[Enhancement of cellular accumulation of cyclosporine by anti-P-glycoprotein monoclonal antibody MRK-16, and their synergistic modulation of multidrug resistance].
Drug resistance is a major obstacle to successful cancer chemotherapy. P-glycoprotein, which transports various antitumor agents outside the resistant tumor cells, plays a key role in multidrug resistance. We found that MRK-16, a monoclonal antibody against P-glycoprotein, and cyclosporine, synergistically enhanced the antitumor effects of vincristine and adriamycin in multidrug-resistant K562/ADM cells. On the other hand, the combined use of MRK-16 with verapamil or FK-506 did not show such synergistic effects. Drug accumulation studies revealed that MRK-16 remarkably increased the accumulation of cyclosporine, but not verapamil, in K562/ADM cells. This increased accumulation of cyclosporine by MRK-16 in K562/ADM cells directly resulted in the enhanced accumulation of vincristine and adriamycin in the cells. The synergistic effect of MRK-16 and cyclosporine was further confirmed by isobologram analysis in three different highly multidrug-resistant tumor cells. Moreover, while MRK-16 alone did not enhance the sensitivity of the KB-8-5 cells moderately resistant to vincristine, it increased two-fold the reversing effect of cyclosporine at 1 microM, an achievable blood concentration. Since MRK-16 alone showed therapeutic effects against multidrug-resistant tumors, the combined use of MRK-16, cyclosporine and antitumor agents would provide therapeutic benefits for the treatment of resistant tumors.
Naito
M
M
Institute of Molecular and Cellular Biosciences, University of Tokyo.
Tsuruo
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002352:Carrier Proteins / Q000276:immunology*; D016572:Cyclosporine / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004357:Drug Synergism; D006801:Humans; D007951:Leukemia, Myeloid / Q000276:immunology / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D014750:Vincristine; D004317:Doxorubicin; D016572:Cyclosporine