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.

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 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.

• Authors: K Niwa, K Yamada, T Furukawa, N Shudo, K Seto, T Matsumoto, S Takao, S Akiyama, H Shimazu
• Journal: Cancer research (Cancer Res) Vol. 52 Issue 13 Pg. 3655-60 (Jul 01 1992) ISSN: 0008-5472 [Print] United States
• PMID: 1617639 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channel Blockers
• Dihydropyridines
• PAK 200
• Vincristine
• Doxorubicin

Topics

• Animals
• Calcium Channel Blockers (pharmacology)
• Dihydropyridines (pharmacology)
• Doxorubicin (pharmacokinetics, pharmacology)
• Drug Resistance
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Neoplasms, Experimental (drug therapy)
• Tumor Cells, Cultured (drug effects)
• Vincristine (pharmacology)