CIRCUMVENTION OF MULTIDRUG RESISTANCE OF LEUKEMIA-CELLS BY THE ANTIALLERGIC AGENT AZELASTINE

Azelastine, an anti-allergic agent, completely overcame the resistance to vincristine (VCR) of a VCR-resistant subline (P388/VCR) of P388 mu rine leukemia cells (P388). Considering our previous result [Yamamoto et al. (1989) J. Clin. Biochem. Nutr., 6, 205] that the drug overcame the resistance to adriamycin (ADM) of an ADM-resistant subline (P388/A DM) of P388, we concluded that the drug circumvents multidrug resistan ce of leukemia cells. This circumvention by azelastine is ascribable t o the accumulation of anticancer agent in drug-resistant leukemia cell s. As for the mechanism of the accumulation, a metabolic inhibition ex periment showed that the accumulation is not due to increased influx o f the drug into the cells but due to an azelastine-effected decrease i n the efflux of the drug from the cells. Thus, the effect of azelastin e on the binding of P-glycoprotein in plasma membrane fraction with VC R was examined. [H-3]VCR binding to the membrane fraction prepared fro m an ADM-resistant human myelogenous leukemia cell line (K562/ADM) was inhibited by azelastine in a concentration-dependent manner. These re sults imply that azelastine circumvents multidrug resistance through, at least partly, the inhibition of the efflux of anti-cancer drug from leukemia cells by its binding to P-glycoprotein. We further noted tha t the treatment with azelastine in combination with VCR significantly prolonged the survival of P388/VCR-bearing mice as compared with those given VCR alone.