title: Ovariectomy aggravates hypersensitivity reactions to paclitaxel in rats.
abstract: The incidence of hypersensitivity reactions is still a matter of serious concern during chemotherapy with paclitaxel, particularly in patients with ovarian cancer. We recently reported that intravenous injection of paclitaxel causes acute lung injury characterized by vascular hyperpermeability, edema and respiratory dysfunction in rats. In the present study, we investigated the influence of ovariectomy on the paclitaxel-induced acute lung injury in rats. Ovariectomy worsened paclitaxel-induced acute lung injury, which was reversed by 17beta-estradiol. The mRNA expression for endothelial nitric oxide synthase was reduced in lungs of ovariectomized rats. To determine the role for nitric oxide, we examined the effects of several agents that modulate nitric oxide concentration on the pulmonary response to paclitaxel. In ovary-intact rats, a nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester exaggerated paclitaxel-induced acute lung injury, while nitric oxide donors such as sodium nitroprusside and isosorbide dinitrate attenuated the lung injury. Sodium nitroprusside was also effective in alleviating the paclitaxel-induced acute lung injury in ovariectomized rats. These findings suggest that ovariectomy enhances the susceptibility to paclitaxel hypersensitivity, in which decrease in estrogen and subsequent reduction in nitric oxide synthesis may be involved.
authors.affiliation: Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Goromaru
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Itoh
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sendo
authors.forename: Kenji
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Takahisa
authors.initials: T
authors.lastname: Yano
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ikesue
authors.forename: Ryozo
authors.initials: R
authors.lastname: Oishi
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D004342:Drug Hypersensitivity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000627:therapeutic use; D005260:Female; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009599:Nitroprusside / Q000494:pharmacology; D010052:Ovariectomy; D017239:Paclitaxel / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000517:prevention & control
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D009599:Nitroprusside; D009569:Nitric Oxide; D004958:Estradiol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D007548:Isosorbide Dinitrate; D017239:Paclitaxel; D019331:NG-Nitroarginine Methyl Ester