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¹ Department of Pharmacology and Therapeutics and ² Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, ³ Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY

Requests for Reprints: Ralph J. Bernacki, Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail: Ralph.Bernacki{at}roswellpark.org

Overexpression of ATP-binding cassette transport proteins, including P-glycoprotein (Pgp), multidrug resistance (MDR) protein (MRP-1), and breast cancer resistance protein (BCRP), is a well-characterized mechanism of MDR in tumor cells. Although the cytotoxic taxanes paclitaxel and docetaxel are substrates for Pgp-mediated efflux, the semisynthetic taxane analogue orataxel inhibits drug efflux mediated by Pgp as well as, as we recently demonstrated, MRP-1 and BCRP. Nevertheless, orataxel is not optimal for development as a clinical MDR modulator because of its cytotoxicity. We sought to identify noncytotoxic taxane-based broad-spectrum modulators from a library of noncytotoxic taxane-based reversal agents (tRAs) designed by eliminating the C-13 side chain of the taxane molecule, which inhibits microtubule depolymerization. Twenty tRAs, selected based on modulation of paclitaxel cytotoxicity in Pgp-overexpressing MDA435/LCC6^mdr1 cells, were studied for modulation of retention and cytotoxicity of substrates of MRP-1 and BCRP as well as Pgp in established cell lines overexpressing each of these transporters. Four tRAs modulated MRP-1 and 17 modulated BCRP in addition to Pgp. The four broad-spectrum tRAs strongly modulated daunorubicin and mitoxantrone efflux and enhanced their cytotoxicity in cell lines overexpressing the three MRPs, decreasing IC₅₀ values by as much as 97%. These tRAs, especially tRA 98006, have promise for development as clinical broad-spectrum MDR modulators and warrant more preclinical analysis to determine pharmacokinetic interactions and efficacy.

Grant support: 1 R01 CA 73872-03 (R.J.B.) and 1 R21 CA 89938-01 (M.R.B.) from the National Cancer Institute, 1 R01 GM-42798 (I.O.) from the National Institute of General Medical Sciences, a Leukemia and Lymphoma Society Translational Research grant (M.R.B.), T32 CA09072-28 from the NIH Department of Pharmacology, shared resources of the Roswell Park Cancer Center Support Grant (P30 CA16056), the Leonard S. Lovullo Memorial Fund for Leukemia Research, and the Dennis J. Szefel, Jr. Endowed Fund for Leukemia Research at Roswell Park Cancer Institute.

Received 6/17/03; revised 8/15/03; accepted 8/28/03.

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