Development of a Panel of 15 Human Ovarian Cancer Xenografts for Drug Screening and Determination of the Role of the Glutathione Detoxification System 1 Geertruida M. Kolfschoten,* Herbert M. Pinedo, M.D., Ph.D.,* Peter G. Scheffer,† Hennie M. M. Schlu ¨per,* Caroline A. M. Erkelens,* and Epie Boven, M.D. Ph.D.* ,2 *Department of Medical Oncology and †Department of Clinical Chemistry, University Hospital Vrije Universiteit, 1081 HV Amsterdam, The Netherlands Received July 21, 1999 Objectives. We have established a panel of 15 human ovarian cancer xenografts grown subcutaneously in the flank of the nude mouse. Similar to the clinic, the xenografts show differences in histological subtype and volume doubling time. We determined whether the panel is useful for drug screening by testing the sensitivity to six conventional anticancer agents. In addition, we investigated whether the glutathione detoxification system affects sensitivity to cisplatin and cyclophosphamide, major drugs in the treatment of ovarian cancer. Methods. Mice bearing well-established tumors were treated at maximum tolerated doses as defined by a reversible weight loss up to 15% of their initial weight: cisplatin 5 mg/kg iv weekly 2, cyclophosphamide 150 mg/kg ip 2-weekly 2, doxorubicin 8 mg/kg iv weekly 2, hexamethylmelamine ip 150 mg/kg every other day 4, methotrexate ip 150 mg/kg weekly 2, and 5-flu- orouracil 60 mg/kg ip weekly 4. Glutathione levels and the activities of three different glutathione-dependent enzymes were measured in untreated xenograft tissues. Results. Growth inhibition > 75% was reached for cisplatin in 40%, forcyclophosphamide in 27%, and fordoxorubicin in 20%of the xenografts. Methotrexate and 5-fluorouracil did not induce growth inhibition of importance. Hexamethylmelamine showed > 75%growth inhibition in 53%of the xenografts, which may have been caused by the favorable metabolism of the drug in mice when compared with that in patients. Glutathione levels varied 3.6-fold in the xenografts and did not show a relation with sensitivity to cisplatin, cyclophosphamide, or doxorubicin. No relation was found between the activities of glutathione S-transferase and glu- tathione peroxidase and the sensitivities to the three anticancer agents. Glutathione reductase activity, however, showed a weak, inverse relation with the efficacy of cisplatin and cyclophospha- mide (r values of 0.55 and 0.58, respectively). Conclusions. The sensitivity to the six anticancer agents of our panel of 15 human ovarian cancerxenografts reflects the response rates known for similar drugs in ovarian cancer patients. In that respect, the panel may be useful for drug screening as well as studies on the relevance of drug resistance features in vivo. The various components of the glutathione detoxification system did not predict for primary drug resistance which confirms clinical data in ovarian cancer. © 2000 Academic Press Key Words: ovarian cancer xenografts; glutathione; glutathione- dependent enzymes; drug resistance. INTRODUCTION Ovarian cancer is the most lethal gynecological malignancy and the fourth highest cause of cancer death among women. Most women present with advanced disease. The treatment of ovarian cancer has improved the response rate, but the 5-year survival rate is only 25–30% [1]. The prognostic factors in ovarian cancer are the stage of the disease at the time of diagnosis, the histological subtype and grade, and the volume of residual disease after cytoreductive surgery. The standard treatment for advanced ovarian cancer consists of cytoreductive surgery followed by chemotherapy. Platinum- based chemotherapy is considered to be the most effective first-line treatment modality. Cisplatin has been studied in several combinations, such as the CHAP-5 regimen (cyclo- phosphamide, hexamethylmelamine, doxorubicin, cisplatin for 5 days). In comparison to the Hexa-CAF regimen (hexameth- ylmelamine, cyclophosphamide, methotrexate, 5-fluoruoracil) CHAP-5 appeared to improve survival from 18 to 37% at 5 years [1]. Although CHAP-5 resulted in a higher response rate, it induced substantial toxicity. In a comparative trial, the CP schedule (cyclophosphamide, cisplatin on 1 day) appeared to be less toxic and showed the same response rate as CHAP-5 resulting in a 5-year survival rate of 28% [1]. The CP schedule has been compared with a combination of paclitaxel plus cisplatin [2]. In that study the progression-free survival was 1 Presented in part at the 4th International Symposium on Cytostatic Drug Resistance; September 1997, Berlin FRG, and at the American Association for Cancer Research; March 1998, New Orleans, LA. 2 To whom correspondence and reprint requests should be addressed at Academic Hospital Vrije Universiteit, Department of Medical Oncology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Fax: (31)-20- 4444355. E-mail: e.boven.oncol@med.vu.nl. Gynecologic Oncology 76, 362–368 (2000) doi:10.1006/gyno.1999.5689, available online at http://www.idealibrary.com on 362 0090-8258/00 $35.00 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.