MITINDOMIDE IS A CATALYTIC INHIBITOR OF DNA TOPOISOMERASE-II THAT ACTS AT THE BISDIOXOPIPERAZINE BINDING-SITE

The antitumor drug mitindomide (NSC 284356) was shown to inhibit the d ecatenation activity of human and Chinese hamster ovary (CHO) topoisom erase II [DNA topoisomerase (ATP-hydrolyzing), EC 5.99.1.1]. Mitindomi de did not induce the formation of topoisomerase II-DNA covalent cleav able complexes in CHO cells. These results taken together indicate tha t mitindomide is a catalytic/noncleavable complex-forming-type inhibit or of topoisomerase II. The growth inhibitory effects of mitindomide a nd dexrazoxane toward a sensitive parent CHO cell line and the dexrazo xane-resistant DZR cell line, which is highly (500-fold) resistant to the bisdioxopiperazine dexrazoxane, were measured. The DZR cell line w as shown to be 30-fold cross-resistant to mitindomide. Mitindomide, li ke dexrazoxane, was shown to inhibit cleavable complex formation by th e topoisomerase II poison etoposide. The attenuated inhibition of etop oside-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 topoisomera se II as does dexrazoxane and other bisdioxopiperazines. Various molec ular parameters obtained by molecular modeling were compared for mitin domide and dexrazoxane. Mitindomide, which is conformationally very ri gid, has highly coplanar imide rings, as does dexrazoxane in the solid state. Other molecular parameters, such as the imide nitrogen-to-imid e nitrogen bond distances, and polar and nonpolar surface areas were a lso very similar. Thus, it is concluded that mitindomide exerts its an titumor effects through its inhibition of topoisomerase II by binding to the bisdioxopiperazine binding site.