CIRCUMVENTION OF VINCRISTINE AND ADRIAMYCIN RESISTANCE INVITRO AND INVIVO BY CALCIUM INFLUX BLOCKERS

Abstract

Ca influx blockers, diltiazem, nicardipine, nifedipine, niludipine and nimodipine, which possess coronary vasodilatory activity, greatly enhanced the cytotoxicity of vincristine (VCR) in tumor cells and especially in VCR-resistant sublines of mouse P388 leukemia (P388/VCR) and human K562 myelogenous leukemia. The extent of enhancement was different among the drugs, and up to a 50- to 70-fold increase in VCR cytotoxicity occurred in P388/VCR cells with nontoxic or marginally toxic concentrations of diltiazem and nicardipine. A 50- to 100-fold enhancement occurred in VCR-resistant human K562 myelogenous leukemia cells with diltiazem, nicardipine, niludipine and nimodipine. VCR resistance of these cell lines was circumvented completely by these blockers. Ca influx blockers also enhanced the cytotoxicity of Adriamycin in P388 leukemia cells and especially in its Adriamycin-resistant subline. The extent of enhancement, however, was lower than that which occurred in VCR-resistant tumor lines with VCR. An .apprx. 10- to 30-fold increase in Adriamycin cytotoxicity occurred in P388 Adriamycin-resistant subline cells with diltiazem, nicardipine, niludipine, and nimodipine. Although VCR alone at 10-200 .mu.g/kg did not confer a significant therapeutic effect in P388/VCR-bearing mice, Ca influx blockers in doses of 30-125 mg/kg administered daily for 10 days with VCR enhanced the chemotherapeutic effect of VCR in P388/VCR-bearing mice. A maximum of .apprx. a 40 to 50% increase in life span occurred with diltiazem, nicardipine, niludipine and nimodipine. The Ca influx blockers also enhanced the therapeutic effect of Adriamycin in P388 Adriamycin-resistant subline-bearing mice, although the extent of enhancement was smaller than that observed with VCR in P388/VCR-bearing mice.