Different efficiencies of interaction between 3-aminobenzamide and various monofunctional alkylating agents in the induction of sister chromatid exchanges.

Abstract

3-Aminobenzamide (3AB), an inhibitor of poly(ADP-ribose) polymerase, interacts synergistically with certain monofunctional alkylating agents to increase the frequency of sister chromatid exchanges (SCEs) in Chinese hamster ovary cells (CHO). Not all alkylating agents interact with 3AB to the same extent. Because 3AB has been reported to inhibit DNA strand break rejoining, experiments were carried out to determine if 3AB interacts preferentially with alkylation-induced DNA strand breaks or some other alkylated DNA lesion in the induction of SCEs. SCE frequency was determined in CHO cells that were pretreated with methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), ethylnitrosourea (ENU) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 2 h before being incubated with 3AB, and compared to the frequency of DNA strand breaks, as measured by alkaline elution, induced by these treatments. MNNG was by far the most potent DNA strand-breaking and SCE-inducing agent, followed in order of reactivity by MMS, EMS and ENU. The 3AB-enhanced SCE frequency was greatest, however, after MMS treatment. Thus the magnitude of the 3AB-mediated potentiation of SCE induction is not directly related to either the number of DNA strand breaks produced by the alkylating agent or the alkylation-induced SCE frequency. Furthermore, when MMS-treated cells were held in a non-cycling state for 2 days before release and treatment with 3AB, a procedure that results in a 60% reduction in MMS-induced SCE frequency, no synergism between MMS and 3AB in SCE induction was detected. These results suggest that 3AB does not interact with alkylation-induced DNA lesions in the induction of SCEs.