Chemoresistance in the clinic: overview 1994

One of the most exciting areas in clinical oncology today is the translation of laboratory research in drug resistance into therapeutic tools to improve responses to antineoplastic drugs. Two areas of investigation are currently under study in both the laboratory and clinic: reversal of gluthathione-mediated resistance and of P-glycoprotein mediated resistance. Studies are directed toward determining the role of the resistance mechanism in cancer, and toward its reversal. Increased expression of gluthathione and related enzymes, such as the gluthathione S-transferases, has been shown in human tumor samples. Phase I clinical studies with buthionine sulfoxime (BSO) have shown that gluthathione can be depleted without undue normal tissue toxicity. Now, clinical studies are underway evaluating the ability of BSO to enhance the efficacy of chemotherapy. Expression of P-glycoprotein has been described in human tumors, with increased levels observed after natural product chemotherapy in some malignancies. Studies with P-glycoprotein antagonists have been conducted in leukemia, lymphoma, multiple myeloma and in a variety of advanced malignancies. These studies have employed "first generation" antagonists such as verapamil and cyclosporine which were toxic at concentrations needed to block P-glycoprotein. Currently, studies are underway with "second generation" antagonists such as the dex stereoisomer of verapamil and the cyclosporine analogue, PSC 833. These agents may help determine the role of P-glycoprotein in clinical drug resistance. Together, these studies are aimed toward improving chemotherapeutic sensitivity in human cancer.