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/Adr r and H6 9LX10). 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 μM) 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 μM. The increase in sensitivity was only 2–3-fold at 2,μM, the maximum plasma concentration achieved in patients. Both the d- and l-isomers of verapamil alone at 6.6 μM 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/Adr r was increased by two-fold in the presence of verapamil (6.6 μM). 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.