RRC ID 37684
著者 Yoshikawa D, Ojima H, Kokubu A, Ochiya T, Kasai S, Hirohashi S, Shibata T.
タイトル Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma.
ジャーナル Br J Cancer
Abstract Cholangiocarcinoma is an intractable cancer, with no effective therapy other than surgical resection. Elevated vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions are associated with the progression of cholangiocarcinoma. We therefore examined whether inhibition of VEGFR and EGFR could be a potential therapeutic target for cholangiocarcinoma. Vandetanib (ZD6474, ZACTIMA), a VEGFR-2/EGFR inhibitor, was evaluated. Four human cholangiocarcinoma cell lines were molecularly characterised and investigated for their response to vandetanib. In vitro, two cell lines (OZ and HuCCT1), both of which harboured KRAS mutation, were refractory to vandetanib, one cell line (TGBC24TKB) was somewhat resistant, and another cell line (TKKK) was sensitive. The most sensitive cell line (TKKK) had EGFR amplification. Vandetanib significantly inhibited the growth of TKKK xenografts at doses > or = 12.5 mg kg(-1) day(-1) (P<0.05), but higher doses (50 mg kg(-1) day(-1), P<0.05) of vandetanib were required to inhibit the growth of OZ xenografts. Vandetanib (25 mg kg(-1) day(-1)) also significantly (P=0.006) prolonged the time to metastasis in an intravenous model of TKKK metastasis. Inhibiting both VEGFR and EGFR signalling appears a promising therapeutic approach for cholangiocarcinoma. The absence of KRAS mutation and the presence of EGFR amplification may be potential predictive molecular marker of sensitivity to EGFR-targeted therapy in cholangiocarcinoma.
巻・号 100(8)
ページ 1257-66
公開日 2009-4-21
DOI 10.1038/sj.bjc.6604988
PII 6604988
PMID 19319137
PMC PMC2676540
MeSH Animals Bile Duct Neoplasms / drug therapy* Bile Ducts, Intrahepatic / drug effects* Cell Division / drug effects Cell Line, Tumor Cholangiocarcinoma / drug therapy* ErbB Receptors / antagonists & inhibitors* ErbB Receptors / genetics Female Gene Amplification Humans In Situ Hybridization, Fluorescence Japan Mice Mice, Inbred BALB C Mice, Nude Piperidines / therapeutic use* Quinazolines / therapeutic use* Reverse Transcriptase Polymerase Chain Reaction Transplantation, Heterologous Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors Vascular Endothelial Growth Factor Receptor-2 / genetics
IF 5.791
引用数 68
WOS 分野 ONCOLOGY
リソース情報
ヒト・動物細胞 TKKK(RCB1907) TGBC24TKB(RCB1196) HuCCT1(RCB1960)