[Reversal of acquired resistance to vinca alkaloids and anthracycline antibiotics by calcium channel blockers and calmodulin inhibitors].

One of the major causes of failure in cancer chemotherapy is the selection and proliferation of specific drug-resistant tumor cells during treatment. The mechanism of acquired resistance of tumor cells to some agents is related to intracellular drug accumulation and retention. For example, in vincristine (VCR)- and adriamycin (ADM)-resistant tumor cell sublines, these agents can be shown to enter the cell but are actively transported to the outside. This results in a relatively low intracellular level of drug and thus to low cytotoxicity. These observations suggest that if we could control the VCR- and ADM-efflux function of resistant tumor cells appropriately, then we could expect a reversal of acquired resistance to these drugs in drug resistant tumor cells. We found that calcium channel blockers and calmodulin inhibitors enhance the intracellular level of vincristine and adriamycin in tumor cells, especially in drug-resistant mouse and human tumor cells by inhibiting their outward transport. The approach using calcium modifiers has the following advantages. (1) Reversal of acquired resistance to vinca alkaloids and anthracyclic antibiotics can be attained. Calcium channel blockers, such as verapamil, diltiazem, nicardipine, niludipine and nimodipine, at doses of 30 to 125 mg/kg administered daily for 10 days with VCR (10-200 micrograms/mg) enhanced the chemotherapeutic effect of VCB (40-50% increase in life span) in P388/VCR-bearing mice. The calcium channel blockers also enhanced the therapeutic effect of ADM in ADM resistant P388 bearing mice. (2) The approach is also effective for the reversal of the inherent resistance of tumor cells to anticancer agents. Less sensitive tumor cells became more susceptible to VCR and the heterogeneity in drug sensitivity among tumor clones has been circumvented. (3) The approach with these calcium modifiers is also effective against other antitumor agents which are transported outside the cells by the similar mechanisms. As one of the mechanisms of cross-resistance is explained by the enhanced drug efflux from resistant tumor cells, antitumor agents which show cross-resistance to VCR and ADM become effective against resistant tumor cells by this approach. The mechanism of this approach is now under investigation. These calcium modifiers enhance the cellular level of antitumor agents by inhibiting their outward transport. The functions of cellular calcium and calmodulin in the membrane architecture and membrane functions might be involved in this process. Clinical evaluation is now under progress by using diltiazen, nicardipine and verapamil.