Differential toxicities of anticancer agents among DNA repair and checkpoint mutants of Saccharomyces cerevisiae

Most cytotoxic anticancer agents damage DNA directly, interfere with DNA me tabolism or chromosome segregation, and are particularly toxic in dividing cells. Although a considerable amount of information on the mechanisms of a ction of these agents is available, the molecular bases for selective tumor cell killing by chemotherapy are largely unknown. Many genetic alterations found in sporadic and hereditary cancers affect functions in DNA repair an d cell cycle control and result in sensitivity to DNA damaging agents. We h ave therefore set out to determine the effects of these cancer mutations on sensitivity or resistance to various chemotherapeutic agents. Because most of the affected genes are well conserved among eukaryotes, ae have carried out a comprehensive analysis of a panel of isogenic yeast strains, each de fective in a particular DNA repair or cell cycle checkpoint function, for s ensitivity to the Food and Drug Administration-approved cytotoxic anticance r agents, Widely different toxicity profiles were observed for 23 agents an d X-rays, indicating that the type of DNA repair and cell cycle checkpoint mutations in individual tumors could strongly influence the outcome of a pa rticular chemotherapeutic regimen.