CHEMORESISTANCE IN THE CLINIC - OVERVIEW 1994

One of the most exciting areas in clinical oncology today is the trans lation of laboratory research in drug resistance into therapeutic tool s to improve responses to antineoplastic drugs. Two areas of investiga tion are currently under study in both the laboratory and clinic: reve rsal of gluthathione-mediated resistance and of P-glycoprotein mediate d resistance. Studies are eirected toward determining the role of the resistance mechanism in cancer, and toward its reversal. Increased exp ression of gluthathione and related enzymes, such as the gluthathione S-transferases, has been shown in human tumor samples. Phase I clinica l studies with buthionine sulfoxime (BSO) have shown that glutathione can be depleted without undue normal tissue toxicity. Now, clinical st udies are underway evaluating the ability of BSO to enhance the effica cy of chemotherapy. Expression of P-glycoprotein has been described in human tumors, with increased levels observed after natural product ch emotherapy in some malignancies. Studies with P-glycoprotein antagonis ts have been conducted in leukemia, lymphoma, multiple myeloma and in a variety of advanced malignancies. These studies have employed ''firs t generation'' antagonists such as verapamil and cyclosporine which we re toxic at concentrations needed to block P-glycoprotein. Currently, studies are underway with ''second generation'' antagonists such as th e dex stereoisomer of verapamil and the cyclosporine analogue, PSC 833 . These agents may help determine the role of P-glycoprotein in clinic al drug resistance. Together, these studies are aimed toward improving chemotherapeutic sensitivity in human cancer.