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.

multidrug resistance

2‐[benzyl(phenyl)amino]ethyl l,4‐dihydro‐2)6‐dimethyl‐5‐(5,5‐dimethyl‐ 2‐oxo‐1,3,2‐dioxaphosphorinan‐ 2‐y1)‐1‐(2‐morphoH‐noethyl)‐4‐(3‐nitrophenyl)‐3‐pyridinecarboxylate

P‐glycoprotein

vincristine

adriamycin

percent increase in the mean survival, treated/control × 100

mean survival time of group treated with PAK‐200 and VCR divided by mean survival time of group treated with VCR alone

P388 mouse leukemia cells resistant to VCR

P388 mouse leukemia cells resistant to ADM

3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazo‐lium bromide