Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma
Huynh, Hung, Ngo, Van Chanh, Fargnoli, Joseph, Ayers, Mark, Soo, Khee Chee, Nung, Koong Heng, Thng, Choon Hua, Ong, Hock Soo, Chung, Alexander, Chow, Pierce, Pollock, Pamela, Byron, Sara, & Tran, Evelyn (2008) Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clinical Cancer Research, 14(19), pp. 6146-6153.
PURPOSE: Hreceptor (VEGFR) and FGF receptor (FGFR) signaling pathways.
EXPERIMENTAL DESIGN: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines.
RESULTS: Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib-induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr(1054/1059), increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation.
CONCLUSION: This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.
Impact and interest:
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|Item Type:||Journal Article|
|Additional Information:||Articles free to read on journal website after 12 months|
|Keywords:||Hepatocellular carcinoma, vascular endothelial growth factor, fibroblast growth factor, angiogenesis, tyrosine kinase inhibitor|
|Subjects:||Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)|
|Divisions:||Past > QUT Faculties & Divisions > Faculty of Science and Technology|
|Deposited On:||24 Aug 2011 22:13|
|Last Modified:||29 Jan 2015 05:14|
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