Repair of damage induced by SR 4233.
The benzotriazine di-N-oxide, SR 4233, was electrolytically reduced at constant potential at pH 4.0 at a reduction rate of 5%/hr under N2 in the presence of phi X174 DNA. During the reduction process, the biological infectivity of the bacterial phage was measured by a double transfection technique, either into the wild-type Escherichia coli strain, or into a series of seven mutants with specific, known defects in their capacity to repair DNA. The survival of phi X174 was evaluated as an index of drug damage and from this we conclude that SR 4233 induces pH-dependent DNA damage in E coli, which is recognized and repaired primarily by the uvrC gene product and by the exonuclease III and endonuclease III gene products. These gene products act primarily upon and are responsible for the recognition of strand breaks and repair of oxidized and fragmented pyrimidine products, indicating that SR 4233 induces strand breaks in DNA resulting from oxidative damage to pyrimidines. As damage is maximized at acid pH, we further propose that the damage mechanism is a process of electron transfer from pyrimidine nucleotides in DNA (i.e., oxidation) to the protonated benzotriazine di-N-oxide one-electron radical anion.
Edwards
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DI
Chemotherapy Research Unit, Polytechnic of East London, U.K.
Virk
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NS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D010584:Bacteriophage phi X 174; D004249:DNA Damage; D004260:DNA Repair; D004269:DNA, Bacterial / Q000187:drug effects; D004279:DNA, Viral / Q000187:drug effects; D004926:Escherichia coli; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000494:pharmacology*; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004269:DNA, Bacterial; D004279:DNA, Viral; D011355:Prodrugs; D014227:Triazines; D000077704:Tirapazamine