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Oxygen and Exposure Kinetics as Factors Influencing the Cytotoxicity of Porfiromycin, a Mitomycin C Analogue, in Chinese Hamster Ovary Cells¹

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

Some factors affecting the cytotoxicity of porfiromycin (PM), an analogue of mitomycin C (MMC), were investigated in suspension cultures of wild-type (AA8-4) and repair-deficient (UV-20) Chinese hamster ovary cells. Oxygen was an important modulator of PM toxicity in AA8-4 cells. The aerobic toxicity was significantly less, and toxicity under extremely hypoxic conditions was significantly greater for PM than MMC. Porfiromycin cytotoxicity at intermediate O₂ levels was similar to that observed previously for MMC. While the aerobic/hypoxic ratio was greater for PM than MMC, survival at intermediate oxygen concentrations could limit the therapeutic utility of these drugs as adjuncts to radiotherapy. Ascorbic acid was found to increase the aerobic, but not hypoxic, cytotoxicity of PM in AA8-4 cells, as was observed previously for MMC. Investigation of various exposure times and drug concentrations revealed that drug toxicity for both aerobic and hypoxic cells was dependent on the product of drug concentration and time, and that the aerobic/hypoxic differential observed in AA8-4 cells was constant over a broad range of exposure conditions. The sensitivity of UV-20 cells was also a linear function of concentration and time, but no aerobic/hypoxic differential was observed in these cells. It is suggested that the sensitivity of UV-20 to PM and MMC, and its lack of an hypoxic/aerobic differential could result from lethality being due to a different lesion than in wild-type 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, at Department of Medical Biophysics, Ontario Cancer Institute, 500 Sherbourne Street, Toronto, Ontario, Canada M4X 1K9.

Received 3/28/88. Revised 7/12/88. Accepted 7/15/88.

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