The effect of calmodulin antagonists on the activation of RAW-264 macrophage-like cells for tumor cell killing.

The effects of several calmodulin antagonists on the activation of RAW-264 macrophage-like cells for tumor cell killing were investigated. At concentrations ranging from 5 X 10(-8) to 5 X 10(-7) M, calmidazolium, trifluoperazine, chlorprothixene, chlorpromazine and W-13 inhibited the development of cytolytic activity, evoked in RAW-264 by treatment with lymphokine and lipopolysaccharide, in a dose-dependent manner. Since the order of the potency of these drugs against the activation of RAW-264 cells was much the same as their ability to inhibit calmodulin-dependent phosphodiestherase activity: calmidazolium greater than trifluoperazine greater than chlorprothixene greater than chlorpromazine greater than W-13, and because W-12, a nonactive analog of W-13, failed to inhibit the process of activation, we believe that the development of cytolytic activity in RAW-264 cells may be dependent on calmodulin. At micromolar concentrations, calmodulin antagonists (except calmidazolium) enhanced the process of activation. The enhancement of cytolytic activity was neither the result of the toxicity of these drugs nor related to their effects on intracellular calcium. It was entirely dependent on the presence of stimulants but occurred independently from the stage of macrophage activation, and most likely was due to the nonspecific interference of these agents with calmodulin-independent processes.