MUTUALLY COOPERATIVE INTERACTIONS BETWEEN MODULATORS OF P-GLYCOPROTEIN

We measured the effects of combinations of verapamil, vinblastine, mef loquine, and tamoxifen, all being modulators of the multidrug resistan ce pump, P-glycoprotein, on the accumulation of labelled daunomycin in to multidrug-resistant P388 leukemia cells at 37 degrees C. We found t hat, contrary to our initial expectations (based on Ayesh, Shao and St ein (1996) Biochim. Biophys. Acta 1316, 8), vinblastine, mefloquine, a nd tamoxifen all appeared to interact with one another synergistically , i.e. by the kinetics of a non-competitive interaction. A simple kine tic analysis showed that pairs of co-operating modulators can give app arent non-competitive behaviour, but refined kinetic analysis enables the two types of interaction to be distinguished. The modulators vinbl astine, mefloquine, and tamoxifen thus appear to co-operate with one a nother in pairs to bring about reversal of P-glycoprotein. This may ha ve important implications for the design of new modulators of P-glycop rotein.