Hei T K, He Z Y, Piao C Q, Hall E J
Center for Radiological Research, College of Physicians & Surgeons, Columbia University, New York, New York 10032.
Radiat Res. 1990 Oct;124(1 Suppl):S44-9.
The oncogenic transforming potential of a series of bioreductive drugs including RSU-1069 and its various alkyl-substituted derivatives, RB-7040, RB-88716, RSU-1164, and RB-88712, has been compared using the C3H 10T1/2 cell system. While the aziridine moiety at the terminal end of the side chain confers greater cytotoxicity to both the 2-nitroimidazole (RSU-1069) and the 5-nitrofuran (RB-88716), it also increases the oncogenic transforming potential of the drugs correspondingly. By substituting the aziridine ring with methyl groups, the cytotoxicity and oncogenicity of these bioreductive drugs decrease in a way that is proportional to the degree of methylation. A clear structure-activity relationship can be demonstrated from these methyl-substituted derivatives such that a tetramethyl-substituent (RB-7040) is much less cytotoxic and oncogenic than a dimethyl-substituent (RSU-1164). RB-7040, which has in vitro and in vivo sensitizing efficiency comparable to the parental compound RSU-1069, is roughly tenfold less cytotoxic and, at concentrations that achieve an in vitro enhancement ratio of 2.9, induces a transforming frequency that is indistinguishable from the spontaneous rate.
利用C3H 10T1/2细胞系统比较了包括RSU-1069及其各种烷基取代衍生物、RB-7040、RB-88716、RSU-1164和RB-88712在内的一系列生物还原药物的致癌转化潜力。虽然侧链末端的氮丙啶部分赋予2-硝基咪唑（RSU-1069）和5-硝基呋喃（RB-88716）更大的细胞毒性，但它也相应地增加了药物的致癌转化潜力。通过用甲基取代氮丙啶环，这些生物还原药物的细胞毒性和致癌性以与甲基化程度成比例的方式降低。从这些甲基取代衍生物中可以证明明显的构效关系，即四甲基取代基（RB-7040）的细胞毒性和致癌性比二甲基取代基（RSU-1164）小得多。RB-7040在体外和体内的致敏效率与母体化合物RSU-1069相当，其细胞毒性大约低十倍，并且在达到体外增强率2.9的浓度下，诱导的转化频率与自发率没有区别。
