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Implementation of a pharmacogenomic approach to predict ABC transporter substrates and compounds selectively targeting multidrug resistant cancer


Although considerable progress has been made in treating cancer over the past decade, there are still over 8 million deaths annually from cancer worldwide. Despite considerable advances in drug discovery, resistance to chemotherapy confounds the effective treatment of cancer patients.

Cancer cells can become resistant to a single drug or they may acquire broad cross-resistance to mechanistically and structurally unrelated drugs. ATP-binding cassette (ABC) proteins comprise the largest protein family, many m embers of which are of immediate medical importance. In particular, ABCB1 (MDR1-Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents.

Thus, innate or acquired expression of P-gp is a major problem in cancer chemotherapy. ABCC2/MRP2 plays a pivotal role in the export of organic anions, bile acids and xenobiotics into the bile and also contributes to protection against orally ingested drugs. The substrate specificity of MRP2 has been widely investigated in the research community. The major challenge of the postgenomic era is to analyze vast amounts of data.

In this context, the application of pharmacogenetics has the potential to improve the management of patients, particularly by providing the molecular basis for choosing among the increasing number of chemotherapeutic agents available for the treatment. The basic hypothesis of this proposal is that a pharmacogenomic approach can be exploited to characterize ABCC2/MRP2 substrates and to discover MDR1-inver se compounds that selectively kill multidrug resistant cancer cells.

The proposed research utilizes a complex array of methodological tools involving chemoinformatics, a custom-made microarray, and biochemical assays for measuring and characterizing transport. These aims will help in determining the mechanism of action of MDR1-inverse compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.

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