Document Detail

Reversal of multidrug resistance by an immunosuppressive agent FK-506.
MedLine Citation:
PMID:  1370765     Owner:  NLM     Status:  MEDLINE    
FK-506, a novel immunosuppressive agent, was examined for its reversing effect on multidrug-resistant tumor cells. FK-506 at 3 microM completely reversed the resistance against vincristine (VCR) in vitro in VCR-resistant mouse leukemia P388 cells (P388/VCR). FK-506 also enhanced the cytotoxicity of VCR in Adriamycin(ADM)-resistant human ovarian cancer A2780 cells (AD10) and ADM-resistant human myelogenous leukemia K562 cells (K562/ADM) in vitro. FK-506 was also effective in modulating sensitivity to ADM in AD10 cells in vitro. FK-506 enhanced the chemotherapeutic effect of VCR in P388/VCR-bearing mice. When 20 mg/kg FK-506 was combined with 200 micrograms/kg VCR, a T/C value of 151% was obtained. Under the protocol used in this study, FK-506 was more potent than cyclosporin A (CsA) and verapamil. FK-506 inhibited [3H]azidopine binding to P-glycoprotein efficiently. The binding of VCR to K562/ADM plasma membrane was inhibited by FK-506 as effectively as by CsA. Moreover, the accumulation of VCR in AD10 cells was increased by FK-506 as efficiently as that of CsA and verapamil. These results indicate that FK-506 directly interacts with P-glycoprotein like CsA and verapamil, inhibits the active efflux of vincristine from resistant cells, increases the vincristine accumulation in resistant cells, and thus overcomes multidrug resistance in vitro and in vivo.
M Naito; T Oh-hara; A Yamazaki; T Danki; T Tsuruo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  29     ISSN:  0344-5704     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  1992  
Date Detail:
Created Date:  1992-03-02     Completed Date:  1992-03-02     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  195-200     Citation Subset:  IM    
Institute of Applied Microbiology, University of Tokyo, Japan.
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MeSH Terms
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Cell Death / drug effects
Cell Division / drug effects
Doxorubicin / administration & dosage,  pharmacology*
Drug Resistance / genetics*
Drug Synergism
Leukemia P388 / drug therapy
Membrane Glycoproteins / antagonists & inhibitors
Ovarian Neoplasms
Tacrolimus / administration & dosage,  pharmacology*
Tumor Cells, Cultured / drug effects*,  metabolism
Vincristine / administration & dosage,  pharmacology*
Reg. No./Substance:
0/Membrane Glycoproteins; 0/P-Glycoprotein; 109581-93-3/Tacrolimus; 23214-92-8/Doxorubicin; 57-22-7/Vincristine

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