Department of Medicine A, University of Muenster, D-48129 Muenster, Germany.
Int J Oncol. 2010 Dec;37(6):1389-97. doi: 10.3892/ijo_00000790.
tTF-NGR consists of the extracellular domain of the (truncated) tissue factor (tTF), a central molecule for coagulation in vivo, and the peptide GNGRAHA (NGR), a ligand of the surface protein aminopeptidase N (CD13). After deamidation of the NGR-peptide moiety, the fusion protein is also a ligand for integrin αvβ3 (CD51/CD61). Both surface proteins are upregulated on endothelial cells of tumor vessels. tTF-NGR showed binding to specific binding sites on endothelial cells in vitro as shown by flow cytometry. Subcutaneous injection of tTF-NGR into athymic mice bearing human HT1080 fibrosarcoma tumors induced tumor growth retardation and delay. Contrast enhanced ultrasound detected a decrease in tumor blood flow in vivo after application of tTF-NGR. Histological analysis of the tumors revealed vascular disruption due to blood pooling and thrombotic occlusion of tumor vessels. Furthermore, a lack of resistance was shown by re-exposure of tumor-bearing mice to tTF-NGR after regrowth following a first cycle of treatment. However, after subcutaneous (s.c.) push injection with therapeutic doses (1-5 mg/kg bw) side effects have been observed, such as skin bleeding and reduced performance. Since lethality started within the therapeutic dose range (LD10 approximately 2 mg/kg bw) no safe therapeutic window could be found. Limiting toxicity was represented by thrombo-embolic events in major organ systems as demonstrated by histology. Thus, subcutaneous injection of tTF-NGR represents an active, but toxic application procedure and compares unfavourably to intravenous infusion.
tTF-NGR 由组织因子（tTF）的细胞外结构域和肽 GNGRAHA（NGR）组成，tTF 是体内凝血的核心分子，NGR 是表面蛋白氨肽酶 N（CD13）的配体。NGR-肽部分脱酰胺后，融合蛋白也是整合素 αvβ3（CD51/CD61）的配体。两种表面蛋白在肿瘤血管的内皮细胞上均上调。如流式细胞术所示，tTF-NGR 在体外与内皮细胞的特异性结合位点结合。将 tTF-NGR 皮下注射到携带人 HT1080 纤维肉瘤肿瘤的无胸腺小鼠中，诱导肿瘤生长迟缓。应用 tTF-NGR 后，体内对比增强超声检测到肿瘤血流量减少。肿瘤的组织学分析显示，由于血液淤积和肿瘤血管血栓闭塞，血管破裂。此外，在第一次治疗周期后肿瘤重新生长时，再次暴露于 tTF-NGR 的荷瘤小鼠显示出缺乏耐药性。然而，在皮下（s.c.）推注治疗剂量（1-5mg/kg bw）后，观察到副作用，如皮肤出血和性能下降。由于致死性始于治疗剂量范围内（LD10 约为 2mg/kg bw），因此未找到安全的治疗窗。限制毒性由血栓栓塞事件在主要器官系统中表现出的组织学所代表。因此，tTF-NGR 的皮下注射是一种有效的，但有毒的应用程序，与静脉输注相比效果不佳。
