Inhibition of mitomycin C's aerobic toxicity by the seleno-organic antioxidant PZ-51.
Mitomycin C (MMC) is a bioreductive alkylating agent that is capable of generating oxygen radicals. Porfiromycin (PM) is an analog to MMC that generates oxygen radicals at a significantly lower level than the parent compound. Under aerobic conditions, the toxicity of MMC to EMT6 cells is 2.5-fold that of PM, whereas hypoxically the two are equitoxic. In the present studies, the protective effect of PZ-51 in combination with NAC was assessed against the dose-dependent toxicity of either MMC or PM under both aerobic and hypoxic conditions. Aerobically, the PZ-51 and NAC combination inhibited the toxicity of MMC at concentrations of between 0.25 and 2 microM but had no effect on PM toxicity. Under hypoxic conditions, the PZ-51 and NAC combination had no effect on either MMC or PM toxicity. These findings support a role for oxygen radical generation in the aerobic toxicity of MMC at clinically relevant doses.
Gustafson
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Department of Nutrition, University of Nevada, Reno 89557.
Pritsos
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CA
D000111:Acetylcysteine / Q000494:pharmacology; D000332:Aerobiosis / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000975:Antioxidants / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D054833:Isoindoles; D051379:Mice; D016685:Mitomycin; D008937:Mitomycins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D016566:Organoselenium Compounds; D011160:Porfiromycin / Q000633:toxicity; D012643:Selenium / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D008937:Mitomycins; D016566:Organoselenium Compounds; C042986:ebselen; D016685:Mitomycin; D011160:Porfiromycin; D012643:Selenium; D000111:Acetylcysteine; D004121:Dimethyl Sulfoxide