title: Studies with bifunctional bioreductive drugs. I. In vitro oncogenic transforming potential.
abstract: 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.
authors.affiliation: Center for Radiological Research, College of Physicians & Surgeons, Columbia University, New York, New York 10032.
authors.forename: T K
authors.initials: TK
authors.lastname: Hei
authors.forename: Z Y
authors.initials: ZY
authors.lastname: He
authors.forename: C Q
authors.initials: CQ
authors.lastname: Piao
authors.forename: E J
authors.initials: EJ
authors.lastname: Hall
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001388:Aziridines / Q000627:therapeutic use; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D008920:Misonidazole / Q000031:analogs & derivatives / Q000633:toxicity; D009581:Nitrofurans / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000633:toxicity*
chemical_list: C049944:1-(2-nitro-1-imidazoly)-3-(2,3-dimethylaziridino)-2-propanol; D000970:Antineoplastic Agents; D001388:Aziridines; D009581:Nitrofurans; C066400:RB 88712; D011838:Radiation-Sensitizing Agents; C049942:RB 7040; C066399:RB 88716; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole