Genetic and biochemical studies on mutants of CHO cells resistant to 7-deazapurine nucleosides: Differences in the mechanisms of action of toyocamycin and tubercidin

Abstract

From mutants of Chinese hamster ovary cells which are resistant to toyocamycin and tubercidin, second-step mutants which exhibit a further 8- to 9-fold increase in resistance to toyocamycin (Toy rII mutants) but no change in resistance to tubercidin have been isolated. The Toy rII mutants are similar to the first-step mutants in their levels of adenosine kinase activity (⋍1%), as well as cellular uptake and phosphorylation of adenosine and its analogs. The increased resistance of the Toy rII mutants to toyocamycin but not to tubercidin provides strong evidence that the mechanism of cellular toxicity of these two analogs is different from each other and suggests that these mutants may be affected in a cellular component which is specifically involved in the toxicity of toyocamycin. The Toy rII mutants also exhibit increased resistance to sangivamycin and the tricyclic nucleoside pentaaza-acenaphthylene riboside (TCN, NSC 154020) indicating that the mechanisms of cellular toxicity of these two analogs may be similar to that of toyocamycin.