Topoisomerase II inhibitors fail to induce chromosome-type aberrations in etoposide-resistant cells: evidence for essential contribution of the cleavable complex formation to the induction of chromosome-type aberrations.

The induction of chromosome-type aberrations is mediated by stabilization of the DNA-topoisomerase II (topo-II) complex, the cleavable complex (CC), induced by topo-II inhibitors. In the present study, in order to confirm the critical contribution of topo-II in producing chromosome-type aberrations, the inducibility of chromosome-type aberrations by topo-II inhibitors was compared between human epidermoid cancer KB cells and their mutant cells (KB/ VP-2 cells) which were resistant to etoposide (VP-16) and which have reduced levels of topo-II and its gene expression. KB/VP-2 cells were resistant to the cytotoxicity of topo-II inhibitors and most resistant to etoposide. In KB cells treated with etoposide which had accumulated CC, chromosome-type aberrations but not chromatid-type aberrations were efficiently induced, as has already been reported in Chinese hamster fibroblasts. In contrast, in KB/VP-2 cells with no accumulation of CC, etoposide induced mainly chromatid-type aberrations, with a few chromosome-type aberrations. Unlike etoposide, however, adriamycin, which was known to accumulate CC in Chinese hamster fibroblastic cells, neither induced chromosome-type aberrations nor accumulated CC in either KB or KB/VP-2 cells. No difference in cell incorporation of [3H]etoposide between the two cell lines was observed. These findings indicate that CC formation contributes to the induction of chromosome-type aberrations, although the reason why adriamycin could not accumulate CC in KB cells is not clear. This may suggest a mechanism for resistance to topo-II inhibitors in cancer chemotherapy.