丙氨酸布立尼布，一种血管内皮生长因子受体和成纤维细胞生长因子受体酪氨酸激酶的双重抑制剂，在人肝细胞癌小鼠模型中可诱导生长抑制。

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.

作者信息

Huynh Hung, Ngo Van Chanh, Fargnoli Joseph, Ayers Mark, Soo Khee Chee, Koong Heng Nung, Thng Choon Hua, Ong Hock Soo, Chung Alexander, Chow Pierce, Pollock Pamela, Byron Sara, Tran Evelyn

机构信息

Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore.

出版信息

Clin Cancer Res. 2008 Oct 1;14(19):6146-53. doi: 10.1158/1078-0432.CCR-08-0509.

DOI:10.1158/1078-0432.CCR-08-0509

PMID:18829493

Abstract

PURPOSE

Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm; surgery is the only curative option but 5-year survival rates are only 25% to 50%. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are known to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the treatment of HCC. The aim of this study was to determine the antineoplastic activity of brivanib alaninate, a dual inhibitor of VEGF receptor (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.

摘要

目的

肝细胞癌（HCC）是第五大常见原发性肿瘤；手术是唯一的治愈选择，但5年生存率仅为25%至50%。已知血管内皮生长因子（VEGF）和成纤维细胞生长因子（FGF）参与HCC的生长和新生血管形成。因此，靶向这些信号通路的药物可能对HCC治疗有效。本研究的目的是确定VEGF受体（VEGFR）和FGF受体（FGFR）信号通路的双重抑制剂——丙氨酸布立尼布的抗肿瘤活性。

实验设计

将六种不同的来源于患者的皮下HCC异种移植瘤植入小鼠体内。与对照组相比，评估用丙氨酸布立尼布治疗的小鼠的肿瘤生长情况。通过免疫组织化学评估丙氨酸布立尼布对细胞凋亡和细胞增殖的影响。使用SK-HEP1和HepG2细胞在体外研究丙氨酸布立尼布对VEGFR-2和FGFR-1信号通路的影响。采用蛋白质印迹法确定这些异种移植瘤和细胞系中蛋白质的变化。

结果

丙氨酸布立尼布显著抑制了六个异种移植瘤系中五个的肿瘤生长。此外，丙氨酸布立尼布诱导的生长抑制与Tyr(1054/1059)位点磷酸化VEGFR-2的减少、细胞凋亡增加、微血管密度降低、细胞增殖抑制以及细胞周期调节因子的下调有关。这些异种移植瘤系中FGFR-1和FGFR-2的表达水平与其对丙氨酸布立尼布诱导的生长抑制的敏感性呈正相关。在VEGF刺激和碱性FGF刺激的SK-HEP1细胞中，丙氨酸布立尼布显著抑制VEGFR-2、FGFR-1、细胞外信号调节激酶1/2和Akt的磷酸化。