Effect of the superoxide dismutase inhibitor, diethyldithiocarbamate, on the cytotoxicity of mitomycin antibiotics.
Mitomycin C (MC) and its structural analogs porfiromycin (PM), BMY-25282 and BL-6783 are toxic to EMT6 cells under aerobic and hypoxic conditions. The mitomycin antibiotics are hypothesized to exert cytotoxicity under hypoxic conditions by cross-linking DNA following reductive activation, while aerobic cytotoxicity may involve DNA cross-linking by these agents and/or damage due to the generation of oxygen radicals. Previous findings (Pritsos and Sartorelli, 1986) indicated that the rank order of cytotoxicity for a series of mitomycins was the same as the rank order for the rate of oxygen consumption induced by these agents. As an additional approach to explore the role of oxygen radicals in the aerobic cytotoxicity of the four agents studied, EMT6 cells were treated with the mitomycins in the presence of the superoxide dismutase inhibitor diethyldithiocarbamate (DETC). DETC, which decreased superoxide dismutase activity in EMT6 cells, increased the cytotoxicity of BMY-25282 and BL-6783 by half an order of magnitude, but did not affect the toxicity of PM or MC to these cells. DNA cross-links, a proposed cytotoxic lesion induced by BMY-25282, however, were not detectably increased in EMT6 cells exposed to this agent in the presence of DETC in spite of the large increase in cytotoxicity under these treatment conditions. No single strand breaks were detected in cells exposed to either BMY-25282 or BMY-25282 plus DETC. The findings support the concept that oxygen radicals may have a role in the aerobic cytotoxicity of some of the mitomycin antibiotics, and that the lesions responsible for cytotoxicity produced by oxygen radicals may not reside entirely at the level of DNA.
Pritsos
C A
CA
Department of Pharmacology, Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT 06510.
Keyes
S R
SR
Sartorelli
A C
AC
D000332:Aerobiosis; D000818:Animals; D015687:Cell Hypoxia; D002470:Cell Survival; D004249:DNA Damage; D004050:Ditiocarb / Q000494:pharmacology*; D005609:Free Radicals; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D016685:Mitomycin; D008937:Mitomycins / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011160:Porfiromycin / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D005609:Free Radicals; D008937:Mitomycins; D016685:Mitomycin; C046941:N(6)-((dimethylamino)methylene)mitomycin C; C062966:7-N-(N',N'-dimethylaminomethylene)aminoporfiromycin; D004050:Ditiocarb; D013482:Superoxide Dismutase; D011160:Porfiromycin; D010100:Oxygen