THE ANTINEOPLASTIC DRUG VINORELBINE ACTIVATES NONIMMUNOLOGICAL HISTAMINE-RELEASE FROM RAT MAST-CELLS

Objective and Design: We explore the mechanism of the antineoplastic d rug vinorelbine activation in its rat mast cell exocytosis. Materials: The study was carried out on mast cells obtained from Sprague-Dawley rats. Treatment: Vinorelbine (5-100 mu g/mL), cholera toxin (200 ng/mL ), pertussis toxin (100 ng/mL), benzalkonium chloride (10 mu g/mL), co mpound 48/80 (1 mu g/mL), okadaic acid (1 mu M), 12-tetradecanoate-ace tate (50 ng/ml), perphenazine (1 mu g/ml), theophylline (10 mM), IBMX (1 mM), rolipram (15 mu M). Methods: Histamine release was measured fl uorimetrically. Results: The drugs that modify G-protein activity, cho lera toxin, pertussis toxin or benzalkonium chloride, do not modify th e response profile. The exocytosis elicited by compound 48/80 is decre ased by Gs or Gi modulation, which suggests that G proteins are not in volved in vinorelbine stimulated secretion. The phosphatase inhibitor okadaic acid shows no effect on vinorelbine-stimulated release, nor on the activation or inhibition of protein kinase C with phorbol 12-tetr adecanoate-acetate or perphenazine. The unspecific phosphodiesterase i nhibitors theophylline and IBMX inhibited histamine release, but not t he phosphodiesterase IV inhibitor rolipram. Conclusions: The overall r esults show that vinorelbine activates histamine release through a rat her selective mechanism that may be mediated by certain phosphodiester ase-dependent transduction pathways.