Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701-9322, USA.
Biochem Pharmacol. 2011 Jan 1;81(1):6-12. doi: 10.1016/j.bcp.2010.09.023. Epub 2010 Oct 12.
The first generation of clinically useful antiangiogenic agents focused on VEGF and targets in the VEGF pathway. The strengths and limitations of these therapeutics are now clear. Some tumors do not respond to VEGF-directed therapies de novo and others become non-responsive or resistant over time by switching to other angiogenic pathways. The next generation of angiogenesis-directed therapeutics will expand the field beyond the VEGF pathway and become more disease selective. Placental growth factor, a protein closely related to VEGF, is induced as tumors lose responsiveness to VEGF-directed therapies. Angiopoietins 1 and 2 are being targeted with a unique peptibody, a human recombinant Fc constant region fused to peptides, in clinical trials. The HGF/c-Met pathway is upregulated in some tumors as an alternate angiogenic pathway. The CXCL12 (SDF-1)/CXCR4 pathway represents a stromal chemokine axis involved in tumor angiogenesis. CXCR2 is a G-protein coupled receptor with several ligands including interleukin-8 and other angiogenic cytokines and may represent a useful target for antiangiogenic agents. The notch pathway is being investigated as a target in the setting of tumor angiogenesis. Sphingosine-1-phosphate is a bioactive lipid that can be neutralized with a monoclonal antibody. The anti-S-1-P antibody is under investigation as an antiangiogenic agent. Finally, several multi-targeted kinase inhibitors each with a unique pattern of inhibitory potency are in clinical trial with a focus on antiangiogenic activity. The expansion of the scope of potential antiangiogenic agents in or entering clinical trial should allow the development of antiangiogenic combination regimens and single agents that address diseases refractory to VEGF-directed therapeutics.
第一代临床可用的抗血管生成药物集中在 VEGF 及其在 VEGF 通路中的靶点。这些治疗药物的优缺点现已明晰。一些肿瘤最初对 VEGF 靶向治疗无反应，而另一些肿瘤则会随着时间的推移通过切换到其他血管生成途径而变得无反应或耐药。下一代血管生成靶向治疗将扩大 VEGF 通路以外的领域，并变得更具疾病选择性。胎盘生长因子是一种与 VEGF 密切相关的蛋白，当肿瘤对 VEGF 靶向治疗失去反应时，其表达会被诱导。在临床试验中，一种独特的肽结合物（一种与人重组 Fc 恒定区融合的肽）被用于靶向血管生成素 1 和 2。在一些肿瘤中，HGF/c-Met 通路被上调作为替代血管生成途径。CXCL12（SDF-1）/CXCR4 通路代表了参与肿瘤血管生成的基质趋化因子轴。CXCR2 是一种 G 蛋白偶联受体，有几种配体，包括白细胞介素 8 和其他血管生成细胞因子，它可能是抗血管生成药物的一个有用靶点。在肿瘤血管生成的背景下， Notch 通路被作为一个靶点进行研究。鞘氨醇-1-磷酸是一种具有生物活性的脂质，可以用单克隆抗体中和。抗 S-1-P 抗体作为一种抗血管生成药物正在研究中。最后，几种多靶点激酶抑制剂，每种抑制剂的抑制效力都具有独特的模式，正在临床试验中进行研究，重点是抗血管生成活性。潜在抗血管生成药物的范围不断扩大，或进入临床试验，这应该允许开发抗血管生成联合方案和单一药物，以解决对 VEGF 靶向治疗耐药的疾病。
