EFFECT OF MDR ANTAGONISTS ON THE CIDAL ACTIVITY OF VINCRISTINE FOR CELLS EXPRESSING MDR-1 IS SUPERIOR TO THOSE EXPRESSING MRP

In an attempt to identify the target protein, P-GP or MRP, of each MDR antagonist, verapamyl (Ver), dipyridamole (Dip), or cyclosporin A (Cy -A), this study was designed to compare the activity of the three afor e-mentioned drugs and to test their combined effect on the cidal activ ity of vincristine (VCR) in five types of wild and the corresponding V CR-resistant cultured eel lines from human leukemia and lymphoma. Thre e of the VCR-resistant cell lines are characterized by the overexpress ion of I?mdr-1, while two cell lines overexpress mrp. We found that al l three antagonists additively to synergistically enhanced the cidal a ctivity of VCR for the five wild-type and VCR-resistant cell lines in a dose dependent manner when used singly. Combinations consisting of a 20% inhibitory concentration (IC20) of VCR plus two antagonists also showed additive to synergistic effects on both wild and VCR-resistant cell lines. It is of interest that the combined effect of IC20 VCR plu s MDR antagonists on the three VCR-resistant cell lines expressing mdr -1 was significantly superior to those of the two cell lines expressin g the mrp gene. These results suggest that the combined effect of MDR antagonists work better than their single use and that the MDR antagon ists work more efficiently in cells showing drug resistance through md r-l than in those utilizing mrp.