Infarction of tumor vessels by NGR-peptide-directed targeting of tissue factor: experimental results and first-in-man experience
Infarction of tumor vessels by NGR-peptide-directed targeting of tissue factor: experimental results and first-in-man experience
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DOI：
10.1182/blood-2008-04-150318
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发表时间：
2009-05-14
期刊：
影响因子：
20.3
通讯作者：
Berdel, Wolfgang E.
中科院分区：
文献类型：
--
作者：
Bieker, Ralf;Kessler, Torsten;Berdel, Wolfgang E.
我们通过由组织因子的胞外结构域（截短的组织因子，tTF）和肽GNGRAHA组成的融合蛋白诱导小鼠实体瘤中的血管血栓形成，所述肽GNGRAHA靶向肿瘤血管内皮上的氨肽酶N（CD 13）和整合素α（v）β（3）（CD 51/CD 61）。所设计的融合蛋白tTF-NGR保留了其凝血活性，如凝血试验所示。在具有已建立的人腺癌（A549）、黑色素瘤（M21）和纤维肉瘤（HT 1080）的小鼠中的体内研究显示，全身施用tTF-NGR诱导肿瘤血管的部分或完全血栓闭塞，如组织学分析所示。tTF-NGR，而非非靶向tTF，在所有3种类型的实体瘤中诱导显著的肿瘤生长迟缓或消退。对比增强磁共振成像（MRI）也显示了tTF-NGR在肿瘤血管中诱导血栓形成。在人纤维肉瘤异种移植模型中，MRI显示通过施用tTF-NGR显著减少肿瘤灌注。低剂量的这种靶向凝血因子的临床首次人体应用显示了良好的耐受性和通过MRI测量的肿瘤灌注减少。tTF-NGR在肿瘤血管系统中诱导靶向血栓形成可能是治疗癌症的有希望的策略。（血。2009; 113：5019-5027）
We induced thrombosis of blood vessels in solid tumors in mice by a fusion protein consisting of the extracellular domain of tissue factor (truncated tissue factor, tTF) and the peptide GNGRAHA, targeting aminopeptidase N (CD13) and the integrin alpha(v)beta(3) (CD51/CD61) on tumor vascular endothelium. The designed fusion protein tTF-NGR retained its thrombogenic activity as demonstrated by coagulation assays. In vivo studies in mice bearing established human adenocarcinoma (A549), melanoma (M21), and fibrosarcoma (HT1080) revealed that systemic administration of tTF-NGR induced partial or complete thrombotic occlusion of tumor vessels as shown by histologic analysis. tTF-NGR, but not untargeted tTF, induced significant tumor growth retardation or regression in all 3 types of solid tumors. Thrombosis induction in tumor vessels by tTF-NGR was also shown by contrast enhanced magnetic resonance imaging (MRI). In the human fibrosarcoma xenograft model, MRI revealed a significant reduction of tumor perfusion by administration of tTF-NGR. Clinical first-in-man application of low dosages of this targeted coagulation factor revealed good tolerability and decreased tumor perfusion as measured by MRI. Targeted thrombosis in the tumor vasculature induced by tTF-NGR may be a promising strategy for the treatment of cancer. (Blood. 2009; 113: 5019-5027)