Kennedy K A, Rockwell S, Sartorelli A C
Cancer Res. 1980 Jul;40(7):2356-60.
Mitomycin C, a bioreductive alkylating agent with clinical utility against several human tumors, was found to be selectively toxic at a relatively low concentration (1.5 micro M) to EMT6 tumor cells made chronically hypoxic by preincubation in 95% N2-5% CO2 for 4 hr prior to drug exposure. This selective cytotoxicity correlated well with the preferential activation and metabolism of mitomycin C by sonicated cell preparations. The bioactivation of mitomycin C to an alkylating agent by EMT6 and Sarcoma 180 cell sonicates required hypoxic conditions and a reduced nicotinamide adenine dinucleotide phosphate-generating system. Furthermore, the formation of reactive drug metabolites and the disappearance of mitomycin C from the reaction mixture were inhibited by carbon monoxide. The presence of potassium cyanide in the incubation mixture did not affect either the rate of overall metabolism or the rate of formation of reactive metabolites. A high rate of disappearance of mitomycin C from the medium of intact cultures of EMT6 cells was found only in those cultures which were made chronically hypoxic. These data suggest that bioreductive alkylating agents like mitomycin C have the potential to attack selectively the chemotherapeutically resistant hypoxic cell component of solid tumors. Thus, agents capable of bioreductive alkylation should be useful adjuncts to existing therapeutic regimens which are effective against well-oxygenated cells.
丝裂霉素C是一种对多种人类肿瘤具有临床效用的生物还原烷基化剂，研究发现它在相对低的浓度（1.5微摩尔）下，对在药物暴露前于95%氮气-5%二氧化碳中预孵育4小时而导致长期缺氧的EMT6肿瘤细胞具有选择性毒性。这种选择性细胞毒性与经超声处理的细胞制剂对丝裂霉素C的优先激活和代谢密切相关。EMT6和肉瘤180细胞超声提取物将丝裂霉素C生物激活为烷基化剂需要缺氧条件和一个还原型烟酰胺腺嘌呤二核苷酸磷酸生成系统。此外，反应混合物中活性药物代谢产物的形成以及丝裂霉素C的消失受到一氧化碳的抑制。孵育混合物中氰化钾的存在既不影响总体代谢速率也不影响活性代谢产物的形成速率。仅在那些长期缺氧的完整EMT6细胞培养物中发现丝裂霉素C从培养基中快速消失。这些数据表明，像丝裂霉素C这样的生物还原烷基化剂有可能选择性地攻击实体瘤中对化疗耐药的缺氧细胞成分。因此，能够进行生物还原烷基化的药物应该是现有针对富氧细胞有效的治疗方案的有用辅助药物。
