AG8 CELLS, WHICH ARE HIGHLY RESISTANT TO HYDROGEN-PEROXIDE, DISPLAY COLLATERAL SENSITIVITY TO THE COMBINATION OF HYDROGEN-PEROXIDE AND L-HISTIDINE

The results obtained in the present study indicate that AG8 cells, whi ch are highly resistant to H2O2, are not cross-resistant to the combin ation of H2O2/L-histidine. In fact, once the influence of elevated cat alase on the AG8 phenotype has been circumvented (by treatment of AG8 cells with aminotriazole), AG8 cells display essentially no cross-resi stance to the H2O2/L-histidine cocktail while retaining considerable r esistance to H2O2 alone (when compared to wild-type AA8 cells), Althou gh H2O2 alone does not produce DNA double strand breaks (DSBs), this t ype of lesion was readily detected upon exposure of sensitive or resis tant cells to the oxidant in the presence of the amino acid, Interesti ngly, similar levels of DNA DSBs were detected in AA8 and catalase-dep leted AG8 cells, An excellent correlation was found when the cytotoxic ity and the level of DNA DSBs obtained in sensitive and resistant cell s (with normal or reduced catalase levels) challenged with the cocktai l H2O2/L-histidine were compared, This would suggest that DSBs produce d on a per cell basis always result in an equal level of toxicity, reg ardless of the cell type (resistant versus sensitive cell line), the l ethality of each of these cell lines being dependent on the number of induced DSBs, In conclusion, the results presented here provide furthe r evidence in support of the hypothesis that cell killing elicited by the combination of H2O2/L-histidine involves a mechanism distinct from that following treatment with H2O2 alone, The fact that H2O2-resistan t AG8 cells, which are not cross-resistant to agents promoting cell de ath via DNA DSB-induction, display collateral sensitivity to the cockt ail H2O2/L-histidine, strongly suggests that cell killing triggered by this treatment is mediated by DNA double strand breakage.