title: Dual-function 2-nitroimidazoles as hypoxic cell radiosensitizers and bioreductive cytotoxins: in vivo evaluation in KHT murine sarcomas.
abstract: The efficacies of a series of potential prodrugs of RSU-1069 and its alkyl-aziridine analogues were assessed. These 1-(2-haloethylamino)-3-(2-nitro-1-imidazolyl)-2-propanol compounds were designed to cyclize in vivo to generate 2-nitro-imidazoles with aziridine (RSU-1069) or alkyl-substituted aziridine (RSU-1164, RB-7040, or RSU-1150) functions. Maximum tolerated single, intraperitoneal doses (MTD) were determined in C3H/He mice bearing subcutaneous KHT sarcomas, and a drug dose-response relationship for radiosensitization was established for each compound administered at the optimum time (45-60 min) before local irradiation of tumors with a 10-Gy dose of X-rays. The potentials of the compounds as bioreductive cytotoxins were studied by administering them immediately after irradiation. Tumor cell survival was measured 18-24 h after treatment in an in vitro soft agar clonogenic assay. Results of toxicity, radiosensitization, and bioreductive cytotoxicity assays for each of the prodrugs (RB-6171, RB-6172, RB-6173, RB-6174, and RB-6175) of the alkyl-substituted aziridines were entirely consistent with complete conversion to their respective target compounds. For example, RB-6171 (the prodrug form of RSU-1164) was only about four times less efficient than RSU-1069 as a radiosensitizer and bioreductive cytotoxin but had an MTD 7.5 times higher. In contrast, prodrugs of RSU-1069 (RB-6144 and RB-6145) were two- to threefold less toxic than their expected product. RB-6144 was a poor radiosensitizer and bioreductive agent compared with RSU-1069 and was similar to RB-6170, a nonalkylating nitroimidazole. This is consistent with the observation that there is limited conversion of RB-6144 to RSU-1069 in vitro. However, radiosensitization and bioreductive cytotoxicity produced by RB-6145 were only slightly less than the effects produced by RSU-1069; thus a therapeutic gain was achieved with RB-6145 in a murine tumor model.
authors.affiliation: Medical Research Council, Radiobiology Unit, Didcot, Oxon, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Cole
authors.forename: I J
authors.initials: IJ
authors.lastname: Stratford
authors.forename: G E
authors.initials: GE
authors.lastname: Adams
authors.forename: E M
authors.initials: EM
authors.lastname: Fielden
authors.forename: T C
authors.initials: TC
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011355:Prodrugs / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000532:radiotherapy*
chemical_list: C049944:1-(2-nitro-1-imidazoly)-3-(2,3-dimethylaziridino)-2-propanol; D000970:Antineoplastic Agents; D011355:Prodrugs; D011838:Radiation-Sensitizing Agents; C049942:RB 7040; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole