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0026-895X/03/6306-1382-1388$20.00
Mol Pharmacol 63:1382-1388, 2003

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DNA Sequence Specificity for Topoisomerase II Poisoning by the Quinoxaline Anticancer Drugs XK469 and CQS

Hanlin Gao1, Edith F. Yamasaki, Kenneth K. Chan, Linus L. Shen, and Robert M. Snapka

Departments of Radiology (H.G., E.F.Y., R.M.S.) and Molecular Virology, Immunology, and Medical Genetics (H.G., R.M.S.), College of Medicine and Public Health and College of Pharmacy (K.K.C.), the Ohio State University, Columbus, Ohio; and Abbott Laboratories (L.L.S.), Abbott Park, Illinois

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 II{alpha} and human topoisomerase II{beta}. The DNA cleavage intensity pattern for topoisomerase II{alpha} poisoning by CQS closely resembled that of VM-26, despite the lack of any apparent common pharmacophore. In contrast, the topoisomerase II{alpha} 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 II{beta}-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 II{alpha} or topoisomerase II{beta}, 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.

Received November 8, 2002; accepted March 10, 2003

Address correspondence to: Dr. Robert M. Snapka, The Ohio State University, Department of Radiology, 103 Wiseman Hall, 400 West 12th Avenue, Columbus, OH 43210. E-mail: snapka.1{at}osu.edu




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