胃癌的血管靶治疗进展.ppt

* Folkman在回顾内皮抑素10年研究近160篇（1997-2006）的文献后，总结了内皮抑素的作用机制，发现内皮抑素能显著调控内皮细胞12％的基因组，上调的基因包括已知的血管生成抑制物，而在下调的基因中包括已知的促血管生成因子。在今天看来，这些因子中包括大量的肿瘤驱动基因，以及肿瘤血管生成与转移相关的关键调控物质。 拓展阅读 Ephrin（肿瘤血管发生和淋巴管生成中的一个潜在的治疗靶点） 来自西班牙国家癌症研究中心（CNIO）的研究人员证实基于抗体阻断与血管形成和淋巴管生成相关的ephrinB2蛋白有可能代表了开发抗血管生成和抗肿瘤治疗的一个有效策略。 西班牙国家癌症研究中心的研究人员生成了对抗ephrin-B2的高度特异性人类抗体。这些特异性抗体能够在体外实验中抑制内皮细胞迁移和血管形成。此外，全身治疗异种移植胰腺癌、肺癌或结肠癌细胞的小鼠导致了血液和淋巴管数量的显著减少。同时，在每个异种移植小鼠模型中还观察到肿瘤生长的强有力抑制。 因此，这些结果验证了ephrinB2是肿瘤血管发生和淋巴管生成中的一个潜在的治疗靶点，表明该研究中开发的ephrinB2特异性抗体可能适合作为先导开发出新的改善的抗血管生成治疗，从而单独或作为其他公认抗血管生成疗法的补充或是协同应用于癌症或其他血管生成相关的疾病。【Blood. 2012 May 10;119(19):4565-76】 ? Cancer Treat Rev.?2014 May;40(4):548-57. doi: 10.1016/j.ctrv.2013.11.009. Epub 2013 Dec 6. Antiangiogenesis?beyond?VEGF?inhibition: a?journey?from?antiangiogenic?single-target?to?broad-spectrum?agents. Mechanisms of angiogenesis inhibition by single-target, multi-target and broad spectrum agents. Single-targets agents, like the monoclonal antibody bevacizumab,inhibit angiogenesis by blocking the interaction between the ligand (e.g., VEGF) and receptor (e.g., VEGFR). Multi-target agents, like tyrosine kinase inhibitors (e.g., axitinib),act through direct competition with ATP or by stabilizing the inactive conformation of the kinase domain, thus blocking the angiogenic signaling downstream the receptor.Tyrosine kinase inhibitors are usually able to block more than one growth factor receptor due to the degree of conservation among the kinase domains. By inhibiting thePDGFR in pericytes, axitinib may also block pericyte recruitment by angiogenic endothelial cells. Broad-spectrum receptors, like endostatin, inhibit several pathways in theangiogenic endothelial cell: besides blocking the signaling of angiogenic factors, endostatin upregulates the expression of anti-angiogenic genes, such as thrombospondin-1,and downregulates many signaling pathways associated with proangiogenic activity, significantly reducing the expression of HIF1-a. It was shown that endostatin affects themigratory