Genotoxic effects of 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233) and nitrogen mustard-N-oxide (nitromin) in Walker carcinoma cells under aerobic and hypoxic conditions.
As judged by alkaline elution, exposure of Walker cells to either 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233) or nitromin results in a dose-dependent increase in DNA damage due to single-strand breaks. With nitromin or SR 4233 there was little difference in the extent of DNA single-strand breaks between Walker cells incubated either hypoxically or aerobically. In contrast, there was a 24-fold enhancement in the differential hypoxic/aerobic response to SR 4233 in clonogenic studies. Following incubation of cells with nitrogen mustard, DNA cross-linking is observed. Bioreduction of nitromin would be expected to yield nitrogen mustard as the putative reactive metabolite. However, only DNA strand-breaks could be detected in Walker cells incubated with nitromin, suggesting that reduction of this pro-drug to nitrogen mustard was not a major activation pathway. In cells incubated under aerobic conditions, SR 4233 induces oxidative DNA damage, as indicated by the formation of 8-hydroxydeoxyguanosine, suggesting the involvement of futile redox cycling. In rats dosed with SR 4233 in vivo, significantly higher levels of 8-hydroxydeoxyguanosine could be detected in liver, compared to vehicle-dosed controls.
Cahill
A
A
MRC Toxicology Unit, Carshalton, Surrey, UK.
Jenkins
T C
TC
Pickering
P
P
White
I N
IN
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000332:Aerobiosis; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D001711:Biotransformation; D002279:Carcinoma 256, Walker / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008466:Mechlorethamine / Q000493:pharmacokinetics / Q000633:toxicity*; D010084:Oxidation-Reduction; D051381:Rats; D000077704:Tirapazamine; D014227:Triazines / Q000493:pharmacokinetics / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004277:DNA, Single-Stranded; D014227:Triazines; D000077704:Tirapazamine; D008466:Mechlorethamine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine