INTERACTION OF CYTOSTATICS AND CHEMOSENSITIZERS WITH THE DEXNIGULDIPINE BINDING-SITE ON P-GLYCOPROTEIN

The interaction of cytostatics and chemosensitizers with the dexniguld ipine binding site of P-glycoprotein was investigated in photoaffinity labeling experiments. A tritiated azidoderivative of the chemosensiti zer dexniguldipine with dihydropyridine structure, [H-3]B9209-005, was used to irreversibly label P-glycoprotein. The apparent affinity of c ytostatics and chemosensitizers to this binding site was estimated fro m labeling experiments in the presence of increasing concentrations of compounds. From the cytostatics tested, the vinca alkaloids and taxol showed the highest affinity, anthracyclins possessed moderate affinit y while methotrexate, ara C and camptothecin, cytostatics not involved in P-glycoprotein-mediated multidrug resistance, were almost inactive . The chemosensitizers GF 120918, cyclosporin A and SDZ PSC-833 inhibi ted photoincorporation with the highest potency. Steep dose-inhibition curves were obtained with the cyclic peptides and S9788, indicating t hat these compounds may bind allosterically to a separate binding site . Compounds with dihydropyridine structure with or without chemosensit izing potency were also tested and some structure-activity relationshi ps could be derived from the data. Our data show that inhibition of ph otoaffinity labeling by [H-3]B9209-005 is a valuable and reliable syst em for measuring the interaction with and potency of chemosensitizing compounds at P-glycoprotein. Furthermore, data obtained in this test s ystem are well suited to investigate structure-activity relationships for chemosensitizers at P-glycoprotein. In addition cytostatics underl ying P-glycoprotein-mediated multidrug resistance can be identified.