Pharmacologic reversal of drug resistance in ovarian cancer

Drug resistance is a major problem in the treatment of ovarian cancer. We have developed human ovarian cancer cell lines with varying degrees of resistance and sensitivity to cisplatin, melphalan, and doxorubicin. The steep dose-response relationships in other lines support the rationale for high-dose therapy either by intraperitoneal or systemic administration of drugs. The demonstration that some of the resistant cell lines have a decreased accumulation of doxorubicin and that resistance in these lines can be reversed by a calcium channel blocker has led to a clinical trial of verapamil plus doxorubicin in refractory ovarian cancer patients. It has also been demonstrated that resistance to cisplatin and melphalan is associated with increased levels of glutathione. Pharmacologic depletion of glutathione with buthionine sulfoximine, an inhibitor of glutathione synthesis, increases the cytotoxicity of melphalan and cisplatin in drug sensitive and resistant cell lines.