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Vol. 60, Issue 5, 1143-1152, November 2001

Acquisition of Human Concentrative Nucleoside Transporter 2 (hCNT2) Activity by Gene Transfer Confers Sensitivity to Fluoropyrimidine Nucleosides in Drug-Resistant Leukemia Cells

Thack T. Lang, Milada Selner, James D. Young, and Carol E. Cass

Canadian Institute of Health Research Membrane Protein Research Group (T.T.L., M.S., J.D.Y., C.E.C.), Departments of Oncology (T.T.L., M.S., C.E.C.) and Physiology (J.D.Y.), University of Alberta; and the Cross Cancer Institute (T.T.L., M.S., C.E.C.), Edmonton, Alberta, Canada

CEM-ARAC leukemia cells with resistance to cytarabine were shown to lack equilibrative transporter (hENT1) expression and activity. Stable transfer of hCNT2 cDNA into CEM-ARAC enabled Na+-dependent transport of purine and pyrimidine nucleoside analogs and provided a unique in vitro model for studying hCNT2. Analysis of [3H]uridine inhibitory activity by test substances in hCNT2 transfectant ARAC/D2 revealed structural requirements for interaction with hCNT2: 1) ribosyl and 2'-deoxyribosyl nucleosides were better inhibitors than 3'-deoxyribosyl, 2',3'-dideoxyribosyl or arabinosyl nucleosides; 2) uridine analogs with halogens at position 5 were better inhibitors than 5-methyluridine or thymidine; 3) 2-chloroadenosine was a better inhibitor than 2-chloro-2'-deoxyadenosine (cladribine); and 4) cytosine-containing nucleosides, 7-deazaadenosine and nucleobases were not inhibitors. Quantification of inhibitory capacity yielded Ki values of 34-50 µM (5-halogenated uridine analogs, 2'-deoxyuridine), 82 µM (5-fluoro-2'-deoxyuridine), 197-246 µM (5-methyluridine < 5-bromo-2'-deoxyuridine < 5-iodo-2'-deoxyuridine), and 411 µM (5-fluoro-5'-deoxyuridine, capecitabine metabolite). Comparisons of hCNT2-mediated transport rates indicated halogenated uridine analogs were transported more rapidly than halogenated adenosine analogs, even though hCNT2 exhibited preference for physiologic purine nucleosides over uridine. Kinetics of hCNT2-mediated transport of 5-fluorouridine and uridine were similar (Km values, 43-46 µM). The impact of hCNT2-mediated transport on chemosensitivity was assessed by comparing antiproliferative activity of nucleoside analogs against hCNT2-containing cells with transport-defective, drug-resistant cells. Chemosensitivity was restored partially for cladribine, completely for 5-fluorouridine and 5-fluoro-2'-deoxyuridine, whereas there was little effect on chemosensitivity for fludarabine, 7-deazaadenosine, or cytarabine. These studies, which demonstrated hCNT2 uptake of halogenated uridine analogs, suggested that hCNT2 is an important determinant of cytotoxicity of this class of compounds in vivo.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics