Antitumour effects and pharmacokinetics of combination of vinblastine with a staurosporine derivative, NA-382, in P388/ADR-bearing mice

J Pharm Pharmacol. 1995 Jun;47(6):524-9. doi: 10.1111/j.2042-7158.1995.tb05843.x.

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.

MeSH terms

  • Alkaloids / administration & dosage
  • Alkaloids / pharmacokinetics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics*
  • Doxorubicin / toxicity
  • Drug Resistance, Multiple
  • Female
  • Leukemia P388 / drug therapy*
  • Mice
  • Mice, Inbred Strains
  • Protein Kinase C / antagonists & inhibitors
  • Staurosporine / analogs & derivatives
  • Tumor Cells, Cultured
  • Verapamil / pharmacology
  • Vinblastine / administration & dosage
  • Vinblastine / pharmacokinetics

Substances

  • Alkaloids
  • N-ethoxycarbonyl-7-oxostaurosporine
  • Vinblastine
  • Doxorubicin
  • Verapamil
  • Protein Kinase C
  • Staurosporine