INTERACTION OF COMBINATIONS OF DRUGS, CHEMOSENSITIZERS, AND PEPTIDES WITH THE P-GLYCOPROTEIN MULTIDRUG TRANSPORTER

P-Glycoprotein functions as an ATP-driven efflux pump for hydrophobic natural products andeptides, and gives rise to resistance to multiple chemotherapeutic drugs. The inhibition of colchicine transport via P-g lycoprotein by various compounds was determined in a plasma membrane v esicle model system. A chemotherapeutic drug (vinblastine) and several chemosensitizers (verapamil, reserpine, cyclosporin A) and hydrophobi c peptides (N acetyl-leucyl-leucyl-methioninal, leupeptin, pepstatin A , valinomycin) were exam ined, both as individual species and as combi nations of compounds. The median effect analysis was used to determine the concentration of each combination required to produce a median ef fect, D-m, as well as the sigmoidicity of the concentration-effect plo t, m. The combination of cyclosporin A and verapamil was the only one established to be mutually nonexclusive, whereas several mutually excl usive pairs of compounds were identified. The combination index, CI, w as calculated for several combinations of drugs, chemosensitizers, and peptides, and used to ascertain whether effects were synergistic, ant agonistic, or additive. Some combinations (vinblastine/verapamil; vera pamil/valinomycin) showed antagonism over the entire concentration ran ge. Other combinations (valinomycinl/N acetyl-leucyl-leucyl-methionina l; cyclosporin A/verapamil) displayed both synergism and antagonism ov er different regions of the CI plot. Many combinations of compounds di splayed additive interactions over most of the CI plot. The median eff ect analysis may be helpful in identifying potentially useful additive or synergistic combinations of compounds for reversal of Pgp-mediated drug resistance. (C) 1997 Elsevier Science Inc.