Analysis of camptothecin resistance in yeast: relevance to cancer therapy

The budding yeast Saccharomyces cerevisiae is a well defined genetic system to investigate various aspects of camptothecin (Cpt)-induced cytotoxicity. This antineoplastic agent and its derivatives specifically poison eukaryotic DNA topoisomerase I, the product of the TOPI gene, by stabilizing a covalent enzyme-DNA intermediate. Analyses of various yeast and human top I mutants in yeast strains deleted for TOPI (top Id) have defined amino acid residues critical for enzyme function and Cpt sensitivity. Cpt cytotoxicity is also mediated by the pleiotropic drug resistance network, primarily through the action of an ABC transporter. The potential clinical relevance of these and related studies are discussed.