- 作者：Wolfgang Sieghart ; Matthias Pinter ; Bernhard Dauser ; Natalya Rohr-Udilova ; Anne-Christine Piguet ; Gerald Prager ; Hubert Hayden ; Hans-Peter Dienes ; Jean-Francois Dufour ; Markus Peck-Radosavljevic
- 关键词：HCC ; hepatocellular carinoma ; VEGF ; vascular endothelial growth factor ; NSCLC ; non-small cell lung cancer ; EGFR ; epidermal growth factor receptor ; BCLC ; Barcelona Liver Cancer Classification ; MH ; Morris Hepatoma 3924A ; RFA ; radiofrequency ablation ; TACE
- 刊名：Journal of Hepatology
- 出版年：2012
- 出版时间：September, 2012
- 年：2012
- 卷：57
- 期：3
- 页码：592-599
- 全文大小：1249 K
Background & Aims
The combination of erlotinib with sorafenib is currently being investigated in a phase III RCT. We studied the effect of erlotinib and sorafenib on HCC in a preclinical model.Methods
The Morris Hepatoma (MH) and HepG2 cells were treated in vitro with sorafenib (1-10 ¦ÌM) and erlotinib (1-5 ¦ÌM) and evaluated for tumor cell viability, apoptosis, and target regulation. Antiangiogenic effects were studied by measuring VEGF levels, endothelial cell viability, apoptosis, migration, and the aortic ring assay.
In vivo, MH cells were implanted into the liver of syngeneic rats and treated with vehicle, sorafenib 5-10 mg/kg, erlotinib 10 mg/kg, and respective combinations.
Results
In vitro, erlotinib downregulated p-ERK but showed no significant effect on tumor cell viability in MH and HEPG2 cells. Despite a similar target regulation, sorafenib significantly reduced cell viability of HCC cells by induction of apoptosis, in a dose-dependent manner (11 ¡À 5 % ; 20 ¡À 10 % ; 51 ¡À 5 % for sorafenib 1, 5, 10 ¦ÌM). No additional effect was observed upon combination with erlotinib.
Of note, erlotinib treatment resulted in endothelial cell migration and vascular sprouting of aortic rings through induction of VEGF mRNA and protein levels in endothelial and tumor cells, which was blocked by sorafenib. In vivo, erlotinib had no single agent antitumor activity, raised serum-VEGF levels, and lacked a synergistic effect in combination with sorafenib.
Conclusions
Erlotinib had no antitumor effect on HCC in vitro nor in vivo, but induced VEGF, which may reflect a resistance mechanism to erlotinib monotherapy. No improvement of sorafenib efficacy was observed upon combination with erlotinib.