Abstract #5491: Determination of Escherichia coli single gene knockout strains hypersensitive to genotoxic agents

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Background. While chemotherapeutic regimens are widely used in the treatment of cancer, negative side effects, secondary mutagenesis, and incidences of drug resistance are often seen. One way to counteract these adverse effects is to discover improved chemotherapeutic regimens that would potentiate cancer-treatment drugs. Potential cellular targets for such drugs are proteins that provide intrinsic drug resistance. Because many agents used in chemotherapy also act as antibiotics, some bacterial proteins also provide intrinsic resistance to anticancer compounds, and suggest that their counterparts in human cells can be targets for drugs that potentiate these anticancer agents. Methods. We have tested a defined and virtually complete collection of close to 4,000 viable single gene knockouts in Escherichia coli to identify genes whose loss increases sensitivity to a set of 6 different chemotherapeutic agents and mutagens: Bleomycin (BLEO), Cisplatin (CPT), ICR-191 (ICR), 5-azacytidine (5AZ), Zebularine (ZEB), and 5-Bromouracil (5BU). We used high throughput screening of one or more sub-inhibitory concentrations of each agent. Results. We discovered a set of 211 strains that display significantly increased sensitivity to at least one of the agents tested. Combining the results generates a comprehensive sensitivity profile for genotoxic agents. This allows a rapid characterization of agents with respect to their mechanism of action based on a comparison with known profiles. The visualization of these results, with color-coding to indicate different cellular functions of the proteins involved, produces a set of striking figures. Conclusions. Although some of the gene knockout mutants are relatively specific to the type of agent tested, close to 40 others are hypersensitive to 3 or more agents. Collectively, these data provide targets for the design of co-drugs that can potentiate existing chemotherapeutic agents. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5491.