Development of a Panel of 15 Human Ovarian Cancer Xenografts for Drug Screening and Determination of the Role of the Glutathione Detoxification System

Kolfschoten, Geertruida M.; Pinedo, H.M.; Scheffer, P; Schlüper, Hennie M.M.; Erkelens, C. A. M.; Boven, Epie

doi:10.1006/gyno.1999.5689

Cited by 35 publications

(22 citation statements)

References 23 publications

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“…Resistance due to elevated GSH, however, is reversible and parallels the decline in this thiol molecule when cisplatin is removed from cell cultures (Hamaguchi et al, 1993). An increase in GSH following chronic cisplatin exposure, however, is not a general occurrence, and this likely contributes to the negative correlation in some studies between GSH levels and cisplatin sensitivity (D'Incalci et al, 1998;Kolfschoten et al, 2000).…”

Section: Increased Inactivation By Thiol-containing Moleculesmentioning

confidence: 97%

Cisplatin: mode of cytotoxic action and molecular basis of resistance

2003

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Cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors. Its cytotoxic mode of action is mediated by its interaction with DNA to form DNA adducts, primarily intrastrand crosslink adducts, which activate several signal transduction pathways, including those involving ATR, p53, p73, and MAPK, and culminate in the activation of apoptosis. DNA damage-mediated apoptotic signals, however, can be attenuated, and the resistance that ensues is a major limitation of cisplatinbased chemotherapy. The mechanisms responsible for cisplatin resistance are several, and contribute to the multifactorial nature of the problem. Resistance mechanisms that limit the extent of DNA damage include reduced drug uptake, increased drug inactivation, and increased DNA adduct repair. Origins of these pharmacologicbased mechanisms, however, are at the molecular level. Mechanisms that inhibit propagation of the DNA damage signal to the apoptotic machinery include loss of damage recognition, overexpression of HER-2/neu, activation of the PI3-K/Akt (also known as PI3-K/PKB) pathway, loss of p53 function, overexpression of antiapoptotic bcl-2, and interference in caspase activation. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to selection pressures dictates the overall extent of cisplatin resistance.

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Section: Increased Inactivation By Thiol-containing Moleculesmentioning

confidence: 97%

Cisplatin: mode of cytotoxic action and molecular basis of resistance

2003

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“…For the animal experiments, ethical approval was obtained from the University Committee on Experimental Animals. Experiments were carried out in human ovarian cancer xenografts OVCAR-3, FMa and A2780 as described by Kolfschoten et al 27 Solid tumors of previous recipients were transferred as tissue fragments with a diameter of 2-3 mm through a small skin incision into both flanks of 8 -10-week-old mice. Upon growth, tumors were measured twice a week in 3 dimensions with vernier calipers.…”

Section: In Vivo Antitumor Efficacymentioning

confidence: 99%

Novel camptothecin derivative BNP1350 in experimental human ovarian cancer: Determination of efficacy and possible mechanisms of resistance

Hattum

Schlüper

Hausheer

et al. 2002

Intl Journal of Cancer

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The novel camptothecin derivative BNP1350 (7-[2-trimethylsilyl)ethyl]-20(S)-camptothecin), also known as Karenitecin, has been developed for superior oral bioavailability and increased lactone stability. In our study, we describe the antiproliferative effects of BNP1350, SN-38 and topotecan in 4 human ovarian cancer cell lines. BNP1350 was found to be slightly more potent than SN-38 (p<0.01) and was considerably more potent than topotecan (p<0.01). We extended these studies to well-established human ovarian cancer xenografts in which we compared the growth inhibition induced by BNP1350 with that of topotecan given in equitoxic schedules. The growth inhibition in all 3 xenografts induced by BNP1350 was >75%, which was significantly better than that resulting from topotecan (p<0.05). We then selected BNP1350-resistant variants of the A2780 human ovarian cancer cell line, 2780K4 (resistance factor: 41) and 2780K32 (resistance factor: 90), to analyze possible resistance mechanisms. These variants exhibited cross-resistance against all camptothecins tested. In comparison with 2780K4 cells, 2780K32 cells were relatively more resistant against SN-38, topotecan, DX-8951f and BNP1350. In addition, 2780K32 cells were highly cross-resistant against mitoxantrone. In both 2780K4 and 2780K32, the amount of topoisomerase I was not changed but the catalytic activity was reduced. Furthermore, 2780K32 cells clearly overexpressed the breast cancer resistance protein (BCRP), as demonstrated for both the gene and the protein. In contrast to topotecan, BNP1350 proved not to be a good substrate for BCRP. Overall, we conclude that BNP1350 offers advantages over topotecan expressed by high efficacy in experimental human ovarian cancer and poor affinity for BCRP.

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“…Preclinical models of ovarian cancer rely on in vitro stabilized cancer cell lines, on tumor xenografts obtained from in vitro cell lines and, to a lesser extent, on patient-derived tumors (10,11). Cancer cell lines are reproducible, easy to use, and useful for studying specific mechanisms, but their resemblance to the original tumor and thus their therapeutic predictive value is very limited (12).…”

Section: Introductionmentioning

confidence: 99%

Patient-Derived Ovarian Tumor Xenografts Recapitulate Human Clinicopathology and Genetic Alterations

et al. 2014

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Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. On the basis of its histopathology and molecular-genomic changes, ovarian cancer has been divided into subtypes, each with distinct biology and outcome. The aim of this study was to develop a panel of patient-derived EOC xenografts that recapitulate the molecular and biologic heterogeneity of human ovarian cancer. Thirty-four EOC xenografts were successfully established, either subcutaneously or intraperitoneally, in nude mice. The xenografts were histologically similar to the corresponding patient tumor and comprised all the major ovarian cancer subtypes. After orthotopic transplantation in the bursa of the mouse ovary, they disseminate into the organs of the peritoneal cavity and produce ascites, typical of ovarian cancer. Gene expression analysis and mutation status indicated a high degree of similarity with the original patient and discriminate different subsets of xenografts. They were very responsive, responsive, and resistant to cisplatin, resembling the clinical situation in ovarian cancer. This panel of patient-derived EOC xenografts that recapitulate the recently type I and type II classification serves to study the biology of ovarian cancer, identify tumor-specific molecular markers, and develop novel treatment modalities. Cancer Res; 74(23); 6980-90. Ó2014 AACR.

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Development of a Panel of 15 Human Ovarian Cancer Xenografts for Drug Screening and Determination of the Role of the Glutathione Detoxification System

Cited by 35 publications

References 23 publications

Cisplatin: mode of cytotoxic action and molecular basis of resistance

Cisplatin: mode of cytotoxic action and molecular basis of resistance

Novel camptothecin derivative BNP1350 in experimental human ovarian cancer: Determination of efficacy and possible mechanisms of resistance

Patient-Derived Ovarian Tumor Xenografts Recapitulate Human Clinicopathology and Genetic Alterations

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