Analysis of comptothecin 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 TOP1 gene, by stabilizing a covalent enzyme-DNA intermediate. Analyses of various yeast and human top1 mutants in yeast strains deleted for TOP1 (top1Δ) 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.