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Reversal of Anticancer Drug Resistance by Macrolide Antibiotics in Vitro and in Vivo
Author(s) -
Wang Li,
Kitaichi Kiyoyuki,
Hui Cai Shao,
Takagi Kenji,
Takagi Kenzo,
Sakai Miyuki,
Yokogawa Koichi,
Miyamoto Kenichi,
Hasegawa Takaaki
Publication year - 2000
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1046/j.1440-1681.2000.03308.x
Subject(s) - vinblastine , pharmacology , verapamil , in vivo , clarithromycin , antibiotics , macrolide antibiotics , p glycoprotein , erythromycin , medicine , in vitro , multiple drug resistance , chemotherapy , chemistry , biology , microbiology and biotechnology , biochemistry , calcium
SUMMARY 1. The combined effects of the macrolide antibiotics erythromycin, josamycin, clarithromycin and YM17K (3,4′‐dideoxy mycaminosyl tylonolide hydrochloride) on in vitro intracellular accumulation of vinblastine or cyclosporine (Cs)A and on the in vivo antitumour activity of vinblastine were investigated using mouse leukaemia P388 cells (P388/S) and anticancer drug‐resistant (P388/ADR) cells. These effects were compared with those of a calcium antagonist (verapamil) or immunosuppressants (FK506 and CsA). 2. All tested macrolide antibiotics increased the accumulation of both vinblastine and CsA in P388/ADR cells in a dose‐ dependent manner, but their potency was lower than that of verapamil, CsA or FK506. 3. When vinblastine (200 μg/kg) was administered intraperitoneally with each of the macrolide antibiotics (10 or 100 mg/kg) or with verapamil (25 mg/kg) once a day for 10 days in P388/ADR‐bearing mice, combined effects of vinblastine with the macrolide antibiotics (erythromycin, clarithromycin and YM17K) or verapamil were observed. 4. The present study suggests that macrolide antibiotics may overcome anticancer drug resistance by inhibiting the binding of vinblastine or CsA to P‐glycoprotein in P388/ADR cells. 5. We believe that these results are encouraging for combination chemotherapy to overcome P‐glycoprotein‐dependent anticancer drug‐resistant tumours in clinical practice.