THE ACTIVITY OF VERAPAMIL AS A RESISTANCE MODIFIER INVITRO IN DRUG-RESISTANT HUMAN TUMOR-CELL LINES IS NOT STEREOSPECIFIC

The l-isomer of verapamil is a more potent calcium antagonist than thed-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 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 thed- and l-isomers of verapamil alone at 6.6 μM were as effective as racemic verapamil and thed-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 μM). Bothd- 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 ofd-verapamil alone in patients could increase the maximum tolerated plasma concentrations of verapamil and thusd-verapamil may be a more effective resistance modifier in vivo than racemic verapamil. © 1990.