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 adriamycin.
A newly synthesized dihydropyridine analogue, 2-[benzyl(phenyl)-amino]ethyl 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorina n-2-yl)-1- (2-morpholinoethyl)-4-(3-nitrophenyl)-3-pyridinecarboxylate (PAK-200), at 5 microM 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 microM, 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.
Niwa
K
K
Department of Cancer Chemotherapy, Faculty of Medicine, Kagoshima University, Japan.
Yamada
K
K
Furukawa
T
T
Shudo
N
N
Seto
K
K
Matsumoto
T
T
Takao
S
S
Akiyama
S
S
Shimazu
H
H
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology*; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004351:Drug Resistance; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C075404:PAK 200; D014750:Vincristine; D004317:Doxorubicin