Effect of Sorafenib on Murine Liver Regeneration
Effect of Sorafenib on Murine Liver Regeneration
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DOI：
10.1002/hep.24037
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发表时间：
2011-02-01
期刊：
影响因子：
13.5
通讯作者：
Dufour, Jean-Francois F.
中科院分区：
文献类型：
--
作者：
Hora, Caroline;Romanque, Pamela;Dufour, Jean-Francois F.
肝细胞癌（HCC）是癌症相关死亡的常见原因。索拉非尼可延长晚期患者的生存期，并被批准用于不可切除的HCC的全身治疗。它通过抑制受体酪氨酸激酶血管内皮生长因子受体2（VEGFR-2）和血小板衍生生长因子受体-β 1/2（PDGFR-β）和激酶RAE而具有抗血管生成和抗增殖特性，索拉非尼代表HCC患者辅助治疗的候选化合物。我们研究的目的是调查索拉非尼是否影响肝再生。C57 BL 6小鼠口服30 mg/kg/天索拉非尼或其溶剂，持续14天，直至肝切除术前一天或手术后第二天开始或两者。在肝切除术后24、72和120小时处死动物。肝再生计算为初始肝重量的百分比。用免疫组化法检测肝组织中BrdU掺入和磷酸化细胞外信号调节激酶（pERIC 1/2）的表达。测量肝组织匀浆中的VEGF-A、PDGF-BB和肝细胞生长因子（HGF）水平。对瘢痕组织进行组织学分析。手术前1天停止治疗对肝再生没有影响。连续索拉非尼治疗和手术后1天开始的治疗在120小时对肝再生具有统计学显著影响，与溶剂治疗的对照动物相比（120小时时72% +/- 12 vs对照88% +/- 15和70% +/- 13 vs对照86% +/- 5，均P
Hepatocellular carcinoma (HCC) is a common cause of cancer-related death. Sorafenib prolongs survival of patients with advanced disease and is approved for the systemic treatment of unresectable HCC. It possesses antiangiogenic and antiproliferative properties by way of inhibition of the receptor tyrosine kinases vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor-beta 1/2 (PDGFR-beta) and the kinase RAE Sorafenib represents a candidate compound for adjuvant therapy in HCC patients. The aim of our study was to investigate whether sorafenib affects liver regeneration. C57BL6 mice received sorafenib orally at 30 mg/kg/day or its vehicle either for 14 days until the day before hepatectomy or starting the day after surgery or both. Animals were sacrificed 24, 72, and 120 hours after hepatectomy. Liver regeneration was calculated as a percent of initial liver weight. Bromodeoxyuridine (BrdU) incorporation and phospho-extracellular signal-regulated kinase (pERIC1/2) were determined by immunohistochemistry on liver sections. VEGF-A, PDGF-BB, and hepatocyte growth factor (HGF) levels were measured in liver tissue homogenates. Histological analysis of scar tissue was performed. Treatment stopped 1 day before surgery had no impact on liver regeneration. Continuous sorafenib treatment and treatment started 1 day after surgery had statistically significant effects on liver regeneration at 120 hours compared to vehicle-treated control animals (72% +/- 12 versus control 88% +/- 15 and 70% +/- 13 versus control 86% +/- 5 at 120 hours, both P