The antineoplastic drug vinorelbine activates non-immunological histamine release from rat mast cells

We explore the mechanism of the antineoplastic drug vinorelbine activation in its rat mast cell exocytosis. The study was carried out on mast cells obtained from Sprague-Dawley rats. Vinorelbine (5-100 micrograms/mL), cholera toxin (200 ng/mL), pertussis toxin (100 ng/mL), benzalkonium chloride (10 micrograms/mL), compound 48/80 (1 microgram/mL), okadaic acid (1 microM), 12-tetradecanoate-acetate (50 ng/ml), perphenazine (1 microgram/ml), theophylline (10 mM), IBMX (1 mM), rolipram (15 microM). Histamine release was measured fluorimetrically. The drugs that modify G-protein activity, cholera toxin, pertussis toxin or benzalkonium chloride, do not modify the response profile. The exocytosis elicited by compound 48/80 is decreased by Gs or Gi modulation, which suggests that G proteins are not involved 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-tetradecanoate-acetate or perphenazine. The unspecific phosphodiesterase inhibitors theophylline and IBMX inhibited histamine release, but not the phosphodiesterase IV inhibitor rolipram. The overall results show that vinorelbine activates histamine release through a rather selective mechanism that may be mediated by certain phosphodiesterase-dependent transduction pathways.