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Effect of Duration of Exposure to Verapamil on Vincristine Activity against Multidrug-resistant Human Leukemic Cell Lines¹

McEachern Laboratory [C. E. C., M. A. L., H. S.], Department of Biochemistry [C. E. C.], and Department of Medicine [A. J-W.], University of Alberta; Department of Medicine [A. J-W., C. E. C.], Cross Cancer Institute, and Blood Transfusion Service [A. J-W.], Edmonton, Alberta, Canada T6G 2H7; Division of Oncology/Hematology [A. A. H.], Winthrop University Hospital, Mineola, Long Island, New York 11501; and Department of Biochemical and Clinical Pharmacology [W. T. B.], St. Jude Children's Research Hospital, Memphis, Tennessee 38101

Verapamil sensitizes multidrug-resistant cell lines to various heterocyclic anticancer drugs by inhibition of energy-dependent release of drug, presumably by interaction with membrane glycoproteins involved in drug efflux. This work assessed verapamil sensitization of human multidrug-resistant lymphocytic and myeloid leukemic cell lines (CEM/VLB₁₀₀, HL-60/AR) to vincristine during exposures of short duration (4 h). When cells were transferred to drug-free medium immediately after simultaneous 4-h exposures to vincristine and verapamil, the antiproliferative activity of vincristine was not altered in CEM/VLB₁₀₀ cells and was only moderately increased in HL-60/AR cells. In contrast, when cells were transferred to verapamil-containing medium, vincristine activity was greatly increased against both CEM/VLB₁₀₀ and HL-60/AR cells. Verapamil enhanced accumulation and inhibited release of [³H]vincristine by CEM/VLB₁₀₀ and HL-60/AR cells, indicating that the sensitization was due to an increase in cell-associated vincristine after transfer of cells to vincristine-free medium. Slot blot analysis of cellular RNA with the pMDR1 probe revealed high levels of expression of the mdr1 gene in CEM/VLB₁₀₀ cells but no detectable expression in HL-60/AR cells. Consistent with this finding, polypeptides (M_r 170,000 to 180,000) that were recognized by a monoclonal antibody (C219) against P-glycoprotein were greatly overexpressed in CEM/VLB₁₀₀ cells, but were expressed at low levels, if at all, in HL-60/AR cells. These results demonstrate the importance of duration of exposure to verapamil in reversing multidrug resistance, not only in cells that overexpress P-glycoprotein but also in cells, such as HL-60/AR, that express little, if any, P-glycoprotein.

¹ This work was supported in part as follows: National Cancer Institute of Canada [C. E. C.]; the Alberta Cancer Board through the Cancer Grants Program of the Alberta Heritage Savings Trust Fund and the Research Trust Endowment Fund [A. J-W.]; Research Grant CH-357A from the American Cancer Society [A. A. H.]; Research Grant CA 40570 [W. T. B.] and Cancer Center Support (CORE) Grant CA 21765 [W. T. B.], from the National Cancer Institute, NIH; and American Lebanese Syrian Associated Charities [W. T. B.]. C. E. C. is a Senior Research Scientist of the National Cancer Institute of Canada, and H. S. was a recipient of summer studentship awards (1987, 1988) from the Alberta Heritage Foundation for Medical Research.

² To whom requests for reprints should be addressed, at Department of Biochemistry, 4-74 Medical Sciences Building, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.

Received 1/12/89. Revised 6/ 9/89. Accepted 7/31/89.

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