Inhibition of macrophage- and neutrophil-mediated cytotoxicity by verapamil

Peripheral blood monocyte-derived macrophages and polymorphonuclear leukocytes (PMNs) obtained from normal donors kill tumor cells in vitro. However, if verapamil is added to the macrophages or neutrophil tumor cell suspensions in microgram concentrations (0.1 microgram to 0.1 mg), there is marked inhibition of tumor cell killing. The inhibitory effect for the macrophages resulted from an effect of verapamil on both the effector and target cells. When either the effector cells or target cells were preincubated with verapamil, they became resistant to the effects of the cytotoxic macrophages. Cytotoxicity was also inhibited when 0.1 mg of verapamil was added to the macrophages monolayers either at the time of addition of the tumor cells or 15-30 min after addition of the tumor cells, whereas no inhibition of cytotoxicity occurred when verapamil was added more than 30 min after the initiation of the cytotoxic reaction. For the neutrophils it was observed that the inhibitory activity resulted from an effect of verapamil on the effector cells rather than the target cells. When the effector cells were preincubated with verapamil they became incapable of killing the tumor cells, whereas preincubation of the target cells with verapamil had no effect on their ability to be killed by the neutrophils. Cytotoxicity was also inhibited when 0.1 mg of verapamil was added to the neutrophil monolayers either at the time of addition of the tumor cells or 15-60 min after addition of the tumor cells, whereas no inhibition of cytotoxicity occurred when verapamil was added more than 60 min after the initiation of the cytotoxic reaction.