Cytotoxicity of BMS-181174. Effects of hypoxia, dicoumarol, and repair deficits.
The mitomycin C (MC) analog BMS-181174 (previously designated as BMY25067) has been shown to be active against a variety of solid tumors in mice. The activity of this compound against tumor cell lines resistant to MC and the different toxicity profiles of BMS-181174 and MC suggested that there may be significant differences in the metabolism and the mechanisms of action of these two compounds. Our studies with a mouse mammary tumor cell line (EMT6), a wild-type Chinese hamster cell line (AA8), and three repair-deficient Chinese hamster cell lines (UV4, UV5, and EM9) supported this concept. BMS-181174 was more toxic to all five cell lines in air than in hypoxia; in contrast, MC is more toxic in hypoxia. Dicoumarol (which increases the cytotoxicity of MC in hypoxia and reduces the cytotoxicity of this drug in air) did not alter the cytotoxicity of BMS-181174. This finding suggests that neither DT-diaphorase nor cytochrome b5 reductase is involved in the activation of BMS-181174. Studies with the repair-deficient cell lines suggest that DNA strand breaks are not important to the cytotoxicity of BMS-181174, and that cross-links and adducts may be the critical lesions; these studies also suggest that the lethal lesions produced by BMS-181174 are the same under aerobic and hypoxic conditions.
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D015687:Cell Hypoxia; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004249:DNA Damage; D001728:Dicumarol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051379:Mice; D016685:Mitomycin / Q000633:toxicity; D008937:Mitomycins; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018906:Antineoplastic Agents, Alkylating; D008937:Mitomycins; D016685:Mitomycin; D001728:Dicumarol; C055172:N-7-(2-(nitrophenyldithio)ethyl)mitomycin C