Differential induction of chromosomal aberrations by topoisomerase inhibitors in cultured Chinese hamster cells.

The inducibility of chromosomal aberration was studied using five mammalian topoisomerase inhibitors in Chinese hamster lung fibroblastic cells (CHL) in two protocols involving 6 and 24 h treatment, with respect to the mechanism of chromosomal aberration. In the 6 h treatment plus 18 h recovery culture (6 h treatment), a high incidence of chromosome-type aberration was observed with three mammalian topoisomerase II (topo-II) inhibitors: etoposide, adriamycin and mitoxantrone, which stabilize the cleavable complex of topo-II and DNA. In the 24 h continuous treatment (24 h treatment), these chemicals induced mainly chromatid-type aberrations. The chromosome-type aberrations which appeared as a result of the 6 h treatment were primarily induced, because the majority of aberrant cells induced by the inhibitors remained in the first metaphase, as determined by the 5-bromodeoxyuridine labelling method. This also indicates that the cells were sensitive to these topo-II inhibitors at the G1-S boundary phase. Aclarubicin, however, which does not form the cleavable complex but is an antagonist against topo-II, and camptothecin, an inhibitor of topoisomerase I, mainly induced chromatid-type aberrations, irrespective of the duration of treatment. These results suggest that the differential induction of chromosomal aberrations by topoisomerase inhibitors reflects different mechanisms of inhibition by the topoisomerases, and that DNA double strand breakages promoted by the stabilization of the cleavable complex formed by topo-II are closely associated with the induction of chromosome-type aberration.