MITOXANTRONE INDUCES NONIMMUNOLOGICAL HISTAMINE-RELEASE FROM RAT MAST-CELLS

The antineoplastic drug mitoxantrone(MTX) elicits a fast noncytotoxic and nonimmunological histamine release from peritoneal and pleural rat mast cells. The non specific phosphodiesterase inhibitor isobuthylmet hylxantine (1 mM) decreases the potency of MTX. Theophylline (10 mM) d ecreases both the potency and the efficacy of MTX-induced histamine se cretion. The protein kinase C (PKC) activator, tetradecanoyl-phorbol-1 3-acetate (50 ng/mL), enhances the effect of MTX, whereas the non spec ific PKC inhibitor trifluoperazine (10 mu M) exerts no effect. Histami ne release was also unaffected by substances acting on G-proteins, nam ely pertussis toxin (200 ng/mL), cholera toxin (300 mg/mL) and benzalk onium chloride (10 mu g/mt). The inhibition of protein phosphatases 1 and 2A by okadaic acid (1 mu M) does not modify the response. The resu lts indicate that mitoxantrone elicits the exocytosis in mast cells by a mechanism similar to the parent compound adriamycine, but different to the polyamine compound 48/80.