Several chemotherapy agents with proven utility, e.g., Anthracylines, Bleomycins, and noble metal derivatives are being studied. The detoxification mechanisms, modification of cellular response by biochemical manipulation of intracellular redox status, and oxygen metabolism, in sensitive and resistant cells are of interest. Deleterious species produced by the antineoplastic drugs and cellular response to these species, as well as thiol compounds, and their metabolic interactions with the drugs, and labile species produced by the drugs are being examined. It has been demonstrated that depletion of cellular glutathione (GSH) by inhibitors of GSH synthesis sensitize cells to Adriamycin and Bleomycin while GSH elevation provides protection. Recently, we have shown that modulation of GSH has a profound effect on Neocarzinostatin biologic activity. Rescue of cells from chemotherapeutic treatment is being studied by utilizing compounds newly synthesized within the laboratory. Modulation of chemotherapeutic response will be studied either by substrate feed forward mechanisms or modulation of enzymic response by amplification of gene products by altering the promoter region. Selective modulation of GSH levels in normal vs tumor cells was demonstrated with subsequent differential response to selected chemotherapy drugs.
