POTENTIATION OF VINCRISTINE AND ADRIAMYCIN EFFECTS IN HUMAN HEMATOPOIETIC TUMOR-CELL LINES BY CALCIUM-ANTAGONISTS AND CALMODULIN INHIBITORS

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (5) , 2267-2272
Abstract
Verapamil, a Ca-influx blocker, enhanced the cytotoxicity of vincristine (VCR) in vitro 6- to 12-fold in 8 human hemopoietic tumor cell lines estabished from acute lymphatic leukemia [P-12/Ichikawa, CCRF-CEM, MOH-3, RPMI-8402, BALL-1], acute myelogenous leukemia [K562], and Burkitt''s lymphoma [Daudi]. Great enhancement of VCR cytotoxicity was obtained in a VCR-resistant subline of K562 myelogenous leukemia. A maximum of .apprx. 100-fold increase in VCR cytotoxicity occurred. Heterogeneity in VCR sensitivity (80-fold difference in sensitivity) was observed in vitro among these human tumor cells. BALL and Daudi cells of B-cell type were more susceptible toVCR. At 6.6 or 20 .mu.M of verapamil, the values for the concentration of drug required for 50% inhibition of cell growth for each cell line fell into a rather narrow range, and heterogeneity in VCR sensitivity among cell lines was circumvented in vitro. Verapamil also enhanced the cytotoxicity of Adriamycin, although the extent of enhancement was considerably small. Enhancement of VCR cytotoxicity also occurred with other Ca antagonists and calmodulin inhibitors [caroverine, olomipramine, trifluoperazine, prenylamine, No. 233]. At maximum effective concentration of these reagents, a 3- to 5-fold increase in VCR cytotoxicity occurred in K562 cells. In VCR-resistant K562 cells, a more prominent enhancement (20- to 45-fold) was observed with these reagents. VCR resistance was circumvented in vitro. The mechanism of enhancement of VCR cytotoxicity was explained by the enhanced accumulation of VCR in K562, especially in resistant cells.