DNA sequence specificity for topoisomerase II poisoning by the quinoxaline anticancer drugs XK469 and CQS.

Abstract

The two known antineoplastic quinoxaline topoisomerase II poisons, XK469 (NSC 697887) and CQS (chloroquinoxaline sulfonamide, NSC 339004), were compared for DNA cleavage site specificity, using purified human topoisomerase IIalpha and human topoisomerase IIbeta. The DNA cleavage intensity pattern for topoisomerase IIalpha poisoning by CQS closely resembled that of VM-26, despite the lack of any apparent common pharmacophore. In contrast, the topoisomerase IIalpha DNA cleavage intensity patterns of XK469 and CQS were very different from one another despite the similar overall structures of the two drugs. This suggests that the differences in DNA site specificity of topoisomerase II poisoning by XK469 and CQS may be caused by differences in their geometry, side chains, or electronic structure. The topoisomerase IIbeta-mediated DNA cleavage sites of CQS and XK469 were also very different from one another, adding further support to this idea. Earlier work has demonstrated that a number of specific topoisomerase II poisons show very similar patterns of DNA cleavage with either topoisomerase IIalpha or topoisomerase IIbeta, suggesting that the topoisomerase II isozymes play only a minor role in choices of DNA cleavage sites. However, both of the quinoxaline topoisomerase II poisons in this study showed distinctly different and unique DNA cleavage intensity patterns with each topoisomerase II isozyme. This indicates that topoisomerase II isozymes can play a major role in DNA cleavage site selection for some classes of topoisomerase II poisons.