Department of Medicine, Roger Williams Medical Center, Providence, Rhode Island 02908, USA.
J Surg Res. 2012 Nov;178(1):242-7. doi: 10.1016/j.jss.2012.01.033. Epub 2012 Mar 29.
Sorafenib is currently approved for advanced hepatocellular carcinoma (HCC) and is presently being studied as an adjuvant treatment for HCC following resection. The effects of sorafenib on liver regeneration have not been clearly defined. Our objective was to identify the effects of sorafenib on liver regeneration in a murine partial hepatectomy (PH) model.
We performed PH in C57Bl/6 mice treated with a range of sorafenib doses with assessments at several time points. Liver sinusoidal endothelial cells (LSEC) and hepatocyte DNA synthesis and proliferation were assessed with 5-bromo-2'-deoxyuridine (BrdU) and Ki67 by flow cytometry and immunohistochemistry.
Treatment with sorafenib did not result in any deaths following PH. When we measured BrdU uptake to assess DNA synthesis, there was a statistically significant increase at 48 h post-PH for nonfibrotic LSEC following treatment with 60 mg/kg of sorafenib. However, BrdU and Ki67 staining among LSEC and hepatocytes was not significantly affected by sorafenib at any of the other doses or time points. BrdU and Ki67 flow cytometry data correlated with immunohistochemistry findings and postoperative liver weights.
In a murine PH model, sorafenib did not alter the repair response of normal or fibrotic livers following PH as measured by changes in liver weight, DNA synthesis, and cellular proliferation. These findings suggest sorafenib administered following hepatic resection does not impair liver regeneration.
索拉非尼目前被批准用于晚期肝细胞癌（HCC），目前正在研究作为 HCC 切除术后的辅助治疗。索拉非尼对肝再生的影响尚未明确。我们的目的是在小鼠部分肝切除术（PH）模型中确定索拉非尼对肝再生的影响。
我们在 C57Bl/6 小鼠中进行了 PH 手术，并使用了一系列索拉非尼剂量进行治疗，并在多个时间点进行评估。通过流式细胞术和免疫组织化学检测 5-溴-2'-脱氧尿苷（BrdU）和 Ki67，评估肝窦内皮细胞（LSEC）和肝细胞的 DNA 合成和增殖。
PH 手术后，索拉非尼治疗组没有导致任何死亡。当我们测量 BrdU 摄取以评估 DNA 合成时，在 60mg/kg 索拉非尼治疗的非纤维化 LSEC 中，在 PH 后 48 小时，BrdU 摄取有统计学显著增加。然而，在任何其他剂量或时间点，LSEC 和肝细胞中的 BrdU 和 Ki67 染色均未受到索拉非尼的显著影响。BrdU 和 Ki67 流式细胞术数据与免疫组织化学结果和术后肝重相关。
在小鼠 PH 模型中，与肝重、DNA 合成和细胞增殖的变化相比，索拉非尼并未改变 PH 后正常或纤维化肝脏的修复反应。这些发现表明，肝切除术后给予索拉非尼不会损害肝再生。
