The antineoplastic drug vinorelbine activates non-immunological histamine release from rat mast cells.
OBJECTIVE
We explore the mechanism of the antineoplastic drug vinorelbine activation in its rat mast cell exocytosis.


METHODS
The study was carried out on mast cells obtained from Sprague-Dawley rats.


METHODS
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.
Estévez
M D
MD
Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago, Lugo, Spain.
Vieytes
M R
MR
Louzao
M C
MC
Alfonso
A
A
Vilariño
N
N
Botana
L M
LM
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001548:Benzalkonium Compounds / Q000633:toxicity; D002118:Calcium / Q000378:metabolism; D002772:Cholera Toxin / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects; D005470:Fluorometry; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006636:Histamine Release / Q000187:drug effects*; D007700:Kinetics; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D010529:Peritoneal Cavity / Q000166:cytology; D037342:Pertussis Toxin; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010994:Pleura / Q000166:cytology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine; D010566:Virulence Factors, Bordetella / Q000633:toxicity; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D001548:Benzalkonium Compounds; D010726:Phosphodiesterase Inhibitors; D010566:Virulence Factors, Bordetella; D003189:p-Methoxy-N-methylphenethylamine; D014747:Vinblastine; D002772:Cholera Toxin; D037342:Pertussis Toxin; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases; D019204:GTP-Binding Proteins; D000077235:Vinorelbine; D002118:Calcium