title: Enhancement of cellular accumulation of cyclosporine by anti-P-glycoprotein monoclonal antibody MRK-16 and synergistic modulation of multidrug resistance.
abstract: BACKGROUND
  Drug resistance is a major obstacle to successful cancer chemotherapy. P-glycoprotein, which transports certain antitumor agents out of resistant tumor cells, is known to be a major factor in some types of multidrug resistance. Studies have shown that verapamil and the immunosuppressors cyclosporine and FK-506 can reverse multidrug resistance in vitro and in vivo and that the P-glycoprotein monoclonal antibody MRK-16 increases drug toxicity in multidrug-resistant tumors.
  
  
  OBJECTIVE
  The purpose of this in vitro study was to establish effective treatment modalities for overcoming multidrug resistance. We assessed the synergistic effects of verapamil, cyclosporine, or FK-506 in combination with MRK-16 and antitumor agents.
  
  
  METHODS
  Human myelogenous leukemia K562 cells and multidrug-resistant K562/ADM cells were treated with vincristine or doxorubicin combined with MRK-16 and cyclosporine alone or together; MRK-16 and verapamil alone or together; or MRK-16 and FK-506. The effects of MRK-16 and cyclosporine or verapamil on the accumulation of vincristine and doxorubicin were examined in K562/ADM cells, and the mechanisms of action were analyzed.
  
  
  RESULTS
  MRK-16 and cyclosporine synergistically enhanced the antitumor effects of vincristine and of doxorubicin in K562/ADM cells. However, the combined use of MRK-16 with verapamil or FK-506 did not show such synergistic effects in these cells. Studies of the effect of MRK-16 on cellular accumulation of cyclosporine and verapamil revealed that MRK-16 substantially increased accumulation of cyclosporine in K562/ADM cells, but did not increase accumulation of verapamil.
  
  
  CONCLUSIONS
  MRK-16 and cyclosporine synergistically enhanced the antitumor effects of vincristine and doxorubicin because MRK-16 increased cellular accumulation of cyclosporine.
  
  
  CONCLUSIONS
  These results, together with our previous finding that intravenous administration of MRK-16 induced regression of multidrug-resistant subcutaneous tumors in athymic mice, support the hypothesis that the combined use of MRK-16 and cyclosporine might increase the efficacy of antitumor agents against multidrug-resistant tumors expressing P-glycoprotein. Clinical phase I trials of MRK-16 in the treatment of multidrug-resistant tumors are under consideration.
authors.affiliation: Institute of Applied Microbiology, University of Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Naito
authors.forename: H
authors.initials: H
authors.lastname: Tsuge
authors.forename: C
authors.initials: C
authors.lastname: Kuroko
authors.forename: T
authors.initials: T
authors.lastname: Koyama
authors.forename: A
authors.initials: A
authors.lastname: Tomida
authors.forename: T
authors.initials: T
authors.lastname: Tatsuta
authors.forename: Y
authors.initials: Y
authors.lastname: Heike
authors.forename: T
authors.initials: T
authors.lastname: Tsuruo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism / Q000627:therapeutic use*; D016572:Cyclosporine / Q000378:metabolism* / Q000494:pharmacology; D004317:Doxorubicin / Q000378:metabolism; D004351:Drug Resistance; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology*; D016559:Tacrolimus / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D008562:Membrane Glycoproteins; D004317:Doxorubicin; D016572:Cyclosporine; D014700:Verapamil; D016559:Tacrolimus