The mechanism of 3-aminobenzamide-mediated increases in spontaneous and induced SCEs.
Cells exposed to the poly-(ADP-ribose)-polymerase inhibitor, 3-aminobenzamide (3AMB), have increased levels of sister chromatid exchanges (SCEs). In addition, cells exposed to certain monofunctional alkylating agents in combination with 3AMB have frequencies of SCEs much greater than expected if the 2 agents acted independently. Because poly-(ADP-ribose)-polymerase is stimulated by the production of DNA strand breaks, and 3AMB is said to inhibit strand-break rejoining, we determined the relationship between DNA strand breakage and SCE formation. Alkylating agents and the incorporation of bromodeoxyuridine (BrdUrd) into DNA led to the production of DNA strand breaks and the most potent SCE-inducing agents were also the most efficient DNA strand-breaking agents. In increasing SCE frequency, 3AMB interacted most strongly with those agents that produced the greatest number of DNA strand breaks. 3AMB also increased the frequency of strand breaks by delaying strand-break rejoining and introducing new strand breaks. The protease inhibitor, antipain, inhibited the formation of 3AMB-induced strand breaks in BrdUrd-containing cells and reduced by half the 3AMB-mediated increase in SCE frequency, suggesting that one mechanism for SCE induction involves the introduction of breaks into DNA possibly in response to changes in chromatin structure. We conclude that the primary lesion responsible for SCE induction after exposure to alkylating agents or incorporation of BrdUrd into DNA is either a DNA strand break or a lesion that can result in a strand break. 3AMB increases SCE frequency in combination with these agents by introducing new breaks and possibly delaying strand-break rejoining.
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D000976:Antipain / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002460:Cell Line; D002869:Chromosome Aberrations; D006224:Cricetinae; D003412:Cricetulus; D003561:Cytarabine / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000648:ultrastructure; D010053:Ovary; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012854:Sister Chromatid Exchange / Q000187:drug effects*
D000477:Alkylating Agents; D001549:Benzamides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003561:Cytarabine; D000976:Antipain; C025160:3-aminobenzamide; D001973:Bromodeoxyuridine