SYNERGISTIC EFFECT OF INHIBITORS OF TOPOISOMERASE-I AND TOPOISOMERASE-II ON CHROMOSOME-DAMAGE AND CELL-KILLING IN CULTURED CHINESE-HAMSTER OVARY CELLS

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