The activity of verapamil as a resistance modifier in vitro in drug resistant human tumour cell lines is not stereospecific

Abstract

The L-isomer of verapamil is a more potent calcium antagonist than the D-isomer. We have examined the two stereoisomers of verapamil for their ability to increase the chemosensitivity in vitro of three drug resistant cell lines (2780AD, MCF7/AdrR and H69LX10). Neither racemic verapamil nor its individual isomers had any effect on the drug sensitivity of the parent cell lines (A2780, MCF7 and NCI-H69). Verapamil (6.6 microM) increased the sensitivity of all three resistant cell lines to Adriamycin by 10-12-fold. This activity was concentration dependent and was maximal at 6-7 microM. The increase in sensitivity was only 2-3-fold at 2 microM, the maximum plasma concentration achieved in patients. Both the D- and L-isomers of verapamil alone at 6.6 microM were as effective as racemic verapamil and the D-isomer demonstrated the same concentration dependent activity as racemic verapamil. The total cellular Adriamycin concentration of both 2780AD and MCF7/AdrR was increased by two-fold in the presence of verapamil (6.6 microM). Both D- and L-verapamil alone increased the amount of drug accumulated to the same extent as racemic verapamil. These results indicate that the resistance modification activity of verapamil is not stereospecific. Use of D-verapamil alone in patients could increase the maximum tolerated plasma concentrations of verapamil and thus D-verapamil may be a more effective resistance modifier in vivo than racemic verapamil.