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SOLVING THE PROBLEM OF MULTIDRUG RESISTANCE: ABC TRANSPORTERS IN CLINICAL ONCOLOGY

S. Bates
Published 2003 · Biology

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Acquired drug resistance was first observed in a laboratory model in 1950, in mouse leukemic cells passaged in mice treated with 4-amino- N 10 -methyl-pteroylglutamic acid. Daunorubicin-selected resistant tumor cells were found to have energy-dependent transport of daunorubicin that could be inhibited by vinblastine, vincristine, and other anthracyclines. Further, selection of cells for resistance to vinblastine resulted in the same phenotype. Tumor cell lines that were selected in the laboratory for resistance to doxorubicin or vincristine became cross-resistant to structurally unrelated anticancer agents, displayed active outward drug efflux, and were characterized by increased expression of a 170 kDa cell membrane glycoprotein that became known as P170 or P-glycoprotein. As critical as this discovery of the first human ATP-binding cassette (ABC) transporter was, it was the observation that drug resistance could be reversed in vitro by several different compounds, including verapamil that brought Pgp into prominence as a potential target for improving cancer therapy. This chapter begins by reviewing the mammalian ABC transporters linked to multidrug resistance. It also reviews the progress that has been made in developing ABC transporters as clinical targets in anticancer therapy.
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