Effect of verapamil in vitro and in vivo on the accumulation of vincristine in leukemic cells from patients with low malignant lymphoma

Abstract

The accumulation of vincristine in leukemic cells and normal mononuclear cells and the effect of verapamil on cellular drug accumulation were studied. Leukemic cells were isolated from 10 patients with chronic lymphocytic leukemia, immunocytoma and prolymphocytic leukemia. Normal mononuclear cells were collected from 3 healthy subjects. The cells were incubated with [3H]-vincristine and cellular drug accumulation was determined. The accumulation of vincristine differed nine-fold between patients. The presence of verapamil, 6.6 microM, during the incubation, increased drug accumulation by 150-550%. The effect increased with increasing verapamil concentrations up to 12-15 microM. The increased accumulation of vincristine caused by verapamil also led to increased in vitro cytotoxicity. However, neither the cellular accumulation of vincristine nor the effect of verapamil on drug accumulation was correlated with the clinical response to vincristine-containing treatment regimens. To study the clinical effect of verapamil on leukemic cell accumulation of vincristine, 4 patients were given verapamil, 120 mg three times orally. The plasma concentrations of verapamil after 3 days of treatment were lower than those required to enhance vincristine accumulation in vitro. In addition, norverapamil could also be detected in all patients. Before and at the end of the verapamil treatment period, blood from the patients was incubated with [3H]-vincristine and the leukemic cells then isolated. Verapamil treatment had no effect on the accumulation of vincristine in leukemic cells.