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Effect of a Dihydropyridine Analogue, 2-[Benzyl(phenyl)amino]ethyl 1,4-Dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1-(2-morpholinoethyl)-4-(3-nitrophenyl)-3-pyridinecarboxylate on Reversing in Vivo Resistance of Tumor Cells to Adriamycin¹

Department of Cancer Chemotherapy, Institute of Cancer Research [K. N., T. F., S. A.], Department of Obstetrics and Gynecology [T. M.], and First Department of Surgery [K. N., K. Y., S. T., H. S.], Faculty of Medicine, Kagoshima University, Kagoshima 890, and Central Research Institute, Nissan Chemical Industries Co., Ltd., Chiba [N. S., K. S.], Japan

A newly synthesized dihydropyridine analogue, 2-[benzyl(phenyl)-amino]lethyl 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1-(2-morpholinoethyl)-4-(3-nitrophenyl)-3-pyridinecarboxylate (PAK-200), at 5 µM inhibited the efflux of [³H]vincristine from KB-C2 cells and increased the accumulation of [³H]vincristine in KB-C2 cells to a level similar to that in KB-3-1 cells. PAK-200 inhibited the photoaffinity labeling of P-glycoprotein in KB-C2 membranes by [³H]azidopine. At 5 µM, PAK-200 enhanced the cytotoxic effect of Adriamycin on drug-sensitive KB-3-1 cells, multidrug-resistant KB-8-5 cells, and two human colorectal carcinoma tumor lines, COK-28LN and COK-36LN, by factors of 2, 5, 2, and 3 times, respectively. The calcium antagonistic activity of PAK-200 was about 1000 and 5 times lower than that of another dihydropyridine analogue, nicardipine, and of verapamil, respectively.

PAK-200 in combination with Adriamycin completely suppressed the growth of KB-3-1 and COK-36LN and partially suppressed the growth of KB-8-5 but had no significant effect on COK-28LN cells xenografted in nude mice. The level of MDR1 expression of COK-36LN was about 3 times higher than that of COK-28LN, but lower than that of KB-8-5 cells.

These results suggest that the interaction of PAK-200 with P-glycoprotein may be partly correlated with the enhancement of the antitumor effect of Adriamycin on xenografted KB-8-5 and COK-36LN cells in nude mice.

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 11/22/91. Accepted 4/20/92.

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