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Enhanced Efflux of [³H]Vinblastine from Chinese Hamster Ovary Cells Transfected with a Full-Length Complementary DNA Clone for the mdr1 Gene¹

Department of Biochemistry, McGill University, Montreal, Canada H3G 1Y6

Multidrug-resistant Chinese hamster ovary cell clones stably transfected with, and overexpressing, the mouse mdr1 complementary DNA clone along with drug-sensitive Chinese hamster ovary control cells were characterized for their capacities to accumulate and retain [³H]vinblastine. Multidrug-resistant mdr1 transfectants show a 3–4-fold decrease in [³H]-vinblastine accumulation, compared to their drug-sensitive counterparts. After ATP depletion, this difference in [³H]vinblastine accumulation between mdr1 transfectants and control cells effectively disappears. This ATP-dependent decreased drug accumulation is paralleled in mdr1 transfectants by an enhanced capacity of these cells to extrude the drug in an ATP-dependent manner. In medium containing glucose and glutamine, the mdr1 transfectants release preloaded drug at a rate five times that of control, drug-sensitive cells. In ATP-depleted control and mdr1-transfected cells, there is little difference in the rate or extent of [³H]vinblastine release. The observation that the mdr1 transfectants show a decreased [³H]vinblastine accumulation and an increased vinblastine release, both of which are abolished when cellular ATP levels are reduced, provides a direct demonstration that the product of the transfected mdr1 gene is responsible for a mechanism controlling cellular drug levels in an ATP-dependent manner. However, attempts to establish competition for [³H]vinblastine transport by vincristine, daunomycin, and actinomycin D were only partly successful in mdr1 transfectants.

¹ This work was supported by grants from the National Cancer Institute of Canada, to whom we express our thanks.

² Recipient of a Research Fellowship from the Alberta Heritage Foundation for Medical Research.

³ To whom requests for reprints should be addressed, at Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, 3655 Drummond Street, Montreal, Quebec H3G 1Y6.

Received 11/ 2/88. Revised 4/ 5/89. Accepted 4/17/89.

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