Wang Zheng, Zhou Jian, Fan Jia, Qiu Shuang-Jian, Yu Yao, Huang Xiao-Wu, Tang Zhao-You
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, PR China.
Clin Cancer Res. 2008 Aug 15;14(16):5124-30. doi: 10.1158/1078-0432.CCR-07-4774.
Novel therapeutic strategies are needed to prevent the tumor recurrence or metastasis after liver transplantation for hepatocellular carcinoma (HCC). This study was to investigate the effect of rapamycin, alone and in combination with sorafenib, on HCC in vivo.
Xenograft of a highly metastatic human HCC tumor (LCI-D20) was used to evaluate primary tumor growth and lung metastasis after treatment with rapamycin alone or in combination with sorafenib. Tumor cell proliferation was determined by Ki-67 immunostaining. To detect tumor cell apoptosis, the terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling assay was used. Tumor angiogenesis was investigated by using a monoclonal anti-CD31 antibody. A vascular endothelial growth factor ELISA kit was used to measure vascular endothelial growth factor protein levels in the mice serum.
Rapamycin, alone and in combination with sorafenib, strongly inhibited primary tumor growth and lung metastases in LCI-D20 model. Furthermore, the combination therapy significantly enhanced the effect of antitumor on primary tumor growth compared with single treatment with either rapamycin (P < 0.001) or sorafenib (P < 0.001). Rapamycin alone inhibited HCC cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Nevertheless, the combination therapy showed a significant inhibition of tumor cell proliferation (P < 0.05). Additionally, the combination therapy also further enhanced suppression of tumor cell angiogenesis compared with rapamycin treatment (P < 0.01). However, the induction of apoptosis in combination therapy group was not significantly higher than in the rapamycin-treated group (P > 0.05).
The combination therapy of rapamycin and sorafenib could be a new and promising therapeutic approach to the treatment of HCC and prevention of HCC recurrence after liver transplantation.
需要新的治疗策略来预防肝细胞癌（HCC）肝移植后的肿瘤复发或转移。本研究旨在探讨雷帕霉素单独及与索拉非尼联合应用对体内HCC的影响。
采用高转移性人HCC肿瘤（LCI-D20）异种移植模型，评估单独使用雷帕霉素或与索拉非尼联合治疗后原发性肿瘤生长和肺转移情况。通过Ki-67免疫染色测定肿瘤细胞增殖。采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法检测肿瘤细胞凋亡。使用单克隆抗CD31抗体研究肿瘤血管生成。用血管内皮生长因子ELISA试剂盒检测小鼠血清中血管内皮生长因子蛋白水平。
雷帕霉素单独及与索拉非尼联合应用均强烈抑制LCI-D20模型中的原发性肿瘤生长和肺转移。此外，与单独使用雷帕霉素（P < 0.001）或索拉非尼（P < 0.001）相比，联合治疗显著增强了对原发性肿瘤生长的抗肿瘤作用。单独使用雷帕霉素可抑制HCC细胞增殖、诱导凋亡并减少肿瘤血管生成。然而，联合治疗显示出对肿瘤细胞增殖的显著抑制（P < 0.05）。此外，与雷帕霉素治疗相比，联合治疗还进一步增强了对肿瘤细胞血管生成的抑制作用（P < 0.01）。然而联合治疗组诱导的凋亡并不显著高于雷帕霉素治疗组（P > 0.05）。
雷帕霉素与索拉非尼联合治疗可能是一种治疗HCC及预防肝移植后HCC复发的新的、有前景的治疗方法。
