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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Quantitation of Doxorubicin Uptake, Efflux, and Modulation of Multidrug Resistance (MDR) in MDR Human Cancer Cells

Departments of Pharmacology and Toxicology (F.S., A.K.B., B.B., X.X., P.A.E., L.C.E.) Indiana University Cancer Center, and Cellular and Integrative Physiology (S.C., M.H.M.), Indiana University School of Medicine, Indianapolis, Indiana; and Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, Illinois (W.T.B.)

P-glycoprotein (Pgp), a membrane transporter encoded by the MDR1 gene in human cells, mediates drug efflux from cells, and it plays a major role in causing multidrug resistance (MDR). Confocal microscopy was used to study in vitro and in vivo drug accumulation, net uptake and efflux, and MDR modulation by P-glycoprotein inhibitors in MDR1-transduced human MDA-MB-435mdr (MDR) cancer cells. The MDR cells were approximately 9-fold more resistant to the anticancer drug doxorubicin than their parental wild-type MDA-MB-435wt (WT) cells. Doxorubicin accumulation in the MDR cells was only 19% of that in the WT cells. The net uptake of doxorubicin in the nuclei of the MDR cells was 2-fold lower than that in the nuclei of the WT cells. Pgp inhibitors verapamil, cyclosporine A, or PSC833 increased doxorubicin accumulation in the MDR cells up to 79%, and it reversed drug resistance in these cells. In living animals, doxorubicin accumulation in MDA-MB-435mdr xenograft tumors was 68% of that in the wild-type tumors. Administration of verapamil, cyclosporine A, or PSC833 before doxorubicin treatment of the animals increased doxorubicin accumulation in the MDR tumors up to 94%. These studies have added direct in vitro and in vivo information on the capacity of the transporter protein Pgp to efflux doxorubicin and on the reversal of MDR by Pgp inhibitors in resistant cancer cells.

Address correspondence to: Dr. Leonard C. Erickson, Indiana Cancer Center, Cancer Research Institute, R4-Room 168, 1044 West Walnut St., Indianapolis, IN 46202. E-mail: lcericks{at}iupui.edu

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