Overcoming of multidrug resistance by VA-033, a novel derivative of apovincaminic acid ester.

Abstract

We have studied the effects of a novel derivative of apovincaminic acid ester, VA-033, on the resistance of tumors to chemotherapeutic agents. VA-033 increased the sensitivity of drug-resistant cell lines (P388/VCR, P388/ADM, AD10, and K562/ADM) to adriamycin or vincristine. The potency of VA-033 was stronger than verapamil. The drug lengthened the survival time of the P388/VCR-implanted mice treated with vincristine. VA-033 increased the intracellular accumulation of vincristine in the tumor cells, and the photolabeling of P-glycoprotein by [3H]azidopine was inhibited by VA-033. VA-033 showed a slight inhibitory effect on the L-type Ca2+ current in the ventricular myocytes, and had less effect on the cardiovascular parameters such as blood pressure, contractile force and atrio-ventricular conduction time than verapamil when administered systemically in the dog. These results suggest that VA-033 may become a beneficial compound as a modifier to the neoplastic cell resistant to multidrugs.

• Authors: K Nanaumi, K Tsuchida, S Nakaike, T Yamagishi, T Ichihara, K Takahashi, H Watajima, Y Suzuki, M Naito, T Tsuruo
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 327 Issue 2-3 Pg. 239-46 (May 30 1997) ISSN: 0014-2999 [Print] Netherlands
• PMID: 9200566 (Publication Type: Journal Article)

Chemical References

• VA 033
• Vinca Alkaloids
• Vincristine
• Doxorubicin
• Verapamil

Topics

• Animals
• Cardiovascular System (drug effects)
• Doxorubicin (pharmacology)
• Drug Interactions
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Hematologic Neoplasms (drug therapy)
• Leukemia P388
• Mice
• Time Factors
• Verapamil (pharmacology)
• Vinca Alkaloids (pharmacology)
• Vincristine (pharmacology)