Verapamil potentiation of VP-16-213 in acute lymphatic leukemia and reversal of pleiotropic drug resistance

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Abstract
Summary Verapamil, the calcium-influx-blocking agent, has previously been shown to have favorable interactions with antineoplastic drugs. Our study of human T cell acute lymphatic leukemia (ALL) GM3639 indicates that verapamil enhances the in vitro cytotoxicity of VP-16-213 against drug-sensitive ALL by reducing the concentration of VP-16-213, resulting in 50% cell viability from 104.5±26.6 nM to 46.0±2.7 nM (PP2F/1 mice bearing P388 leukemia from 27.8±3.7 to 49.1±5.0 days (P23, by continuous exposure of drug-sensitive cells to VCR. This subline demonstrates pleiotropic cross resistance to VP-16-213 and daunorubicin. The addition of verapamil to VCR, to VP-16-213, and to daunorubicin completely restores responsiveness to these drugs, as indicated by the normalization of the VCR and VP-16-213 concentrations required for cytotoxicity and the concentration of daunorubicin required for inhibition of thymidine incorporation.