Several chemotherapy agents with proven utility such as anthracyclines, bleomycins, alkylators, neocarcinostatin, nobel metal derivatives, VP-16, and radiosensitizers are being studied. The detoxification mechanisms, modification of cellular response by altered intercellular redox status, and oxygen metabolism in sensitive and resistant cells are of interest to the area of cancer treatment and directly related to our studies. Deleterious species produced by the antineoplastic drugs and cellular response to these species, as well as sulfhydryl containing compounds as they relate to metabolism, activation, and detoxification of antineoplastics are being explored. It has been demonstrated that depletion of glutathione levels either by directly conjugating or inhibition of de novo synthesis results in sensitization of cells by adriamycin, bleomycin, cisplatin, VP-16, alkylators, and radiosensitizers. Alternatively, increasing glutathione levels by providing direct precursors results in protection of cells from the above reagents. Rescue of cells after treatment by supplying glutathione directly by modifying the molecule such that it becomes membrane permeable is being studied. We have completed synthesis of a series of glutathione esters and are presently evaluating them in vitro under a wide variety of conditions. Following these studies we hope to determine whether or not differential elevations in GSH and tumor versus normal tissues in animals is possible and whether such manipulation can modulate chemotherapy drug response to yield a therapeutic gain. We have also exposed human breast cancer cells to 20 weekly adriamycin treatments (each treatment yields about 50% survival) and isolated a clone that is approximately 2 fold more resistant to adriamycin that the original parent cell line. This cell line does not express MDR nor does it have elevated GSH or GSH transferase levels. This cell line will be extensively studied to determine other factors important in drug resistance.
