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Title: Regorafenib suppresses sinusoidal obstruction syndrome in rats.
Authors: Okuno, Masayuki
Hatano, Etsuro
Nakamura, Kojiro
Miyagawa-Hayashino, Aya
Kasai, Yosuke
Nishio, Takahiro
Seo, Satoru  kyouindb  KAKEN_id
Taura, Kojiro  kyouindb  KAKEN_id
Uemoto, Shinji
Author's alias: 奥野, 将之
波多野, 悦朗
Keywords: Colorectal liver metastasis
Kinase inhibitor
Drug-induced liver injury
Metalloproteinase-9
Extracellular signal-regulated kinase
Issue Date: Feb-2015
Publisher: Elsevier Inc.
Journal title: The Journal of surgical research
Volume: 193
Issue: 2
Start page: 693
End page: 703
Abstract: [Background]Sinusoidal obstruction syndrome (SOS), a form of drug-induced liver injury related to oxaliplatin treatment, is associated with postoperative morbidity after hepatectomy. This study aimed to examine the impact of regorafenib, the first small-molecule kinase inhibitor to show efficacy against metastatic colorectal cancer, on a rat model of SOS. [Methods]Rats with monocrotaline (MCT)-induced SOS were divided into two groups according to treatment with either regorafenib (6 mg/kg) or vehicle alone, which were administered at 12 and 36 h, respectively, before MCT administration. Histopathologic examination and serum biochemistry tests were performed 48 h after MCT administration. Sinusoidal endothelial cells were evaluated by immunohistochemistry and electron microscopy. To examine whether regorafenib preserved remnant liver function, a 30% hepatectomy was performed in each group. [Results]The rats in the vehicle group displayed typical SOS features, whereas these features were suppressed in the regorafenib group. The total SOS scores were significantly lower in the regorafenib group than in the vehicle group. Immunohistochemistry and electron microscopy showed that regorafenib had a protective effect on sinusoidal endothelial cells. The postoperative survival rate after 7 d was significantly better in the regorafenib group than that in the vehicle group (26.7% versus 6.7%, P < 0.05). Regorafenib reduced the phosphorylation of extracellular signal-regulated kinase, which induced matrix metalloproteinase-9 (MMP-9) activation and decreased the activity of MMP-9, one of the crucial mediators of SOS development. [Conclusions]Regorafenib suppressed MCT-induced SOS, concomitant with attenuating extracellular signal-regulated kinase phosphorylation, and MMP-9 activation, suggesting that regorafenib may be a favorable agent for use in combination with oxaliplatin-based chemotherapy.
Rights: © 2015 Elsevier Inc.
この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。This is not the published version. Please cite only the published version.
URI: http://hdl.handle.net/2433/193267
DOI(Published Version): 10.1016/j.jss.2014.08.052
PubMed ID: 25266603
Appears in Collections:Journal Articles

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