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: K Miyamoto, K Takeda, K Koga, T Ohshima, S Wakusawa
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 47 Issue 6 Pg. 524-9 (Jun 1995) ISSN: 0022-3573 [Print] England
• PMID: 7674138 (Publication Type: Journal Article)

Chemical References

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

Topics

• Alkaloids (administration & dosage, pharmacokinetics)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, 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, pharmacokinetics)