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-am ino-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. Wi th nitromin or SR 4233 there was little difference in the extent of DN A single-strand breaks between Walker cells incubated either hypoxical ly or aerobically. In contrast, there was a 24-fold enhancement in the differential hypoxic/aerobic response to SR 4233 in clonogenic studie s. Following incubation of cells with nitrogen mustard, DNA cross-link ing is observed. Bioreduction of nitromin would be expected to yield n itrogen mustard as the putative reactive metabolite. However, only DNA strand-breaks could be detected in Walker cells incubated with nitrom in, suggesting that reduction of this pro-drug to nitrogen mustard was not a major activation pathway. In cells incubated under aerobic cond itions, SR 4233 induces oxidative DNA damage, as indicated by the form ation of 8-hydroxydeoxyguanosine, suggesting the involvement of futile redox cycling. In rats dosed with SR 4233 in vivo, significantly high er levels of 8-hydroxydeoxyguanosine could be detected in liver, compa red to vehicle-dosed controls.