title: Antitumour effects and pharmacokinetics of combination of vinblastine with a staurosporine derivative, NA-382, in P388/ADR-bearing mice.
abstract: The effects of a staurosporine derivative, N-ethoxycarbonyl-7-oxostaurosporine (NA-382), on the pharmacokinetics of vinblastine were evaluated, compared with those of verapamil, in multidrug-resistant P388/ADR-bearing mice. At first, the in-vitro experiments indicated that NA-382 permeated into the cells better and were more effective in combined cytotoxicity with vinblastine and on accumulation of vinblastine than with verapamil in P388/ADR cells. In combined intraperitoneal injection with vinblastine (200 micrograms kg-1) into P388/ADR-bearing mice, NA-382 in a suspension form (10 mg kg-1) prolonged the life-span of the mice near to that of P388/S-bearing mice treated with vinblastine alone, but verapamil even at the maximum tolerated dosage (30 mg kg-1) barely affected the in-vivo antitumour effect of vinblastine. When simultaneously administered with vinblastine to P388/ADR-bearing mice, NA-382 maintained significantly higher vinblastine levels in the tumour cells for 24 h and gave a larger area under the time-intracellular vinblastine concentration curve (0 to 24 h) than those receiving vinblastine alone, with long retention of the agent in ascitic fluid. Verapamil increased the cellular vinblastine content for only 6 h, accompanying a rapid elimination of the agent from the ascitic fluid. This study indicates that NA-382 is more effective against multidrug-resistance than verapamil, and its suspension is also advantageous for cancer chemotherapy of multidrug-resistant tumours.
authors.affiliation: Research Laboratory for Development of Medicine, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Miyamoto
authors.forename: K
authors.initials: K
authors.lastname: Takeda
authors.forename: K
authors.initials: K
authors.lastname: Koga
authors.forename: T
authors.initials: T
authors.lastname: Ohshima
authors.forename: S
authors.initials: S
authors.lastname: Wakusawa
mesh_terms: D000470:Alkaloids / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004317:Doxorubicin / Q000633:toxicity; D018432:Drug Resistance, Multiple; D005260:Female; D007941:Leukemia P388 / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D019311:Staurosporine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000470:Alkaloids; C075317:N-ethoxycarbonyl-7-oxostaurosporine; D014747:Vinblastine; D004317:Doxorubicin; D014700:Verapamil; D011493:Protein Kinase C; D019311:Staurosporine