The detoxification mechanisms, modification of cellular response by altered intercellular redox status, and oxygen metabolism in sensitive and resistant cells to chemotherapy drugs 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, we have recently shown that GSH depletion results in subsequent resistance to the new chemotherapy drug Taxoltm (paclitaxel). GSH depletion by buthionine sulfoximine results in a partial cell cycle arrest which contributes to subsequent resistance to paclitaxel. That cell cycle blocks cause resistance to paclitaxel has been confirmed by demonstrating that plateau phase cells (arrested in G1 of the cell cycle) are resistant to paclitaxel. We have also observed an unusual dose response curve for paclitaxel in that for low concentrations (ranging from 5-100 nM for 24 hr) about 1-2 logs of cell kill are observed for most human tumor cell lines; however, for concentrations r 1000 nM in some cell lines an actual increase in survival is observed. Further we have shown that combination paclitaxel/adriamycin, VP16 leads to antagonism; either agent given first leads to resistance upon exposure to the second agent. The resistance relates to cell cycle perturbations. These findings question the use of such combinations in clinical settings.
