The activity of verapamil as a resistance modifier in vitro in drug resistant human tumour cell lines is not stereospecific.
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.
Plumb
J A
JA
CRC Department of Medical Oncology, University of Glasgow, U.K.
Milroy
R
R
Kaye
S B
SB
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism / Q000627:therapeutic use*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000097:blood / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D004317:Doxorubicin; D014700:Verapamil