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Chinese Hamster Ovary Cell Lines Resistant to Mitomycin C under Aerobic but not Hypoxic Conditions Are Deficient in DT-Diaphorase¹

Physics Division of the Ontario Cancer Institute and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M4X 1K9

We have previously reported the isolation of CHO cell lines resistant to mitomycin C under aerobic conditions of drug exposure. Here it is reported that these cell lines have the same response to mitomycin C under hypoxic conditions as do controls. The cells are shown to have lower levels of DT-diaphorase activity than controls, but similar levels of activity of NADPH:cytochrome c reductase, another enzyme involved in the metabolism of mitomycin C. Evidence for molecular defects in the DT-diaphorase gene or gene transcript is presented for the deficient cell lines. The consequences of this DT-diaphorase deficiency is further explored by testing the toxicity of menadione, an established enzyme substrate. The isolation of CHO cell lines deficient in DT-diaphorase activity and resistant to mitomycin C under aerobic but not hypoxic conditions suggests that mitomycin C reduction by this enzyme has a significant impact on cytotoxicity under aerobic but not hypoxic conditions. Similarly, DT-diaphorase metabolism of menadione does not appear to have a significant impact on cytotoxicity in CHO cells.

¹ Supported in part by the National Cancer Institute of Canada and the Ontario Cancer Treatment and Research Foundation.

² Present address: Research Institute, Hospital for Sick Children, Cystic Fibrosis Research Development Program, 555 University Ave., Toronto, Ontario, Canada M5G 1X8.

Received 9/21/90. Accepted 1/24/91.

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