title: Regorafenib suppresses sinusoidal obstruction syndrome in rats.
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.
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Okuno
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan. Electronic address: etsu@kuhp.kyoto-u.ac.jp.
authors.forename: Etsuro
authors.initials: E
authors.lastname: Hatano
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Miyagawa-Hayashino
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kasai
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nishio
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Seo
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Taura
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006498:Hepatectomy / Q000401:mortality; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016686:Monocrotaline; D009336:Necrosis; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley
chemical_list: D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib; D016686:Monocrotaline; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: Colorectal liver metastasis; Drug-induced liver injury; Extracellular signal-regulated kinase; Kinase inhibitor; Metalloproteinase-9