Assessment of the repair and damage of DNA induced by parent and reduced RSU-1069, a 2-nitroimidazole-aziridine.
The cellular repair and damage of DNA induced by parent and reduced RSU-1069, a 2-nitroimidazole-aziridine, was assessed at both the molecular and cellular level. At the molecular level, after in vitro incubation with parent or reduced RSU-1069, plasmid DNA was transfected into Escherichia coli (AB1157) with subsequent selection for gene expression. For equivalent levels of DNA strand breakage following such treatment it is evident from the relative transformation frequencies that interactions with reduced RSU-1069 lead to DNA damage consistent with bifunctional action of a metabolite(s). At the cellular level, the cytoxicity of RSU-1069 was determined for a series of repair deficient mutants of E. coli under both aerobic and hypoxic conditions. The differential aerobic:hypoxic cytotoxicity ratio is approximately 3. We conclude that the repair of cellular DNA damage induced by RSU-1069 involves activation of the gene products under the control of the recA gene and not those under the control of the ada gene. The ability of cellular systems to repair damage induced by RSU-1069 may play a significant role in determining its efficiency to act as a hypoxic cell radiosensitizer and a hypoxia selective cytotoxin.
O'Neill
P
P
Medical Research Council Radiobiology Unit, Didcot, Oxon, U.K.
Cunniffe
S M
SM
D000332:Aerobiosis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004926:Escherichia coli; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010957:Plasmids; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014158:Transcription, Genetic
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole