My laboratory investigates the mechanisms by which cells survive cytotoxic stress with the hope of modulating these functions to sensitize cells to chemotherapy and reduce it side-effects. For certain cancer, with no biological therapeutic targets, or as tumors progress, losing them, cytotoxic chemotherapy becomes the only therapeutic alternative. Using a genetic screen in the yeast S. cerevisiae, 71 genes were identified, which when inactivated, hypersensitize cells to anthracyclines, a commonly used chemotherapeutic agent. Mutants defective in genes involved in DNA repair, chromatin remodeling, protein folding and amino acid biosynthesis display the greatest sensitivity to the drug. These genes are potential targets for drugs that will inactivate their function in cancer cell and make them amenable to killing by low doses of chemotherapy and current work is aimed at determining the relevant sites in these proteins which can be used for drug development. The human homologs of these genes have been shown to efficiently complement the yeast defects, protecting the mutants from chemotherapy, suggesting that these genes play similar roles in mammalian cells. We are currently testing this hypothesis by inactivating the human genes in human cancer cells.