Single Nucleotide Polymorphism in BCRP and Effects on Flavopiridol Transport
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Publisher:The Ohio State University
Series/Report no.:The Ohio State University. Department of Pharmaceutical Sciences Honors Theses; 2008
Flavopiridol is a promising therapeutic agent currently under phase I and phase II clinical investigation for the treatment of Chronic Lymphocytic Leukemia (CLL) and other hematologic and solid tumor malignancies. Flavopiridol is a potent inhibitor of CDks (cyclin-dependent kinases), and its cytotoxic activity is associated with the arrest of cells in G1 or G2 phases of the cell cycle.1 Breast cancer resistance protein (BCRP) is a 70 kDA transmembrane transporter involved in multidrug resistance.2 BCRP exports flavopiridol from cells3 resulting in decreased intracellular drug accumulation and resistance to its cytotoxic effects. A single nucleotide polymorphism in BCRP is known to change amino acid 141 from glutamine to lysine. To determine the effects on flavopiridol transport caused by this mutation, HEK-293 (human embryonic kidney) cells both stably and transiently transfected with wild-type and mutant BCRP were evaluated in flavopiridol cytotoxicity and transport assays. While early differences were observed in cytotoxicity assays with cells stably transfected with empty vector and BCRP, significant differences have not been observed with transiently transfected cells. In addition, no differences between the wild type and Q141K mutant were observed in both cytotoxicity assays comparing IC50 values and transport assays measuring the amount of intracellular flavopiridol. This report summarizes early efforts to develop the methods for evaluating the effects of the Q141K mutant. Further work to clarify the impact of this mutation on BCRP transport of flavopiridol is ongoing.
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