Cross-resistance of nocodazole-resistant mutants of CHO cells toward other microtubule inhibitors: similar mode of action of benzimidazole carbamate derivatives and NSC 181928 and TN-16

RS Gupta

Stable mutants which are between 1.6- and 2.2-fold resistant to the microtubule inhibitor, nocodazole (NocR mutants) have been isolated in Chinese hamster ovary cells after a single-step selection. The different NocR mutants exhibit specific changes in their cross- resistance or collateral sensitivity toward various microtubule inhibitors (viz. colchicine, podophyllotoxin, taxol, vinblastine, and maytansine), but they show no change in resistance toward unrelated compounds, indicating that the genetic lesions in these mutants are microtubule related. The set of NocR mutants examined and a second-step podophyllotoxin-resistant cell line, PodRII6 (which is highly resistant to nocodazole) were found to exhibit proportionately increased cross- resistance toward various benzimidazole carbamate derivatives (viz. mebendazole, fenbendazole, carbendazim, parbendazole, oxibendazole, albendazole, benomyl, and cambendazole) as well as two additional microtubule inhibitors, NSC 181928 (ethyl 5-amino-1,2-dihydro-3[N- methylanilino)methyl]pyrido [3,4-b]-pyrazin-7-ylcarbamate) and TN-16 [3- (1-anilinoethylidene)-5-benzyl-pyrrolidine-2,4-dione]. These results indicate that the mechanism of action of these latter two inhibitors is very similar to that of nocodazole. The lack of cross-resistance of the NocR and Podrii6 cell lines to thiabendazole provides evidence that the mechanism of action of this compound is different from that of other benzimidazole carbamate derivatives. Based on structure-activity relationship studies between various nocodazole-like compounds, a number of structural features of these compounds which appear important/essential for this type of biological activity have been identified.

Volume 30, Issue 2, pp. 142-148, 08/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics