RELATIONSHIP BETWEEN THE INHIBITION OF AZIDOPINE BINDING TO P-GLYCOPROTEIN BY MDR MODULATORS AND THEIR EFFICIENCY IN RESTORING DOXORUBICIN INTRACELLULAR ACCUMULATION

Using three different cell lines exhibiting the MDR phenotype, we have studied the ability of eight different modulators to restore doxorubi cin intracellular accumulation and to inhibit azidopine binding to mem brane extracts. One cell line was of human origin (KB V1) and two of m urine origin, overexpressing two different isoforms of the mdr1 gene ( C6 1V and C6 0.5). The modulators were distributed in different drug c lasses: cyclosporine A and PSC-833, quinine and quinidine, nifedipine and nicardipine, and verapamil and S-9788. We observed that there was no strict parallelism between restoration of doxorubicin intracellular accumulation and inhibition of azidopine binding. However, when consi dering separately each group of drugs, it appeared that the most poten t drug in inhibiting azidopine labelling of P-glycoprotein (P-gp) was also the most potent in restoring doxorubicin accumulation. This indic ates that azidopine binding cannot be used as a general screening test for the identification of new modulators, but rather at the level of the selection of potent analogues within a chemical family. The three cell lines behaved similarly, indicating that the structural diversity of P-pgs did not influence the efficiency and binding of modulators.