RADIOSENSITIZATION OF AERATED AND HYPOXIC MAMMALIAN CELLS

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A major portion of this study has dealt with the importance of cellular redox systems such as glutathione (GSH) and related enzymes to the cell's defense against ionizing radiation and chemotherapy drugs. Recent studies have clearly shown that inherent GSH levels do not significantly contribute to the radiation response. This statement is substantiated by our work using drugs that result in GSH depletion to <5% of control or elevation to 2 fold. Under these conditions, radiosensitivity was affected modestly (approximately 10%). Recently using a mutant CHO cell line, radiosensitivity was found to be identical to the parental cell line, despite the fact that the mutant cell line has GSH levels 2 fold higher. Incidentally, this mutant cell line was markedly resistant to a wide variety of chemotherapy drugs. Thus, a link with chemoresistance and radiosensitivity was not found. GSH modulation was found to significantly alter the chemotherapy response particularly for drugs such as melphalan and cisplatin. Particular attention was directed toward the development of an automated drug sensitivity (MTT assay) to screen a large panel (30 cell lines) of human lung cancer lines to determine if a relationship between chemosensitivity and GSH levels exists. Basically, the results showed that cell lines (small cell) low in GSH were more sensitive to cisplatin, melphalan, and adriamycin than cell lines 2-3 fold higher in GSH (non-small cell). The patterns of chemosensitivity observed correlated with what is seen clinically. These studies warrant further investigation as to the possibility of using GSH levels as a predictor of tumor response to chemotherapy drugs.