We are studying the biology of ovarian cancer, the mechanisms of antineoplastic drug resistance in ovarian cancer, and the pharmacologic reversal of the drug resistant phenotype. This work required the development of appropriate model systems of human ovarian cancer including in vitro cell lines and a nude mouse xenograft bearing a transplantable intraperitoneal human ovarian carcinoma. We have characterized 5 new ovarian cancer cell lines including a line which has steroid hormone receptors. Drug resistant variant cell lines have been developed by stepwise incubation of sensitive cell lines with progressively increasing concentrations of melphalan, adriamycin, and cisplatin. The drug resistant variants are 6-100 more resistant to chemotherapy than the sensitive parental cell lines. The intraperitoneal model of human ovarian cancer produces ascites, pulmonary metastases, and death from intraabdominal carcinomatosis. Using these model systems we have demonstrated that resistance to melphalan, cisplatin, and adriamycin is linked, in part, to glutathione levels. We have shown that buthionine sulfoximine, a synthetic amino acid which inhibits the synthesis of glutathione, leads to a decrease in glutathione levels in the drug resistant cell lines and increases the cytotoxicity of melphalan, cisplatin and adriamycin. In addition, we have demonstrated that some drug resistant human ovarian cancer cell lines have a decreased accumulation of adriamycin which can be reversed by exposure of the cells to verapamil. These studies led to a trial of verapamil plus adriamycin in refractory ovarian cancer patients and the results with buthionine sulfoximine have led to the preclinical evalution of buthionine sulfoximine by the Decision Network of the NCI.
