RRC ID 43871
著者 Sieghart W, Pinter M, Dauser B, Rohr-Udilova N, Piguet AC, Prager G, Hayden H, Dienes HP, Dufour JF, Peck-Radosavljevic M.
タイトル Erlotinib and sorafenib in an orthotopic rat model of hepatocellular carcinoma.
ジャーナル J Hepatol
Abstract 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 μM) and erlotinib (1-5 μM) 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 5-10mg/kg, erlotinib 10mg/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 ± 5%; 20 ± 10%; 51 ± 5% for sorafenib 1, 5, 10 μM). 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.
巻・号 57(3)
ページ 592-9
公開日 2012-9-1
DOI 10.1016/j.jhep.2012.04.034
PII S0168-8278(12)00364-9
PMID 22634341
MeSH Animals Apoptosis / drug effects Benzenesulfonates / pharmacology Benzenesulfonates / therapeutic use* Carcinoma, Hepatocellular / drug therapy* Carcinoma, Hepatocellular / metabolism Cell Movement / drug effects Cell Survival / drug effects Drug Therapy, Combination Endothelial Cells / drug effects Endothelial Cells / metabolism ErbB Receptors / metabolism Erlotinib Hydrochloride Hep G2 Cells Humans Liver Neoplasms / drug therapy* Liver Neoplasms / metabolism Neoplasm Transplantation Neovascularization, Pathologic / metabolism Niacinamide / analogs & derivatives Phenylurea Compounds Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use* Pyridines / pharmacology Pyridines / therapeutic use* Quinazolines / pharmacology Quinazolines / therapeutic use* RNA, Messenger / metabolism Rats Sorafenib Vascular Endothelial Growth Factor A / drug effects Vascular Endothelial Growth Factor A / genetics Vascular Endothelial Growth Factor A / metabolism
IF 20.582
引用数 21
WOS 分野 GASTROENTEROLOGY & HEPATOLOGY
リソース情報
ヒト・動物細胞 HuH-7