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Molecular Pharmacology, Volume 52, Issue 5, 839-845

Mitindomide Is a Catalytic Inhibitor of DNA Topoisomerase II That Acts at the Bisdioxopiperazine Binding Site

Brian B. Hasinoff, Andrew M. Creighton, Hanna Kozlowska, Padmakumari Thampatty, William P. Allan, and Jack C. Yalowich

Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, R3T 2N2 Canada (B.B.H., H.K.), Department of Pharmacology, University of Pittsburgh School of Medicine and Cancer Institute, Pittsburgh, Pennsylvania 15261(P.T., W.P.A., J.C.Y.), and Medicinal Chemistry Laboratory, Department of Reproductive Physiology, St. Bartholomew's Hospital Medical College, West Smithfield, London, United Kingdom (A.M.C.)

The antitumor drug mitindomide (NSC 284356) was shown to inhibit the decatenation activity of human and Chinese hamster ovary (CHO) topoisomerase II [DNA topoisomerase (ATP-hydrolyzing), EC 5.99.1.1]. Mitindomide did not induce the formation of topoisomerase II-DNA covalent cleavable complexes in CHO cells. These results taken together indicate that mitindomide is a catalytic/noncleavable complex-forming-type inhibitor of topoisomerase II. The growth inhibitory effects of mitindomide and dexrazoxane toward a sensitive parent CHO cell line and the dexrazoxane-resistant DZR cell line, which is highly (500-fold) resistant to the bisdioxopiperazine dexrazoxane, were measured. The DZR cell line was shown to be 30-fold cross-resistant to mitindomide. Mitindomide, like dexrazoxane, was shown to inhibit cleavable complex formation by the topoisomerase II poison etoposide. The attenuated inhibition of etoposide-induced cleavable complexes in DZR compared with CHO cells was, likewise, very similar for dexrazoxane and mitindomide. Together these results suggest that mitindomide acts at the same site on topoisomerase II as does dexrazoxane and other bisdioxopiperazines. Various molecular parameters obtained by molecular modeling were compared for mitindomide and dexrazoxane. Mitindomide, which is conformationally very rigid, has highly coplanar imide rings, as does dexrazoxane in the solid state. Other molecular parameters, such as the imide nitrogen-to-imide nitrogen bond distances, and polar and nonpolar surface areas were also very similar. Thus, it is concluded that mitindomide exerts its antitumor effects through its inhibition of topoisomerase II by binding to the bisdioxopiperazine binding site.

Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics


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