title: Reversal of anticancer drug resistance by macrolide antibiotics in vitro and in vivo.
abstract: 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 microg/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.
authors.affiliation: Department of Medical Technology, Nagoya University School of Health Sciences, Japan.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: K
authors.initials: K
authors.lastname: Kitaichi
authors.forename: C S
authors.initials: CS
authors.lastname: Hui
authors.forename: K
authors.initials: K
authors.lastname: Takagi
authors.forename: K
authors.initials: K
authors.lastname: Takagi
authors.forename: M
authors.initials: M
authors.lastname: Sakai
authors.forename: K
authors.initials: K
authors.lastname: Yokogawa
authors.forename: K I
authors.initials: KI
authors.lastname: Miyamoto
authors.forename: T
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007941:Leukemia P388 / Q000378:metabolism; D018942:Macrolides; D051379:Mice; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002121:Calcium Channel Blockers; D007166:Immunosuppressive Agents; D018942:Macrolides; D014747:Vinblastine; D016572:Cyclosporine; D014700:Verapamil