Multiplex Screening for ABC Transporter Inhibitors

University Of New Mexico, Albuquerque NM

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The presence of residual tumor cells (MRD, minimal residual disease) after initial induction therapy is a key predictor of patient outcome. Several sets of observations suggest that a relatively small number of tumor cells either have or acquire resistance to chemotherapeutics during induction therapy. In order to improve patient outcome, there is a critical need to identify new targets and antagonists for pharmaceutical intervention. Furthermore, an increasing and persistent number of drug resistant cells correlate with patient outcome in a number of cancers. Recently, ABC gene products, including ABCB1 (P-glycoprotein, MDR-1), multidrug resistance protein ABCC1 (MRP1), ABCC2 (MRP2, cMOAT), and ABCG2 (BCRP, MXR, ABCP) have been described and been shown to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins on human cancer have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. One of the most widely studied multidrug resistance (MDR)-ABC transporter is ABCB1. This particular member of the ABC transporter proteins functions to remove lipids and drugs as they intercalate and diffuse through the cell membrane. While more than 48 members of the ABC transporter superfamily have been identified, a relatively few such as ABCB1, ABCC1 and lung resistance protein (LRP) appear to have the greatest clinical impact on therapy resistance. The goal of this proposal is to first screen for ABCB1 inhibitors in a developed flow cytometry based assay and then to develop and employ a multiplex assay that can screen for inhibitors of multiple members of the ABC family. [unreadable] [unreadable] [unreadable]