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Correlation between Reversing of Multidrug Resistance and Inhibiting of [³H]Azidopine Photolabeling of P-Glycoprotein by Newly Synthesized Dihydropyridine Analogues in a Human Cell Line¹

Department of Cancer Chemotherapy, Institute of Cancer Research [H. K., A. Y., T. S., S. A.], and Department of Obstetrics and Gynecology [M. K., Y. N.], Faculty of Medicine, Kagoshima University, Kagoshima 890, and Central Research Institute, Nissan Chemical Ind., Ltd., Fuabashi, Chiba 274 [N. S., R. S., K. S.], Japan

Ten synthetic dihydropyridine analogues were investigated for their ability to reverse drug resistance in a multidrug-resistant human carcinoma cell line, KB-CI. Four dihydropyridine analogues completely reversed the resistance, three lowered the resistance, and three had little effect.

The radioactive photoactive dihydropyridine calcium channel blocker, [³H]azidopine, photolabels P-glycoprotein in membrane vesicles from KB-Cl cells. This photolabeling was almost completely inhibited by excess dihydropyridine analogues that reversed or lowered drug resistance. In contrast, the labeling was not significantly inhibited by analogues that do not reverse resistance. Among other reversing agents, cepharanthine and reserpine inhibited the [³H]azidopine photolabeling, but thioridazine did not. N-Solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine slightly inhibited the labeling at 100 µM. An anticancer agent, vinblastine, also inhibited the labeling.

The correlation between the reversing of the drug resistance and the inhibition of the [³H]azidopine photolabeling of P-glycoprotein by dihydropyridine analogues suggests a role for P-glycoprotein in multidrug resistance and also the reversing of the resistance by dihydropyridine analogues.

¹ This study was supported by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science and Culture, Japan.

² To whom requests for reprints should be addressed.

Received 9/27/88. Revised 3/21/89. Accepted 3/22/89.

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