Department of Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
J Surg Oncol. 2013 Mar;107(4):393-401. doi: 10.1002/jso.23224. Epub 2012 Aug 23.
Post-operative liver regeneration may contribute to tumor recurrence. There is a theoretical need for an adjuvant therapy that can suppress tumor growth without adversely affecting post-operative liver regeneration.
To evaluate the effect of RAF inhibitor Sorafenib on cell viability and proliferation of hepatoma cells and hepatocytes in vitro and in an in vivo rat model.
Cell viability, DNA synthesis, and RAF/MAPK kinase activity in the primary hepatocyte and hepatoma cell lines were investigated after Sorafenib exposure. Sequence analysis of the B-RAF gene in hepatic cells was determined. Tumor markers were compared within the rats after 70% hepatectomy with or without daily oral gavages of Sorafenib. Liver regeneration was assessed by liver function tests and proliferation markers.
Primary hepatocytes showed higher cell viability, proliferation rate, and stronger RAF/MAPK kinase activity compared with hepatoma cell lines. The in vivo tumor volumes, size, and metastases were significantly decreased (P < 0.05) whereas no significant change in liver regeneration related to Sorafenib exposure was found (P > 0.05). B-RAF V600E mutation was not detected neither in the hepatic cells nor untransformed hepatocytes.
The RAF targeted inhibitor can reduce tumor growth without retarding liver regeneration in this experiment.
术后肝脏再生可能导致肿瘤复发。因此，需要一种辅助疗法，既能抑制肿瘤生长，又不会对术后肝脏再生产生不利影响。
评估 RAF 抑制剂索拉非尼对体外肝癌细胞和肝细胞活力及增殖的影响，并在体内大鼠模型中进行验证。
索拉非尼作用后，检测原代肝细胞和肝癌细胞系的细胞活力、DNA 合成和 RAF/MAPK 激酶活性。检测肝组织细胞中 B-RAF 基因的序列变化。70%肝切除术后，大鼠口服索拉非尼与否，比较肿瘤标志物的变化。通过肝功能试验和增殖标志物评估肝脏再生情况。
与肝癌细胞系相比，原代肝细胞具有更高的细胞活力、增殖率和更强的 RAF/MAPK 激酶活性。体内肿瘤体积、大小和转移明显减少（P<0.05），但未发现索拉非尼暴露与肝脏再生相关的显著变化（P>0.05）。在肝组织细胞和未转化的肝细胞中均未检测到 B-RAF V600E 突变。
在本实验中，RAF 靶向抑制剂可抑制肿瘤生长，而不影响肝脏再生。
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