Synergistic effect of inhibitors of topoisomerase I and II on chromosome damage and cell killing in cultured Chinese hamster ovary cells

Simultaneous treatment of cultured Chinese hamster ovary cells with the topoisomerase I inhibitor camptothecin and the topoisomerase II inhibitor 4-(9-acridinylamino)-methanesulfon-m-anisidide results in a clear synergistic effect on both chromosome damage detected at metaphase and loss of colony-forming ability. In contrast, the effect of combined treatment with these topoisomerase inhibitors on sister chromatid exchanges was not significantly different from that expected if the effects were additive. Taken as a whole, these results seem to support the hypothesis that topoisomerase inhibitors can lead to cell death, presumably when DNA replication forks collide with drug-stabilized cleavable complexes. Nevertheless, no evidence of apoptosis was obtained from DNA fragmentation analysis. The possible clinical implications of our findings are discussed.