RESPONSE OF MAMMALIAN CELLS TO CHEMOTHERAPY DRUGS

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Several chemotherapy agent with proven utility such as anthracyclines, bleomycins, alkylators, neocarcinostatin, nobel metal derivatives, VP-16, and hypoxic radiosensitizers are being studied. The detoxification mechanisms, modification of cellular response by altered intracellular 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. 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 hypoxic 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. Timing of delivery of the rescue agents, how the rescue agents interact with other biochemical pathways, cellular clearance and in vivo clearance are being investigated.