OVERCOMING OF VINCRISTINE RESISTANCE IN P388 LEUKEMIA INVIVO AND INVITRO THROUGH ENHANCED CYTO-TOXICITY OF VINCRISTINE AND VINBLASTINE BY VERAPAMIL

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  • 1 January 1981
    • journal article
    • research article
    • Vol. 41  (5) , 1967-1972
Abstract
A noncytotoxic dose of verapamil, a coronary vasodilator, enhances the cytotoxicity of vincristine (VCR) and vinblastine in [mouse] P388 leukemia cells and its VCR-resistant subline, P388/VCR. When 2.2-6.6 .mu.M verapamil was added along with VCR to the P388/VCR culture in vitro, VCR resistance was completely overcome. Verapamil in doses of 50-100 mg/kg administered daily for 10 days with VCR also enhances the chemotherapeutic effect of VCR in P388- and, especially, P388/VCR-bearing mice. When approximately 3 times the amount of VCR was given to a P388/VCR bearer as compared to a P388 bearer, VCR resistance was almost completely overcome in vivo with 50-100 mg/kg doses of verapamil. The amount of VCR incorporated into P388 cells was larger than that in P388/VCR cells. Verapamil (6.6 .mu.M) enhanced the cellular level of VCR in P388 cells 2-fold and enhanced the level of VCR in P388/VCR cells 10-fold. The amount of VCR in P388/VCR cells reached the same level as that found in P388 cells. The overcoming of VCR resistance in vivo and in vitro could be explained by the effective accumulation of VCR by verapamil in P388/VCR cells mediated by the inhibition of a VCR efflux function of the cells, a mechanism which remains to be solved.