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Reversal of Multidrug Resistance by Verapamil and Modulation by ₁-Acid Glycoprotein in Wild-type and Multidrug-resistant Chinese Hamster Ovary Cell Lines

Cancer Research Unit, University of Newcastle Upon Tyne, Medical School, Framlington Place, Newcastle Upon Tyne, United Kingdom NE2 4HH [M. C.], and Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom OX3 9DU [C. N. R., A. L. H.]

Multidrug resistance can be reversed by a range of "calcium channel"-blocking drugs in vitro, of which verapamil is the most widely used. Verapamil is bound to ₁-acid glycoprotein (AAG) in vivo in humans but is absent from calf serum, used in tissue culture media. The effect of AAG on the ability of verapamil to alter Adriamycin cytotoxicity was assessed in parental Chinese hamster ovary cells (CHO-K1) and in a multidrug-resistant subline (CHO-Adr^r). In both the parental and the resistant cells, there was a dose-related potentiation of Adriamycin cytotoxicity by verapamil. At 10 µM verapamil, there was a 5-fold decrease in the concentration of Adriamycin that caused 50% reduction in growth of CHO-K1 cells but a 15-fold decrease in CHO-Adr^r cells. In the presence of increasing AAG concentrations within the range found in cancer patients, there was a concentration-related reduction in the effects of verapamil. In CHO-Adr^r cells, there was complete reversal of the potentiating effect of 10 µM verapamil at 2 mg/ml AAG. In contrast, in CHO-K1 cells, AAG reduced the effects of verapamil by only 20% at a similar concentration. There was a much higher internal uptake of fluorescein-labeled AAG by CHO-Adr^r cells than by CHO-K1 cells. These results suggest that, in addition to a plasma membrane site, there may be a major endosomal site of action of verapamil in multidrug-resistant cells. The implications are that verapamil in vivo in the presence of AAG may effectively reverse low levels of multidrug resistance, but not high levels. Thus selection of patients with low AAG levels may be appropriate for clinical studies.

¹ To whom requests for reprints should be addressed.

Received 7/28/89. Revised 1/ 9/90.