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Strategies for Inhibition of MDR1 Gene Expression

Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina

Several distinct strategies have been used to modulate the expression of cancer-associated genes, including antisense oligonucleotides, small interfering RNAs (siRNAs), and artificial transcriptional factors. One major cause for chemotherapeutic treatment failure in cancer is the overexpression of P-glycoprotein, the product of the multidrug resistance gene MDR1. In this study, we tested the ability of siRNAs to inhibit MDR1 gene expression. We evaluated the efficiency of chemically synthesized dsRNAs as well as vector-based hairpin siRNAs and investigated the behavior of clones of multidrug-resistant NCI/ADR-RES breast carcinoma cells stably transfected with hairpin siRNA vectors. The effects of siRNA on the MDR phenotype were compared with those elicited by antisense oligonucleotides or by designed transcription factors targeting the MDR1 promoter. These studies suggest that there are several comparably effective strategies for inhibiting MDR1 expression.

Address correspondence to: Rudy L. Juliano, Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599. E-mail: arjay{at}med.unc.edu

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