Several chemotherapy agents 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 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 & 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. We have synthesized a series of glutathione esters and have demonstrated in preliminary studies that these esters rapidly increase intracellular GSH levels. As a result of elevated GSH, cells are made markedly resistant to cisplatin and melphalan. Not only is introcellular GSH levels increased but also there is a marked elevation of introcellular cysteine. After we have selected the most efficient GSH ester we will proceed to determine if there is a differential increase in GSH levels in tumor as opposed to nominal cell lines. Following these studies we hope to determine whether or not differential elevations in GSH and tumor versus norma tissues in animals is possible. 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.
