Department of Clinical Research, University of Bern, Switzerland.
Hepatology. 2011 Feb;53(2):577-86. doi: 10.1002/hep.24037. Epub 2011 Jan 4.
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-β) and the kinase RAF. 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 (pERK1/2) 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 ≤ 0.02). BrdU incorporation showed decreased numbers of positive nuclei in both groups receiving sorafenib after surgery. Phospho-ERK levels were reduced in sorafenib-treated animals. An increase of VEGF-A levels was observed in mice receiving sorafenib. Wound-healing complications were observed in animals receiving sorafenib after surgery and confirmed on histological sections.
This preclinical study shows that sorafenib did not impact on liver regeneration when ceased before surgery; however, administration after hepatectomy affected late liver regeneration.
本研究旨在探讨索拉非尼是否影响肝再生。
C57BL6 小鼠每天口服 30mg/kg 索拉非尼或其载体，连续 14 天，直至肝切除术前 1 天或术后第 1 天开始，或两者兼用。动物在肝切除后 24、72 和 120 小时被处死。肝再生率以初始肝重的百分比计算。肝组织切片通过免疫组化检测 BrdU 掺入和磷酸化细胞外信号调节激酶（pERK1/2）。肝组织匀浆中测定血管内皮生长因子 A（VEGF-A）、血小板衍生生长因子 BB（PDGF-BB）和肝细胞生长因子（HGF）水平。对疤痕组织进行组织学分析。手术前 1 天停药对肝再生无影响。连续索拉非尼治疗和术后第 1 天开始治疗在 120 小时时与对照组相比对肝再生有统计学显著影响（72%±12%对对照组 88%±15%和 70%±13%对对照组 86%±5%，均 P≤0.02）。手术后接受索拉非尼治疗的两组 BrdU 阳性核数量均减少。磷酸化 ERK 水平在索拉非尼治疗组降低。接受索拉非尼治疗的小鼠 VEGF-A 水平升高。术后接受索拉非尼治疗的动物出现伤口愈合并发症，并在组织学切片上得到证实。
这项临床前研究表明，手术前停药对肝再生没有影响；然而，肝切除术后给药会影响晚期肝再生。
