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Modulation of the Cytotoxicity of Mitomycin C to EMT6 Mouse Mammary Tumor Cells by Dicoumarol in Vitro¹

Departments of Therapeutic Radiology (S. R.) and Pharmacology (S. R. K., A. C. S.), Developmental Therapeutics Program, Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510-8040

Aerobic and hypoxic cultures of EMT6 mouse mammary tumor cells were used to study the effects of dicoumarol (DIC) on the cytotoxicity of mitomycin C (MC). DIC protected aerobic cells from MC toxicity, but sensitized hypoxic cells to the cytotoxic actions of this antibiotic. Survival curves for cells treated with 1.5 µM MC ± 100 µM DIC for different periods of time under aerobic or hypoxic conditions showed that DIC acted as a dose-modifying agent, that is, an agent which changed the slopes, but not the shapes, of the MC survival curves. Experiments that examined the effects of the DIC concentration on the modulation of MC cytotoxicity revealed significant perturbations in MC toxicity with a DIC concentration of 100 µM and increased sensitization/protection with increasing levels of DIC. DIC altered the toxicity of MC only when it was present during exposure of the cells to MC. Treatment with DIC before or after (but not during) MC did not alter the amount of cytotoxicity. Addition of DIC to cell cultures seconds before the addition of MC was as effective as addition of DIC 30 min to 2 h before MC. Taken together, these findings suggest that DIC reversibly inhibits one or more enzymes involved in the activation and inactivation of MC, and that this modulation of the enzymatic processing of MC alters the cytotoxicity of the drug.

¹ This study was supported by Grant PDT-145 from the American Cancer Society (S. R.) and Grant CA-43659 from the National Cancer Institute (S. R. K., A. C. S.).

² To whom requests for reprints should be addressed.

Received 3/21/88. Revised 6/14/88. Accepted 7/ 6/88.

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