Studies with Bifunctional Bioreductive Drugs: I. In Vitro Oncogenic Transforming Potential

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.