Regorafenib suppresses sinusoidal obstruction syndrome in rats.

• 奥野, 将之

• 波多野, 悦朗

• Nakamura, Kojiro

• Miyagawa-Hayashino, Aya

• Kasai, Yosuke

• Nishio, Takahiro

• Seo, Satoru

• Taura, Kojiro

• Uemoto, Shinji

抄録

[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.

収録刊行物

• The Journal of surgical research

  The Journal of surgical research 193 (2), 693-703, 2015-02

  Elsevier Inc.

キーワード

• Colorectal liver metastasis
• Kinase inhibitor
• Drug-induced liver injury
• Metalloproteinase-9
• Extracellular signal-regulated kinase

詳細情報

• CRID: 1050845760732601984
• NII論文ID: 120005530955
• NII書誌ID: AA00708021
• ISSN: 00224804
• HANDLE: 2433/193267
• 本文言語コード: en
• 資料種別: journal article
• データソース種別:
  • IRDB
  • CiNii Articles