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The antineoplastic drug vinorelbine activates non-immunological histamine release from rat mast cells
M D Estévez1, M R Vieytes, M C Louzao
1Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago, Lugo, Spain.
Objective And Design:
We explore the mechanism of the antineoplastic drug 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 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).
Methods:
Histamine release was measured fluorimetrically.
Results:
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.
Conclusions:
The overall results show that vinorelbine activates histamine release through a rather selective mechanism that may be mediated by certain phosphodiesterase-dependent transduction pathways.