Potentiation of the vincristine effect on P388 mouse leukemia cells by a newly synthesized dihydropyridine analogue, PAK-200.

Abstract

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.

• Authors: N Shudo, R Fujii, T Matsumoto, T Mizoguchi, K Seto, R Sakoda, S Akiyama
• Journal: Japanese journal of cancer research : Gann (Jpn J Cancer Res) Vol. 83 Issue 9 Pg. 1011-7 (Sep 1992) ISSN: 0910-5050 [Print] Japan
• PMID: 1429198 (Publication Type: Journal Article)

Chemical References

• Dihydropyridines
• PAK 200
• Vincristine
• Nicardipine

Topics

• Animals
• Blood Pressure (drug effects)
• Dihydropyridines (pharmacology)
• Drug Resistance
• Drug Synergism
• Leukemia P388
• Male
• Mice
• Nicardipine (pharmacology)
• Vincristine (pharmacology)