Potentiation of the vincristine effect on P388 mouse leukemia cells by a newly synthesized dihydropyridine analogue, PAK-200.
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 1 microM completely reversed the resistance to vincristine in vincristine-resistant P388 mouse leukemia cells (P388/VCR), in vitro. PAK-200 at 2 microM inhibited the efflux of [3H]vincristine from P388/VCR and increased the accumulation of [3H]vincristine in P388/VCR to a level similar to that in P388 cells. P-Glycoprotein in membrane vesicles from P388/VCR cells was photolabeled with [3H]azidopine. The labeling was completely inhibited by 10 microM PAK-200. The calcium antagonistic activity of PAK-200 was about 1000 times lower than that of another dihydropyridine analogue, nicardipine. Experiments with P388 and P388/VCR-bearing mice showed that PAK-200 enhanced the effect of vincristine on both leukemia cells in vivo. These results suggest that PAK-200 interacts with P-glycoprotein and reverses drug resistance in P388 mouse leukemia cells in vitro, and that PAK-200 has an ability to potentiate the effect of vincristine on P388 mouse leukemia cells in vivo.
Shudo
N
N
Department of Cancer Chemotherapy, Faculty of Medicine, Kagoshima University.
Fujii
R
R
Matsumoto
T
T
Mizoguchi
T
T
Seto
K
K
Sakoda
R
R
Akiyama
S
S
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D004351:Drug Resistance; D004357:Drug Synergism; D007941:Leukemia P388; D008297:Male; D051379:Mice; D009529:Nicardipine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology*
D004095:Dihydropyridines; C075404:PAK 200; D014750:Vincristine; D009529:Nicardipine