Target therapy using a small molecule inhibitor against angiogenic receptors in pancreatic cancer
Target therapy using a small molecule inhibitor against angiogenic receptors in pancreatic cancer
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DOI：
10.1593/neo.06616
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发表时间：
2007-02-01
期刊：
影响因子：
4.8
通讯作者：
Hines, Oscar J.
中科院分区：
文献类型：
--
作者：
Buechler, Peter;Reber, Howard A.;Hines, Oscar J.
目的：PD173074 是 VEGF-RII 和 FGF-RI 的小分子抑制剂，靶向新生血管生成和有丝分裂发生。本研究旨在分析单一化合物驱动的胰腺癌中 FGF 和 VEGF 受体的抑制作用。实验设计：进行RT-PCR和蛋白质印迹来量化蛋白质表达和磷酸化。使用贴壁依赖性和独立生长测定来研究细胞生长。通过流式细胞术，研究细胞周期分析和细胞凋亡。体内 HPAF-II 和 MIA PaCa-2 细胞异种移植。连续10周每天对动物进行治疗。使用免疫组织化学来量化微血管密度和细胞凋亡。结果：在 MIA PaCa-2 细胞中可检测到最高水平的 FGF-RI，在 HPAF-II 细胞中最低。 PD173074 在表达高水平 FGF-RI 的细胞中抑制细胞生长最为显着。通过阻断 G(0)/G(1) 期的转变来抑制细胞周期进程，从而增加细胞凋亡。在 PD173074 治疗的动物中，通过抑制有丝分裂、诱导细胞凋亡和减少血管生成的综合作用，实现了体内原位肿瘤生长的显着抑制。结论：这些数据强调 VEGF-RII 和 FGF-RI 作为治疗靶点，并表明联合使用酪氨酸激酶抑制剂在无法手术的胰腺癌患者的治疗中具有潜在作用。
PURPOSE: PD173074, a small molecule inhibitor of VEGF-RII and FGF-RI, targets neoangiogenesis and mitogenesis. This study aimed to analyze a single-compound-driven inhibition of FGF and VEGF receptors in pancreatic cancer. EXPERIMENTAL DESIGN: RT-PCR and Western blots were performed to quantify protein expression and phosphorylation. Anchorage dependent and independent growth assays were used to study cell growth. With flow cytometry, cell cycle analysis and apoptosis were studied. In vivo HPAF-II and MIA PaCa-2 cells were xenografted. Animals were treated daily for 10 weeks. Immunohistochemistry was used to quantify microvessel density and apoptosis. RESULTS: Highest levels of FGF-RI were detectable in MIA PaCa-2 cells, lowest in HPAF-II cells. PD173074 inhibited cell growth most prominently in cells expressing high levels of FGF-RI. Cell cycle progression was inhibited by blocking transition in the G(0)/G(1) phase, and consequently, apoptosis was increased. In vivo significant inhibition of orthotopic tumor growth was achieved by a combination effect of inhibition of mitogenesis, induction of apoptosis, and reduction of angiogenesis in PD173074-treated animals. CONCLUSIONS: These data highlight VEGF-RII and FGF-RI as therapeutic targets and suggest a potential role for the combined use of tyrosine kinase inhibitors in the management of inoperable pancreatic cancer patients.