Effects of verapamil enantiomers and major metabolites on the cytotoxicity of vincristine and daunomycin in human lymphoma cell lines

Abstract

Verapamil, a calcium channel blocker, is used as the racemate. Recently, racemic verapamil has been shown to increase the cytotoxicity of vinca alkaloid and anthracycline derivatives in several resistant tumour cell lines. With respect to its cardiovascular activity S-verapamil is an order of magnitude more potent than R-verapamil. Since it was not known whether the effect on multi-drug resistance was also enantioselective a comparison has been made of the potency of the R and S enantiomers and racemic verapamil in their ability to increase the cytotoxicity of vincristine and daunomycin in sensitive (MOLT 4B) and drug resistant human T-lymphoma cell lines (MOLT/VCR-5 x 9, MOLT/DAU-8 and VCR 1000, a highly resistant subline of CCRF-CEM). Two major metabolites, norverapamil and D617 were tested in the same system. (+)-R, (-)-S-, racemic verapamil, norverapamil and D617 alone had no effect on cell growth in sensitive or resistant cell lines in concentrations up to 20 microM. In combination with vincristine, verapamil and norverapamil but not D617 produced a concentration dependent increase in the sensitivity of the resistant lines. Racemic verapamil, its individual enantiomers and norverapamil were equipotent. The concentration of the modifiers required to elicit 50% of the maximum effect (EC50) was of the order of 0.5 microM. No significant difference in the slopes of the concentration-effect curves were observed. The effect of verapamil and norverapamil was additive. In the sensitive MOLT 4B cell line both enantiomers and norverapamil increased sensitivity towards vincristine. However, the EC50 values were at least an order of magnitude higher (2.5-8 microM) than in the resistant cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)