Whitmore G F, Gulyas S
Int J Radiat Oncol Biol Phys. 1986 Jul;12(7):1219-22. doi: 10.1016/0360-3016(86)90262-2.
RSU-1069 combines an aziridine function with a 2-nitroimidazole and has been reported to exhibit extraordinary radiosensitization both in vitro and in vivo. Such sensitization appears to be at variance with the electron affinity of the compound. In addition, recent experiments suggest that the compound is highly toxic to hypoxic tumor cells in vivo. On the assumption that the observed radiosensitizing ability may be a manifestation of toxicity and because of the high in vivo toxicity, we have investigated aerobic and hypoxic toxicity, both in wild type CHO cells and in mutants sensitive to a variety of DNA damaging agents. With wild type cells under aerobic conditions, the compound is approximately 50 times as toxic as misonidazole and under hypoxic conditions, approximately 250 times as toxic. The ratio of hypoxic to aerobic toxicity is approximately 80 times. Under aerobic conditions, repair-deficient mutants are 10 times as sensitive to RSU-1069 as wild type cells and approximately 100 times as sensitive under hypoxic conditions. The ratio of hypoxic to aerobic toxicity for the mutant cells is approximately 900. Based on these observations, we suggest that under aerobic conditions the aziridine function is primarily responsible for toxicity, whereas, under hypoxic conditions, the aziridine moiety combined with a reduced 2-nitroimidazole moiety produces a bifunctional agent.
RSU - 1069将氮丙啶功能与2 - 硝基咪唑结合在一起，据报道在体外和体内均表现出非凡的放射增敏作用。这种增敏作用似乎与该化合物的电子亲和力不一致。此外，最近的实验表明该化合物在体内对缺氧肿瘤细胞具有高度毒性。基于观察到的放射增敏能力可能是毒性的一种表现，并且由于其在体内的高毒性，我们研究了其在野生型CHO细胞和对多种DNA损伤剂敏感的突变体中的需氧和缺氧毒性。在需氧条件下，对于野生型细胞，该化合物的毒性约为米索硝唑的50倍，在缺氧条件下，毒性约为米索硝唑的250倍。缺氧毒性与需氧毒性之比约为80倍。在需氧条件下，修复缺陷型突变体对RSU - 1069的敏感性是野生型细胞的10倍，在缺氧条件下约为100倍。突变体细胞的缺氧毒性与需氧毒性之比约为900。基于这些观察结果，我们认为在需氧条件下，氮丙啶功能主要负责毒性，而在缺氧条件下，氮丙啶部分与还原的2 - 硝基咪唑部分结合产生一种双功能剂。
