ETHYLPHENYL)THIO]-2(1H)-ISOQUINOLINEHEPTANENITRILE (CL-329,753) - A NOVEL CHEMOSENSITIZING AGENT FOR P-GLYCOPROTEIN-MEDIATED RESISTANCE WITH IMPROVED BIOLOGICAL PROPERTIES COMPARED WITH VERAPAMIL AND CYCLOSPORINE-A

Agents that inhibit P-glycoprotein may restore sensitivity to some ant itumor drugs in cancer patients. Optimization of the specificity and p otency of one class of chemosensitizing agents related to verapamil ha s led to the identification of thylphenyl)thio]-2(1H)-isoquinolinehept anenitrile, designated CL 329,753. In vitro, 0.1 to 2.0 mu M CL 329,75 3 restored sensitivity to drugs in the multidrug resistance (MDR) phen otype in cell lines that overexpress P-glycoprotein. CL 329,753 was gr eater than 10-fold more potent and efficacious than cyclosporine A or verapamil in vitro, particularly in cells that express high levels of P-glycoprotein. The enhanced activity of CL 329,753 may be related to its inability to be transported by P-glycoprotein, since low drug accu mulation of cyclosporine or verapamil but not CL 329,753 was found in P-glycoprotein-containing cells, yet all three agents inhibited vinbla stine binding to membranes containing P-glycoprotein and inhibited pho toaffinity labeling of P-glycoprotein. In vivo, CL 329,753 resensitize d drug-resistant tumors to vinblastine or doxorubicin in an ascitic or solid tumor model, respectively. No alteration in the plasma pharmaco kinetic profile of doxorubicin by CL 329,753 has been found. Furthermo re, the compound had 70-fold less calcium channel antagonistic activit y compared with verapamil.