. The CVI decreases significantly on initiation of cell to surface interactions as cells establish their cytoskeletal structures. During the cell adhesion process, MCF-7 cells were consistently softer, exhibiting up to a 2.5-fold smaller CVI when compared with HMECs. PMID:22119070

Zhou, Tiean; Marx, Kenneth A; Dewilde, Abiche H; McIntosh, Donna; Braunhut, Susan J

2011-11-07

328

Malignant transformation of diploid human fibroblasts by transfection of oncogenes. Part 2, Progress report, July 1989--June 1992  

SciTech Connect

This document consist of brief reports prepared by postdoctoral students supported by the project, each describing his accomplishments under the grant. Topics include (1) Malignant Transformation of MSU-1. 1 Cells by Gamma Radiation, (2) Correlation between Levels of ras Expression and Presence of Transformed Phenotypes Including Tumorigenicity, Using a Modulatable Promoter, (3) Relation between Specific rad Oncogene Expression, (4) Correlation of Genetic Changes in Fibroblastic Tumors with Malignancies, (5)Transformation of MSU-1.1 Cells by sis Oncogene, (6) Malignant Transformation of MSU-1.0 Cells, (7) Correlation of Urokinase Plasminogen Activation (mu-PA) with Malignant Phenotype, (8)Two Dimensional Gel Electrophoresis Studies of the Proteins of the Major Cell Strains of the MSU-1 Family of Cells, and (9) Correlation between Proteinase Activity Levels and Malignancy.

McCormick, J.J.

1992-12-31

329

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.

2012-01-01

330

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

331

Expression of hemidesmosomal and extracellular matrix proteins by normal and malignant human prostate tissue.  

PubMed Central

The progression of prostate carcinoma may be influenced by the biochemical nature of the basal lamina surrounding the primary carcinoma cells. As a first step toward understanding this process, the composition and structure of the basal lamina in normal prostate, prostatic intraepithelial neoplasia, and human carcinoma were determined. In addition, a comparison was made between the attachments of the normal basal cell to its underlying basal lamina and those made by primary prostate carcinoma. The normal basal cells form both focal adhesions and hemidesmosomal-like structures as observed by transmission electron microscopy. The normal basal cells exhibited a polarized distribution of hemidesmosomal associated proteins including BP180, BP230, HD1, plectin, laminin-gamma 2(B2t), collagen VII, and the corresponding integrin laminin receptors alpha 6 beta 1 and alpha 6 beta 4. The expression and distribution pattern of these proteins were retained in the prostate intraepithelial neoplasia lesions. In contrast, the carcinoma cells uniformly lacked hemidesmosomal structures, the integrin alpha 6 beta 4, BP180, laminin-gamma 2 (B2t), and collagen VII but did express BP230 (30%), plectin, HD1 (15%), and the integrin laminin receptors alpha 3 beta 1 and alpha 6 beta 1. These results suggest that, although a detectable basal lamina structure is present in carcinoma, its composition and cellular attachments are abnormal. The loss of critical cellular attachments may play a role in influencing the progression potential of prostate carcinoma. Images Figure 1 Figure 2 Figure 3 Figure 4

Nagle, R. B.; Hao, J.; Knox, J. D.; Dalkin, B. L.; Clark, V.; Cress, A. E.

1995-01-01

332

Abnormal expression of Pygopus 2 correlates with a malignant phenotype in human lung cancer  

PubMed Central

Background Pygopus 2 (Pygo2) is a Pygo family member and an important component of the Wnt signaling transcriptional complex. Despite this data, no clinical studies investigating Pygo2 expression in lung cancer have yet been reported. Methods In the present study, the expression patterns of Pygo2 were evaluated by immunochemistry in 168 patients with non-small cell lung cancer (NSCLC). We used small interfering RNA (siRNA) to specifically silence Pygo2, and investigated its effect on cell growth by an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis in human lung cancer cell lines. Results Immunohistochemical analysis showed low expression of Pygo2 in normal lung tissues and increased nuclear expression in lung cancer tissues, either with or without perinuclear expression. Abnormal Pygo2 expression was associated with poor differentiation and a high Tumor (T), Node (N) and Metastases (M) stage in NSCLC patients, and correlated with poor prognosis. Using MTT assay we observed that Pygo2 downregulation inhibited cell proliferation; in addition, flow cytometry analysis showed that Pygo2 knockdown induced apoptosis and increased numbers of G1-phase cells and a reduction in S-phase cells. Conclusions We therefore conclude that abnormal Pygo2 protein expression may be a marker for advanced NSCLC. Furthermore, Pygo2 knockdown suppresses cell growth.

2013-01-01

333

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.

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

334

Laser scanning cytometric analysis of cyclin B1 in primary human malignancies.  

PubMed

Cyclins are key components of the cell cycle progression machinery. They activate their partner-dependent kinases (CDKs) and target them to respective substrate proteins within the cell. CDK-mediated phosphorylation of specific sets of proteins drives the cell through particular phases or checkpoints of the cell cycle. During unperturbed growth of normal cells, the timing of expression of several cyclins is discontinuous, occurring at discrete and well-defined periods of the cell cycle. Immunocytochemical detection of cyclins in relation to cell cycle position (DNA content) by multiparameter flow cytometric techniques has provided a new approach to cell cycle studies. This approach, like no other method, can be used to detect the "unscheduled" expression of cyclins, namely, the presentation of G1 cyclins by cells in G2/M and of G2/M cyclins by G1 cells, without the need for cell synchronization. By use of multiparameter flow cytometric and laser scanning cytometric analysis, we correlated the expression of cyclin B1 with cell cycle position in normal lymphocytes stimulated to proliferate by the mitogen phytohemagglutinin and in 28 primary human tumors of different organ and type. Eighteen of the 28 tumors expressed the cyclin B1 in more than 5% of cells (B1 positive), and the rest showed cyclin expression from 2.1 to 5% (B1 negative). In normal lymphocytes, the expression of cyclin B1 was restricted to very late S and G2 + M phases of the cell cycle. In 15 of 18 primary tumors studied, the expression of cyclin B1 was "unscheduled" (unrestricted to particular phases of the cycle). The data suggest that the "unscheduled" expression of cyclin B1 might be a common defect in neoplasia. PMID:9160310

Gorczyca, W; Sarode, V; Juan, G; Melamed, M R; Darzynkiewicz, Z

1997-05-01

335

Overexpression of GPR39 contributes to malignant development of human esophageal squamous cell carcinoma  

PubMed Central

Background By using cDNA microarray analysis, we identified a G protein-coupled receptor, GPR39, that is significantly up-regulated in ESCC. The aim of this study is to investigate the role of GPR39 in human esophageal cancer development, and to examine the prevalence and clinical significance of GPR39 overexpression in ESCC. Methods The mRNA expression level of GPR39 was analyzed in 9 ESCC cell lines and 50 primary ESCC tumors using semi-quantitative RT-PCR. Immunohistochemistry was used to assess GPR39 protein expression in tissue arrays containing 300 primary ESCC cases. In vitro and in vivo studies were done to elucidate the tumorigenic role of GPR39 in ESCC cells. Results We found that GPR39 was frequently overexpressed in primary ESCCs in both mRNA level (27/50, 54%) and protein level (121/207, 58.5%), which was significantly associated with the lymph node metastasis and advanced TNM stage (P < 0.01). Functional studies showed that GPR39 has a strong tumorigenic ability. Introduction of GPR39 gene into ESCC cell line KYSE30 could promote cell proliferation, increase foci formation, colony formation in soft agar, and tumor formation in nude mice. The mechanism by which amplified GPR39 induces tumorigenesis was associated with its role in promoting G1/S transition via up-regulation of cyclin D1 and CDK6. Further study found GPR39 could enhance cell motility and invasiveness by inducing EMT and remodeling cytoskeleton. Moreover, depletion of endogenous GPR39 by siRNA could effectively decrease the oncogenicity of ESCC cells. Conclusions The present study suggests that GPR39 plays an important tumorigenic role in the development and progression of ESCC.

2011-01-01

336

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

2013-01-12

337

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.

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

338

Levels of ?-human Chorionic Gonadotropin in Cerebrospinal Fluid of Patients with Malignant Germ Cell Tumor Can Be Used to Detect Early Recurrence and Monitor the Response to Treatment  

Microsoft Academic Search

Background: Tumor marker-producing germ cell tumors of the central nervous system are malignant and require radiation and\\/or chemotherapy. Although serum ?-human chorionic gonadotropin (hCG) has been used to monitor the course of treatment, the levels of ?-hCG in the cerebrospinal fluid (CSF) have not been measured routinely in the clinic. To determine whether they can be used to evaluate parameters

Takamitsu Fujimaki; Kazuhiko Mishima; Ken Tabuchi; Miyuki Kobayashi; Takaaki Kirino

339

Induction of apoptosis and immune response by all- trans retinoic acid plus interferon-gamma in human malignant glioblastoma T98G and U87MG cells  

Microsoft Academic Search

Glioblastoma is the most common and highly malignant brain tumor. It is also one among the most therapy-resistant human neoplasias.\\u000a Patients die within a year of diagnosis despite the use of available treatment strategies such as surgery, radiotherapy, and\\u000a chemotherapy. Thus, there is a critical need to find a novel therapeutic strategy for treating this disease. Here, we have\\u000a investigated

Azizul Haque; Arabinda Das; Laela M. Hajiaghamohseni; Austin Younger; Naren L. Banik; Swapan K. Ray

2007-01-01

340

Treatment of recurrent malignant glioma by repeated intracerebral injections of human recombinant interleukin-2 alone or in combination with systemic interferon-?. Results of a phase I clinical trial  

Microsoft Academic Search

Nine patients with a recurrent malignant glioma were treated with repeated intracavitary or intracerebroventricular injections of human recombinant interleukin-2 (rIL-2) alone or in combination with systemic interferon-a (IFN-a). Five patients received only rIL-2 and four were treated with rIL-2 plus subcutaneous injections of IFN-a. Therapy was administered on a Monday, Wednesday, Friday schedule for up to 10 weeks, beginning with

Randall E. Merchant; Daniel W. McVicar; Lynn H. Merchant; Harold F. Young

1992-01-01

341

Expression of the c-kit ProtoOncogene and Its Ligand Stem Cell Factor (SCF) in Normal and Malignant Human Testicular Tissue  

Microsoft Academic Search

Recent findings suggest an important role of the proto-oncogene c-kit, a surface membrane receptor of the tyrosine kinase family, and its ligand stem cell factor (SCF) in normal spermatogenesis and possibly in the pathogenesis of certain testicular germ cell tumors. To further investigate this potential role, the expression of c-kit and SCF was studied in normal and malignant human testicular

Torsten Strohmeyer; David Reese; Rolf Ackermann; Michael Hartmann; Dennis Slamon

1995-01-01

342

Malignant hyperthermia  

PubMed Central

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%.

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

2007-01-01

343

The non-homologous end-joining pathway is not involved in the radiosensitization of mammalian cells by heat shock.  

PubMed

A synergistic increase in cell killing is observed when a heat-shock is administered prior to, during, or immediately after exposure to ionizing radiation (IR). This phenomenon, known as heat-radiosensitization, is believed to be mediated by inhibition of repair of radiation-induced double strand breaks (DSB) when cells are exposed to temperatures above 42 degrees C. However, the mechanism by which heat inhibits DSB repair is unclear. The bulk of radiation-induced DSBs are repaired via the non-homologous end-joining pathway (NHEJ). Several reports indicate that the Ku70 and Ku80 subunits of the mammalian DNA-dependent protein kinase (DNA-PK), a complex involved in NHEJ, appear to be susceptible to a heat-induced loss of DNA-binding activity, with Ku80 representing the heat-sensitive component. Since the heat-induced loss and subsequent recovery of Ku-DNA binding activity correlates well with heat-radiosensitization, a role for Ku80 and NHEJ in heat-radiosensitization has been proposed. However, direct evidence implicating Ku80 (and NHEJ) in heat-radiosensitization has been indeterminate. In this study, we demonstrate that equitoxic heat treatments at 42.5-45.5 degrees C induce a similar amount of aggregation of Ku80 in human U-1 melanoma cells. These data suggest that the time-temperature-dependent relationship between heat lethality and Ku80 aggregation are similar. However, the aggregation/disaggregation of Ku80 and its transient or permanent inactivation is unrelated to heat-radiosensitization. When survival curves were obtained for irradiated or irradiated and heated Ku80(-/-) mouse embryo fibroblasts (MEFs) and compared with survival curves obtained for wild-type (WT) cells, we found that heat-radiosensitization was not reduced in the Ku80(-/-) cells, but actually increased. Thus, our findings indicate that Ku80 is not essential for heat-radiosensitization. Non-involvement of Ku-dependent or Ku-independent NHEJ pathways in heat-radiosensitization was confirmed by comparing clonogenic survival between DNA ligase IV-defective and WT human cells. Our data therefore implicate homologous recombination in inhibition of repair of radiation-induced DSBs and as a target for heat-radiosensitization. PMID:12891712

Dynlacht, Joseph R; Bittner, M Eric; Bethel, Jody A; Beck, Brian D

2003-09-01

344

Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs  

PubMed Central

A role for microRNA (miRNA) has been recognized in nearly every biologic system examined thus far. A complete delineation of their role must be preceded by the identification of all miRNAs present in any system. We elucidated the complete small RNA transcriptome of normal and malignant B cells through deep sequencing of 31 normal and malignant human B-cell samples that comprise the spectrum of B-cell differentiation and common malignant phenotypes. We identified the expression of 333 known miRNAs, which is more than twice the number previously recognized in any tissue type. We further identified the expression of 286 candidate novel miRNAs in normal and malignant B cells. These miRNAs were validated at a high rate (92%) using quantitative polymerase chain reaction, and we demonstrated their application in the distinction of clinically relevant subgroups of lymphoma. We further demonstrated that a novel miRNA cluster, previously annotated as a hypothetical gene LOC100130622, contains 6 novel miRNAs that regulate the transforming growth factor-? pathway. Thus, our work suggests that more than a third of the miRNAs present in most cellular types are currently unknown and that these miRNAs may regulate important cellular functions.

Jima, Dereje D.; Zhang, Jenny; Jacobs, Cassandra; Richards, Kristy L.; Dunphy, Cherie H.; Choi, William W. L.; Yan Au, Wing; Srivastava, Gopesh; Czader, Magdalena B.; Rizzieri, David A.; Lagoo, Anand S.; Lugar, Patricia L.; Mann, Karen P.; Flowers, Christopher R.; Bernal-Mizrachi, Leon; Naresh, Kikkeri N.; Evens, Andrew M.; Gordon, Leo I.; Luftig, Micah; Friedman, Daphne R.; Weinberg, J. Brice; Thompson, Michael A.; Gill, Javed I.; Liu, Qingquan; How, Tam; Grubor, Vladimir; Gao, Yuan; Patel, Amee; Wu, Han; Zhu, Jun; Blobe, Gerard C.; Lipsky, Peter E.; Chadburn, Amy

2010-01-01

345

Human papillomavirus type 16 E6/E7-specific cytotoxic T lymphocytes for adoptive immunotherapy of HPV-associated malignancies.  

PubMed

Vaccines prevent human papillomavirus (HPV)-associated cancer but, although these tumors express foreign, viral antigens (E6 and E7 proteins), they have little benefit in established malignancies, likely due to negative environmental cues that block tumor recognition and induce T-cell anergy in vivo. We postulated that we could identify mechanisms by which ex vivo stimulation of T cells could reactivate and expand tumor-directed T-cell lines from HPV cancer patients for subsequent adoptive immunotherapy. A total of 68 patients with HPV-associated cancers were studied. Peripheral blood T cells were stimulated with monocyte-derived dendritic cells loaded with pepmixes [peptide libraries of 15-mers overlapping by 11 amino acids (aa)] spanning E6/E7, in the presence or absence of specific accessory cytokines. The resulting T-cell lines were further expanded with pepmix-loaded activated B-cell blasts. Interferon-? release and cytotoxic responses to E6/E7 were assessed. We successfully reactivated and expanded (>1200-fold) E6-specific/E7-specific T cells from 8/16 cervical and 33/52 oropharyngeal cancer patients. The presence of the cytokines interleukin (IL)-6, IL-7, IL-12, and IL-15 is critical for this process. These T-cell lines possess the desirable characteristics of polyclonality, multiple T-cell subset representation (including the memory compartment) and a TH1 bias, and may eliminate E6/E7 targets. In conclusion, we have shown it is possible to robustly generate HPV16 E6/E7-directed T-cell lines from patients with HPV16-associated cancers. Because our technique is scalable and good-manufacturing procedures-compliant, these lines could be used for adoptive cellular immunotherapy of patients with HPV16 cancers. PMID:23211628

Ramos, Carlos A; Narala, Neeharika; Vyas, Gayatri M; Leen, Ann M; Gerdemann, Ulrike; Sturgis, Erich M; Anderson, Matthew L; Savoldo, Barbara; Heslop, Helen E; Brenner, Malcolm K; Rooney, Cliona M

2013-01-01

346

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.

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

2000-01-01

347

Reduced Expression of GINS Complex Members Induces Hallmarks of Pre-malignancy in Primary Untransformed Human Cells  

PubMed Central

In cancer cells ablation of the GINS complex member Psf2 elicits chromosome mis-segregation yet the precise role of Psf2 in mitosis is unknown. We investigated the putative mitotic role of the GINS complex using synchronized cultures of untransformed Human Dermal Fibroblasts (HDF). Metaphase spreads from Psf1/Psf2-depleted HDF were normal and mitotic exit of Psf1/Psf2-depleted cells was only slightly delayed, suggesting no direct role for the GINS complex in mitosis of untransformed cells. Because the GINS complex is required for initiation and elongation events during DNA replication we hypothesized that the mitotic delay of Psf1/Psf2-deficient cells resulted indirectly from defective DNA synthesis during a prior S-phase. Therefore, we investigated the effects of Psf1/Psf2-depletion on DNA replication. Recruitment of Mcm7 to chromatin during G1 was unaffected by Psf1/Psf2-ablation, indicating that replication licensing does not require GINS. However, chromatin-binding of Cdc45 and PCNA and the onset of DNA synthesis were delayed in Psf1/Psf2-ablated cells. The S-phase delay of Psf1/Psf2-depleted cells was associated with hallmarks of pre-malignancy including acquisition of the DNA damage marker ?H2AX, activation of Chk2, and increased Tyr 15 phosphorylation of Cdc2. Ectopic expression of catalytically-inactive Chk2 prevented Cdc2 phosphorylation and resulted in increased numbers of aberrant mitotic cells containing micronuclei, thereby recapitulating the effect of Psf2-deficiency in cancer cells. Therefore, S-phase progression of untransformed cells containing sub-optimal levels of Psf1/2 is associated with replication stress and acquisition of DNA damage. The ensuing Chk2-mediated DNA damage signalling is important for preventing mitotic defects and guarding genome integrity.

Barkley, Laura R.; Song, Ihnyoung; Vaziri, Cyrus

2011-01-01

348

Procaine in Malignant Hyperpyrexia  

Microsoft Academic Search

The caffeine contracture of normal human muscle, which has been used as a model for malignant hyperpyrexia, is greatly potentiated by halothane. Prior administration of procaine markedly reduces the halothane-potentiated caffeine contracture, and procaine given at the height of the contracture induces relaxation. Lignocaine, on the other hand, produces a variable response and sometimes increases the contracture.The muscle from a

R. F. W. Moulds; M. A. Denborough

1972-01-01

349

Radiosensitization of cancer cells by hydroxychalcones  

Microsoft Academic Search

Radiation sensitization is significantly increased by proteotoxic stress, such as a heat shock. We undertook an investigation, seeking to identify natural products that induced proteotoxic stress and then determined if a compound exhibited radiosensitizing properties. The hydroxychalcones, 2?,5?-dihydroxychalcone (D-601) and 2,2?-dihydroxychalcone (D-501), were found to activate heat shock factor 1 (Hsf1) and exhibited radiation sensitization properties in colon and pancreatic

Rory Pruitt; Nidhish Sasi; Michael L. Freeman; Konjeti R. Sekhar

2010-01-01

350

Proliferative activity and malignancy in human gastric cancers. Significance of the proliferation rate and its clinical application.  

PubMed

The authors sought useful indicators for predicting the proliferative activity of human gastric cancer and attempted to evaluate its clinical significance. One hundred seventy-two patients with gastric cancer were entered in this study. All patients received bromodeoxyuridine at 200 to 1000 mg/body before laparotomy. Cell kinetics studies using the migration chase method were done for 56 patients, and the DNA synthesis time (Ts) was found to be prolonged in tumors, especially in aneuploid tumors, compared with normal mucosae. Ts correlated with bromodeoxyuridine (BrdUrd) labeling indices (LI) (r = 0.453, P less than 0.0005) and DNA indices (DI) (r = 0.534, P less than 0.0005). Thus, the DNA synthesis time was significantly prolonged in the tumors having a high S-phase fraction or DNA aneuploidy. The result of multivariate analysis indicated that LI/DI was the most potent indicator for predicting the proliferation rate (PR), which was calculated by the formula LI/Ts, and correlated significantly with PR (r = 0.863, P less than 0.0001). As was clear from the result of Cox's proportional hazard model, the predicted proliferation rate (pPR) was the most notable factor for the prognosis because pPR correlated clinically with metastasis, such as that to liver and lymph nodes. The patients with a high pPR (greater than 10%) had a worse prognosis (4-year survival rate: 16.3%) than did those with a low value (less than 10%) (4-year survival rate: 85.1%). In vitro pPR obtained by in vitro BrdUrd labeling of the specimens obtained at biopsy correlated significantly with the in vivo pPR (r = 0.960, P less than 0.0001). The authors concluded that the proliferation rate was the most important factor in judging the malignancy of human gastric cancers and that this rate should be most helpful in determining the treatment and evaluating the prognosis of individual patients. PMID:1728362

Ohyama, S; Yonemura, Y; Miyazaki, I

1992-01-15

351

Human IgG responses to macrocyclic chelating agents (DOTA and TETA) in patients with B-lymphocytic malignancies  

SciTech Connect

Several metallic radionuclides have promise for immunoimaging and therapy. Macrocyclic chelating agents provide stable radioimmunoconjugates but have been reported to be immunogenic. The purpose of this study was to assess human antibody responses to macrocycles in 18 patients that were imaged and/or treated with In-111-21T-BAD-Lym-1 (5 patients) or Cu-67-21T-BAT-Lym-1 (13 patients) for B-lymphocytic malignancies. Lym-1 ranged from 1 to 6 doses (median 1) and from 6 to 285 mg (median 33) for each of the patients. A solid phase ELISA utilizing HSA-BAD, HSA-BAT, HSA-BABE or Lym-1 as the coating antigen was used to characterize and quantitate human antibodies in patient serum against DOTA, TETA, 21T or Lym-1, respectively. No patient that received In-111-21T-BAD-Lym-1 developed antibodies of any kind. Two (15%) of the 13 patients that received Cu-67-21T-BAT-Lym-1 developed antibodies against both TETA and Lym-1, and one additional patient developed antibodies against Lym-1 only. None of the patients had symptoms of serum sickness. The maximum number of doses of metal chelated Lym-1 without an immune response was 6. The smallest amount of TETA macrocycle that induced an anti-TETA response was 400 ug; the greatest amount of TETA that did not induce an anti-TETA response was 1,156 ug. The smallest amount of Lym-1 that induced a HAMA was 39 mg; the greatest amount of Lym-1 that did not induce a HAMA response was 285 mg. The relative amounts of anti-TETA to anti-Lym-1 were 1:30 and 1:95 in the two patients that developed both antibodies. None of the patients developed antibodies to the 2IT linker. Using different antibodies in patients with ovarian cancer, others have reported a high frequency of anti-macrocycle antibodies to DOTA. Although macrocycles such as DOTA and TETA can be haptens, our findings do not support the conclusion that they are more immunogenic than other radiometal chelating agents.

DeNardo, G.L.; Mirick, G.R.; Kroger, L.A. [Univ. of California-Davis, Sacramento, CA (United States)] [and others

1995-05-01

352

Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells  

PubMed Central

Background Although lung cancer is among the few malignancies for which we know the primary etiological agent (i.e., cigarette smoke), a precise understanding of the temporal sequence of events that drive tumor progression remains elusive. In addition to finding that cigarette smoke (CS) impacts the functioning of key pathways with significant roles in redox homeostasis, xenobiotic detoxification, cell cycle control, and endoplasmic reticulum (ER) functioning, our data highlighted a defensive role for the unfolded protein response (UPR) program. The UPR promotes cell survival by reducing the accumulation of aberrantly folded proteins through translation arrest, production of chaperone proteins, and increased degradation. Importance of the UPR in maintaining tissue health is evidenced by the fact that a chronic increase in defective protein structures plays a pathogenic role in diabetes, cardiovascular disease, Alzheimer's and Parkinson's syndromes, and cancer. Methods Gene and protein expression changes in CS exposed human cell cultures were monitored by high-density microarrays and Western blot analysis. Tissue arrays containing samples from 110 lung cancers were probed with antibodies to proteins of interest using immunohistochemistry. Results We show that: 1) CS induces ER stress and activates components of the UPR; 2) reactive species in CS that promote oxidative stress are primarily responsible for UPR activation; 3) CS exposure results in increased expression of several genes with significant roles in attenuating oxidative stress; and 4) several major UPR regulators are increased either in expression (i.e., BiP and eIF2?) or phosphorylation (i.e., phospho-eIF2?) in a majority of human lung cancers. Conclusion These data indicate that chronic ER stress and recruitment of one or more UPR effector arms upon exposure to CS may play a pivotal role in the etiology or progression of lung cancers, and that phospho-eIF2? and BiP may have diagnostic and/or therapeutic potential. Furthermore, we speculate that upregulation of UPR regulators (in particular BiP) may provide a pro-survival advantage by increasing resistance to cytotoxic stresses such as hypoxia and chemotherapeutic drugs, and that UPR induction is a potential mechanism that could be attenuated or reversed resulting in a more efficacious treatment strategy for lung cancer.

Jorgensen, Ellen; Stinson, Andy; Shan, Lin; Yang, Jin; Gietl, Diana; Albino, Anthony P

2008-01-01

353

[Seasonal radiosensitivity of rats and dogs].  

PubMed

The data are submitted obtained on 10.5 thousands Wistar rats and 350 mongrel dogs exposed to gamma-radiation (LD40-LD100) in different seasons. The radiosensitivity of both animal species was the highest in autumn (August and September) and the lowest in winter (February and January). The seasonal DMF for rats and dogs with LD16, LD50 and LD84 was 1.24 and 1.31, 1.13 and 1.17 and 1.04 and 1.07, respectively. The curves for seasonal radiosensitivity of dogs with LD84, LD50 and LD16, exhibited a single--phase character throughout a year. For rats, the seasonal radiosensitivity curves with LD84 were single-phase, and the curve with LD50, and particularly LD16, exhibited the second peak of radioresistance in June. The increase in radioresistance of rats and dogs correlated with the increase in number of leukocytes in the peripheral blood of animals. PMID:6844558

Rogacheva, S A; Luzanova, O V; Kirillova, E N; Murzina, L D; Uriadnitskaia, T I

354

Gene therapy and radiation of malignant glioma by targeting glioma specific lactate transporter  

Microsoft Academic Search

Glioblastoma multiforme are highly malignant tumors that produce large amounts of lactate as a by-product of glucose consumption. We investigated inhibition of lactate efflux as a novel method to destructively alter the metabolite profile in these tumors to induce tumor-specific apoptosis and radiosensitization, thus adding a wing to our current growing armament of gene therapies against cancer. Thus, our main

Chaim B Colen

2005-01-01

355

Human Myeloid and Lymphoid Malignancies in the Non-Obese Diabetic\\/Severe Combined Immunodeficiency Mouse Model: Frequency of Apoptotic Cells in Solid Tumors and Efficiency and Speed of Engraftment Correlate with Vascular Endothelial Growth Factor Production  

Microsoft Academic Search

Recent studies have suggested that non-obese diabetic\\/severe combined immunodeficiency (NOD\\/SCID) mice transplanted with human hemato- logical malignancies show higher levels of engraftment compared with other strains. We used this model to compare xenotransplantability of human leukemia and lymphoma cell lines and to investigate angiogenesis in hematopoietic malignancies. Ten of 12 evaluated cell lines were able to engraft NOD\\/SCID mice within

Lisa Fusetti; Giancarlo Pruneri; Alberto Gobbi; Cristina Rabascio; Nadia Carboni; Fedro Peccatori; Giovanni Martinelli; Francesco Bertolini

356

Comparison of microwave and magnetic nanoparticle hyperthermia radiosensitization in murine breast tumors  

Microsoft Academic Search

Hyperthermia has been shown to be an effective radiosensitizer. Its utility as a clinical modality has been limited by a minimally selective tumor sensitivity and the inability to be delivered in a tumor-specific manner. Recent in vivo studies (rodent and human) have shown that cancer cell-specific cytotoxicity can be effectively and safely delivered via iron oxide magnetic nanoparticles (mNP) and

Andrew J. Giustini; Alicia A. Petryk; Paul J. Hoopes

2011-01-01

357

Treatment of Malignant Glioma Cells with the Transfer of Constitutively Active Caspase6 Using the Human Telomerase Catalytic Subunit (Human Telomerase Reverse Transcriptase) Gene Promoter1  

Microsoft Academic Search

Because the apoptotic pathway is often disrupted in tumor cells, its genetic restoration is a very attractive approach for the treatment of tumors. To treat malignant gliomas with this approach, it would be preferred to restrict induction of apoptosis to tumor cells by establishing a tumor-specific expression system. Telomerase is an attractive target because the vast majority of malignant gliomas

Tadashi Komata; Yasuko Kondo; Takao Kanzawa; Satoshi Hirohata; Shoji Koga; Hideaki Sumiyoshi; Srinivasa M. Srinivasula; Barbara P. Barna; Isabelle M. Germano; Masahiro Takakura; Masaki Inoue; Emad S. Alnemri; Jerry W. Shay; Satoru Kyo; Seiji Kondo

358

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.

Inamoto, Teruo; Azuma, Haruhito

2012-01-01

359

Novel radiosensitizers for locally advanced epithelial tumors: inhibition of the PI3K\\/Akt survival pathway in tumor cells and in tumor-associated endothelial cells as a novel treatment strategy?  

Microsoft Academic Search

In locally advanced epithelial malignancies, local control can be achieved with high doses of radiotherapy (RT). Concurrent chemoradiotherapy can improve tumor control in selected solid epithelial adult tumors; however, treatment-related toxicity is of major concern and the therapeutic window often small. Therefore, novel pharmacologic radiosensitizers with a tumor-specific molecular target and a broad therapeutic window are attractive. Because of clonal

Oliver Riesterer; Angela Tenzer; Daniel Zingg; Barbara Hofstetter; Van Vuong; Martin Pruschy; Stephan Bodis

2004-01-01

360

Voltammetry of hypoxic cells radiosensitizer etanidazole radical anion in water  

Microsoft Academic Search

Cytotoxic properties of radiosensitizers are due to the fact that, in the metabolic pathway, these compounds undergo one-electron reduction to generate radical anions. In this study we focused our interest on the electrochemical transfer of the first electron on radiosensitizer Etanidazole (ETN) and, consequently, on the ETN radical-anion formation in the buffered aqueous media. ETN was electrochemically treated in the

Miroslav Gál; Magdaléna Hromadová; Lubomír Pospíšil; Ján Híveš; Romana Sokolová; Viliam Kolivoška; Jana Bulí?ková

2010-01-01

361

Malignant hyperthermia.  

PubMed Central

Malignant hyperthermia is a rare autosomal dominant trait that predisposes affected individuals to great danger when exposed to certain anaesthetic triggering agents (such as potent volatile anaesthetics and succinylcholine). A sudden hypermetabolic reaction in skeletal muscle leading to hyperthermia and massive rhabdomyolysis can occur. The ultimate treatment is dantrolene sodium a nonspecific muscle relaxant. Certain precautions should be taken before anaesthesia of patients known to be susceptible to malignant hyperthermia. These include the prohibition of the use of triggering agents, monitoring of central body temperature and expired CO2, and immediate availability of dantrolene. In addition, careful cleansing of the anaesthesia machine of vapours of halogenated agents is recommended. If these measures are taken, the chances of an MH episode are greatly reduced. When malignant hyperthermia-does occur in the operating room, prompt recognition and treatment usually prevent a potentially fatal outcome. The most reliable test to establish susceptibility to malignant hyperthermia is currently the in vitro caffeine-halothane contracture test. It is hoped that in the future a genetic test will be available.

Ben Abraham, R.; Adnet, P.; Glauber, V.; Perel, A.

1998-01-01

362

Hematologic malignancies  

SciTech Connect

The principle aim of this book is to give practical guidelines to the modern treatment of the six important hematologic malignancies. Topics considered include the treatment of the chronic leukemias; acute leukemia in adults; the myeloproliferative disorders: polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis/agnogenic myeloid metaplasia; Hodgkin's Disease; non-Hodgkin's lymphoma; and Multiple Myeloma.

Hoogstraten, B.

1986-01-01

363

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

Microsoft Academic Search

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

A. Serafino; E. Balestrieri; P. Pierimarchi; C. Matteucci; G. Moroni; E. Oricchio; G. Rasi; A. Mastino; C. Spadafora; E. Garaci; P. Sinibaldi Vallebona

2009-01-01

364

In vivo tracing of indium-111 oxine-labeled human peripheral blood mononuclear cells in patients with lymphatic malignancies  

SciTech Connect

The in vivo migration of (/sup 111/In)oxine-labeled peripheral mononuclear cells (PMNC) was studied in 20 patients with various lymphatic malignancies and palpable enlarged lymph nodes. The maximal labeling dose of 10 microCi (0.37 MBq) (/sup 111/In)oxine/10(8) PMNC was found not to adversely influence either cell viability or lymphocyte proliferation in vitro. For in vivo studies, 1.5 X 10(9) PMNC were gained by lymphapheresis and reinjected intravenously after radioactive labeling, 150 microCi (5.55 MBq). The labeling of enlarged palpable lymph nodes was achieved in three out of three patients with Hodgkin's disease and in five out of five with high-malignant lymphoma, whereas three out of seven patients with low malignant lymphoma and no patient with chronic lymphatic leukemia had positive lymph node imaging. We thus conclude that PMNC retain their ability to migrate after (/sup 111/In)oxine labeling and that these cells traffic to involved lymph nodes of some, but not all hematologic malignancies.

Mueller, C.Z.; Zielinski, C.C.; Linkesch, W.; Ludwig, H.; Sinzinger, H.

1989-06-01

365

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

PubMed Central

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 expression of NFP, NSE, and e-cadherin and also decreases in 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 expression and activity of calpain and caspase-3. Combination therapy decreased migration of cells through matrigel and inhibited proliferative (p-Akt and NF-?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.

Hossain, Md. Motarab; Banik, Naren L.; Ray, Swapan K.

2012-01-01

366

Isolation and characterization of transforming growth factors from human malignant gliomas: possible role of transforming growth factors in the pathogenesis of the gliosarcoma  

SciTech Connect

This study provides the first direct experimental evidence that human malignant gliomas secrete soluble polypeptides with TGF-like activity. The conditioned medium from three well-characterized malignant glioma cell lines promote the growth of NRK indicator cells in soft agar. Following acid extraction and gel filtration, TGF-like activity was recovered from all three cell lines. Active fractions from gel filtration in two of the glioma cell lines (U-343 MG-A and SF-210) were further purified by reverse-phase HPLC. The TGF isolated from U-343 MG-A by HPLC is an acid- and heat-stable protein complex whose activity is destroyed by reducing agents and incubation with monospecific anti-TGF-alpha monoclonal antibodies. The NRK colony stimulating activity of this TGF is potentiated by the addition of TGF-beta. The partially purified U-343 MG-A TGF competes with radiolabeled (/sup 125/I)-ECF for the EGF-receptor on A431 epidermoid carcinoma cells. Finally, a total RNA preparation from U-343- MG-A contains a 4.8 kilobase mRNA for TGF-alpha. Therefore, U-343 MG-A secretes a soluble polypeptide with TGF-alpha-like activity. In contrast, the purified SF-210 malignant glioma cell line secretes an acid- and heat-stable TGF with neither TGF-alpha- nor TGF-beta-like activity.

Rutka, J.T.

1987-01-01

367

Nup88 (karyoporin) in human malignant neoplasms and dysplasias: correlations of immunostaining of tissue sections, cytologic smears, and immunoblot analysis.  

PubMed

Nuclear pore complexes (NPCs) are elaborate macromolecular structures that regulate the bidirectional nucleocytoplasmic traffic system. In vertebrate cells, NPCs include a family of 50 to 100 proteins termed nucleoporins (Nups). The 88-kD Nup has been found to be linked in a dynamic subcomplex with the oncogenic CAN/Nup214. Applying a polyclonal antiserum to Nup88 on paraffin sections, we found that it immunoreacts with numerous malignant neoplasms. All carcinomas reacted irrespective of site, type, or degree of differentiation; often, high-grade carcinomas stained more strongly and extensively. Some sarcomas (e.g., fibrosarcomas, leiomyosarcomas, liposarcomas, and rhabdomyosarcomas) reacted intensely; melanomas, gliomas, mesotheliomas, and malignant lymphomas also stained. In situ carcinomas of the colon, stomach, breast, and prostate stained convincingly, as did in situ melanomas; some samples of fetal tissues also reacted. Cytologic smears of some of the aforementioned tumors also stained. In selected samples, enhanced immunostaining of tissue sections and cytologic smears correlated strongly and consistently with immunoblot data. Immunoblots of the same tumors with antibodies to 2 other Nups (Nup214 and Nup153) showed no comparable enhancement. Therefore, it seems that in some malignant tumors, Nup88 overexpression is not parallelled by an overexpression of other Nups. Benign tumors, hyperplasias, and normal tissues showed weak and sporadic staining or absence of staining; immunoblots of the same samples yielded weak signals. Occasional highly proliferative hyperplastic-reactive processes showed focal staining. Thus, our correlative histologic, cytologic, and molecular data indicate that Nup88 may be viewed as a potentially useful, broadly based histodiagnostic and molecular marker of many malignancies and premalignant dysplasias, and further suggest that in some malignant tumors, Nup88 may be selectively overexpressed as compared with other Nups. Thus, we propose that Nup88 be designated as karyoporin. PMID:12094380

Gould, Victor E; Orucevic, Amila; Zentgraf, Hanswalter; Gattuso, Paolo; Martinez, Nerea; Alonso, Angel

2002-05-01

368

??Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy.  

PubMed

Integrin signaling critically contributes to the progression, growth, and therapy resistance of malignant tumors. Here, we show that targeting of ?? integrins with inhibitory antibodies enhances the sensitivity to ionizing radiation and delays the growth of human head and neck squamous cell carcinoma cell lines in 3D cell culture and in xenografted mice. Mechanistically, dephosphorylation of focal adhesion kinase (FAK) upon inhibition of ?? integrin resulted in dissociation of a FAK/cortactin protein complex. This, in turn, downregulated JNK signaling and induced cell rounding, leading to radiosensitization. Thus, these findings suggest that robust and selective pharmacological targeting of ?? integrins may provide therapeutic benefit to overcome tumor cell resistance to radiotherapy. PMID:22378044

Eke, Iris; Deuse, Yvonne; Hehlgans, Stephanie; Gurtner, Kristin; Krause, Mechthild; Baumann, Michael; Shevchenko, Anna; Sandfort, Veit; Cordes, Nils

2012-03-01

369

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

370

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

371

Inhibition of the insulin-like growth factor 1 receptor pathway enhances the antitumor effect of cisplatin in human malignant mesothelioma cell lines.  

PubMed

Human malignant mesothelioma (HMM) is a fatal tumor and is poorly responsive to current therapeutic regimens. The insulin-like growth factor 1 receptor (IGF-1R) pathway is activated in HMM cell lines and tissues. Treatment with AG1024, an inhibitor of the IGF-1R pathway, significantly decreased cell proliferation and attenuated the phosphorylation of Akt and p44/42. In addition, it significantly enhanced the cytotoxic effects of cisplatin in HMM cell lines. This study supports the conjecture that inhibition of the IGF-1R pathway may be a useful target for reducing toxicity and alleviating chemoresistance to traditional anticancer drugs in HMM patients. PMID:19178995

Kai, Kiyonori; D'Costa, Susan; Sills, Robert C; Kim, Yongbaek

2009-06-01

372

MN1TEL, the product of the t(12;22) in human myeloid leukemia, immortalizes murine myeloid cells and causes myeloid malignancy in mice  

Microsoft Academic Search

MN1-TEL is the product of the recurrent t(12;22)(p12;q11) associated with human myeloid malignancies. MN1-TEL functions as an activated transcription factor, exhibiting weak transforming activity in NIH3T3 fibroblasts that depends on the presence of a functional TEL DNA-binding domain, the N-terminal transactivating sequences of MN1 and C-terminal sequences of MN1. We determined the transforming activity of MN1-TEL in mouse bone marrow

C Carella; J Bonten; J Rehg; G C Grosveld

2006-01-01

373

Malignant mixed mullerian tumor of the vagina: case report with review of the literature, immunohistochemical study, and evaluation for human papilloma virus.  

PubMed

The patient was a 57-year-old white woman who presented with a 3.0 x 2.0-cm partially ulcerated vaginal polyp. Histology revealed a malignant mixed mullerian tumor composed of invasive squamous cell carcinoma with deeper areas of undifferentiated pleomorphic sarcoma. Invasive carcinoma had overlying high-grade vaginal intraepithelial neoplasia (VaIN III), which contained koilocytic atypia. In situ hybridization detected high-risk human papillomavirus DNA in both the carcinoma and the sarcoma components. PMID:17640554

Sebenik, Matjaz; Yan, Zhijije; Khalbuss, Walid E; Mittal, Khush

2007-08-01

374

Myofibroblastic malignancies.  

PubMed

Malignant tumors composed of myofibroblasts are increasingly being recognized, but their existence remains controversial. Currently accepted examples within this category represent spindle cell or pleomorphic neoplasms of the soft tissues with a spectrum of histological grades. Low- and intermediate-grade myofibrosarcomas are fascicular spindle cell neoplasms resembling fibrosarcoma or leiomyosarcoma. They infiltrate deep soft tissue with disproportionate involvement of head and neck sites and can recur locally but infrequently metastasize. They variably express myoid immunohistochemical markers, and their differential diagnosis includes benign myofibroblastic proliferations such as fasciitis and fibromatosis as well as other types of spindle cell sarcoma. High-grade (pleomorphic) myofibrosarcomas are an ultrastructurally defined subset of malignant fibrous histiocytoma, which they resemble in morphology and behavior. Inflammatory myofibroblastic tumor and infantile fibrosarcoma are neoplasms that have myofibroblastic features and have been included in this category, but they have distinctive genetic findings. This article reviews the concept of myofibrosarcoma and describes its variants. PMID:15220822

Fisher, Cyril

2004-07-01

375

The Pattern of Mutational Involvement of RAS Genes in Human Hematologic Malignancies Determined by DNA Amplification and Direct Sequencing  

Microsoft Academic Search

DNA from 161 patients with various forms of hematologic malignancies were investigated for mutations in exons 1 and 2 of the N-RAS. K-RAS and Ha-RAS gene by direct sequencing of DNA amplified in vitro by the polymerase chain reaction. Mutations involving either codons 11,12, or 13 of the N-RAS gene were identified in 18 of the 161 patients. The relative

H. G. Ahuja; A. Foti; M. Bar-Eli; M. J. Cline

1990-01-01

376

Microbiome and Malignancy  

PubMed Central

Current knowledge is insufficient to explain why only a proportion of individuals exposed to environmental carcinogens or carrying a genetic predisposition to cancer develop disease. Clearly, other factors must be important and one such element that has recently received attention is the human microbiome, the residential microbes including Bacteria, Archaea, Eukaryotes, and viruses that colonize humans. Here, we review principles and paradigms of microbiome-related malignancy, as illustrated by three specific microbial-host interactions. We review the effects of the microbiota on local and adjacent-neoplasia, present the estrobolome model of distant effects, and discuss the complex interactions with a latent virus leading to malignancy. These are separate facets of a complex biology interfacing all the microbial species we harbor from birth onward toward early reproductive success and eventual senescence.

Plottel, Claudia S.; Blaser, Martin J.

2011-01-01

377

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.

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

2013-01-01

378

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

379

Modulation of oxygen consumption rate and vascular endothelial growth factor mRNA expression in human malignant glioma cells by hypoxia  

PubMed Central

Cellular responses to hypoxia include modulation of respiration rate and up-regulation of genes which encode for angiogenesis factors. We tested whether human malignant glioma cells vary in their response to hypoxic stress over the range of oxygen concentrations which exist in tumours. In five cell lines tested, decreased oxygen availability resulted in decreased rates of oxygen utilization, however substantial differences in the magnitude of the response were observed. Northern blot analysis was used to study induction of vascular endothelial growth factor mRNA in response to hypoxia. In two cell lines, modest hypoxia increased vascular endothelial growth factor mRNA levels compared with those of aerobic controls. In two additional cell lines, vascular endothelial growth factor mRNA was constituitively expressed under aerobic conditions and was not further increased by hypoxia. These findings demonstrate that differences in the response to hypoxia exist among human malignant glioma cell lines and suggest that therapies designed to exploit tumour hypoxia may have varying effects in tumours with different hypoxic stress responses. © 1999 Cancer Research Campaign

Allalunis-Turner, M J; Franko, A J; Parliament, M B

1999-01-01

380

Radiosensitization of mouse skin by oxygen and depletion of glutathione  

SciTech Connect

To determine the oxygen enhancement ratio (OER) and shape of the oxygen sensitization curve of mouse foot skin, the extent to which glutathione (GSH) depletion radiosensitized skin, and the dependence of such sensitization on the ambient oxygen tension. Carbogen caused the greatest radiosensitization of skin, with a reproducible enhancement of 2.2 relative to the anoxic response. The OER of 2.2 is lower than other reports for mouse skin. This may indicate that the extremes of oxygenation were not produced, although there was no direct evidence for this. Depletion of GSH caused minimal radiosensitization when skin was irradiated under anoxic or well-oxygenated conditions. Radiosensitization by GSH depletion was maximal at intermediate oxygen tensions of 10-21% O{sub 2} in the ambient gas. Increasing the extent of GSH depletion led to increasing radiosensitization, with sensitization enhancement ratios of 1.2 and 1.1, respectively, for extensive and intermediated levels of GSH depletion. In mice exposed to 100% O{sub 2}, a significant component of skin radiosensitivity was due to diffusion of oxygen directly through the skin. Pentobarbitone anesthesia radiosensitized skin in mice exposed to 100% O{sub 2} by a factor of 1.2, but did not further sensitize skin in mice exposed to carbogen. Glutathione levels and the local oxygen tension at the time of irradiation were important determinants of mouse foot skin radiosensitivity. The extent to which GSH levels altered the radiosensitivity of skin was critically dependent on the local oxygen tension. These results have significant implications for potential clinical applications of GSH depletion. 53 refs., 7 figs., 2 tabs.

Stevens, G.; Joiner, M.; Joiner, B. [Gray Lab., Middlesex (United Kingdom)] [and others

1995-09-30

381

Exploratory study on the effects of biodegradable nanoparticles with drugs on malignant B cells and on a human/mouse model of Burkitt lymphoma.  

PubMed

The aim of this study was to determine if Rituximab coated Biodegradable Nanoparticles (BNPs) loaded with Chlorambucil and Hydroxychloroquine could induce apoptosis of B-Chronic Lymphocytic Leukemia (B-CLL), MEC-1 and BJAB cells in vitro and evaluate their toxic and therapeutic effects on a Human/Mouse Model of Burkitt Lymphoma at an exploratory, proof of concept scale. We found that Rituximab-Chlorambucil-Hydroxychloroquine BNPs induce a decrease in cell viability of malignant B cells in a dose-dependent manner. The mediated cytotoxicity resulted from apoptosis, and was confirmed by monitoring the B-CLL cells after Annexin V/propidium iodide staining. Additional data revealed that these BNPs were non toxic for healthy animals, and had prolonged survival in this mice model of human lymphoma. PMID:20925646

Marín, Gustavo H; Mansilla, Eduardo; Mezzaroba, Nelly; Zorzet, Sonia; Núñez, Luis; Larsen, Gustavo; Tau, José M; Maceira, Alberto; Spretz, Ruben; Mertz, Carol; Ingrao, Sabrina; Tripodo, Claudio; Tedesco, Francesco; Macor, Paolo

2010-11-01

382

?1 Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy  

PubMed Central

Integrin signaling critically contributes to the progression, growth, and therapy resistance of malignant tumors. Here, we show that targeting of ?1 integrins with inhibitory antibodies enhances the sensitivity to ionizing radiation and delays the growth of human head and neck squamous cell carcinoma cell lines in 3D cell culture and in xenografted mice. Mechanistically, dephosphorylation of focal adhesion kinase (FAK) upon inhibition of ?1 integrin resulted in dissociation of a FAK/cortactin protein complex. This, in turn, downregulated JNK signaling and induced cell rounding, leading to radiosensitization. Thus, these findings suggest that robust and selective pharmacological targeting of ?1 integrins may provide therapeutic benefit to overcome tumor cell resistance to radiotherapy.

Eke, Iris; Deuse, Yvonne; Hehlgans, Stephanie; Gurtner, Kristin; Krause, Mechthild; Baumann, Michael; Shevchenko, Anna; Sandfort, Veit; Cordes, Nils

2012-01-01

383

Nimotuzumab promotes radiosensitivity of EGFR-overexpression esophageal squamous cell carcinoma cells by upregulating IGFBP-3  

PubMed Central

Background Epidermal growth factor receptor (EGFR) is suggested to predict the radiosensitivity and/or prognosis of human esophageal squamous cell carcinoma (ESCC). The objective of this study was to investigate the efficacy of