Clinical reversal of drug resistance in ovarian cancer.

Human ovarian cancer cell lines and relevant in vivo model systems have been used to identify mechanisms of resistance associated with alkylating agents and platinum compounds. Drug resistance in ovarian cancer is multifactorial and it is probable that additional mechanisms than those already identified may be responsible for clinical drug resistance. Presently drug transport, increased inactivation in the cytosol, increased repair of damaged DNA, and alterations in signal transduction pathways have been shown to account for resistance of alkylating agents and platinum compounds. Clinical trials have been initiated with agents such as buthionine-sulfoximine, an inhibitor of glutathione biosynthesis which decreases the ability of resistant cells to inactivate platinum compounds prior to their interaction with DNA. In a phase I trial, it has been demonstrated that glutathione levels can be depleted both in normal tissues and tumor biopsies from drug-resistant ovarian cancer patients. Additional clinical trials are needed to determine the effect that glutathione reduction has upon response rate to alkylating agents and platinum compounds. Ultimately, successful modulation of drug resistance may require a combination of agents which inhibit multiple critical biochemical sites. In addition, an understanding of the mechanisms associated with antineoplastic drug resistance may lead to novel therapeutic strategies aimed at preventing the emergence of clinically relevant resistance.