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Modification of the Cytotoxic Activity of Mitomycin C by Oxygen and Ascorbic Acid in Chinese Hamster Ovary Cells and a Repair-deficient Mutant¹

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

The cellular and molecular damage produced by mitomycin C (MMC) in Chinese hamster ovary cells, AA8-4, and a repair deficient mutant of this line, UV-20, was studied by utilizing a system in which oxygen levels could be altered and monitored in solution during acute drug exposures. The cytotoxic activity of MMC decreased from hypoxic conditions to 1% oxygen in solution, while from 1 to 20% there was little change. The relative level of DNA cross-linking in cells was examined under these conditions by alkaline elution and found to increase as cell survival decreased. Utilizing a cell-free assay which detects formation of alkylating species it was confirmed that, while alkylation was observed under aerobic conditions, overall levels increased in the absence of oxygen. The presence of ascorbic acid in the exposure medium (0.284 mM) increased the aerobic but not the hypoxic cytotoxicity of MMC. This resulted in a diminished differential toxicity for cells exposed under aerobic versus hypoxic conditions in the presence of ascorbic acid. When ascorbic acid was present, net alkylation increased under aerobic conditions but was unchanged under hypoxic conditions. One interpretation of these results is that at least two mechanisms of activation of MMC to toxic intermediates may be present in these cells.

¹ Supported by research grants from the National Cancer Institute of Canada, the Medical Research Council of Canada, and the Ontario Cancer Treatment and Research Foundation.

² To whom requests for reprints should be addressed.

Received 9/23/85. Revised 2/25/86. Accepted 2/28/86.