Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides: Activity and toxicity profile

• Published in: International journal of oncology Vol. 37; no. 6; pp. 1389 - 1397
• Main Authors: DREISCHALÜCK, Johannes, SCHWÖPPE, Christian, MESTERS, Rolf M, BERDEL, Wolfgang E, SPIEKER, Tilmann, KESSLER, Torsten, TIEMANN, Klaus, LIERSCH, Ruediger, SCHLIEMANN, Christoph, KREUTER, Michael, KOLKMEYER, Astrid, HINTELMANN, Heike
• Format: Journal Article
• Language: English
• Published: Athens Editorial Academy of the International Journal of Oncology 01.12.2010
• Subjects: Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - adverse effects; Animals; Biological and medical sciences; Blood Vessels - drug effects; Blood Vessels - pathology; Cell Line, Tumor; Cells, Cultured; Drug Delivery Systems - methods; Humans; Infarction - chemically induced; Injections, Subcutaneous; Medical sciences; Mice; Mice, Nude; Neoplasms - blood supply; Neoplasms - drug therapy; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Oligopeptides - administration & dosage; Oligopeptides - adverse effects; Oligopeptides - chemistry; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - adverse effects; Recombinant Fusion Proteins - chemistry; Thromboplastin - administration & dosage; Thromboplastin - adverse effects; Thromboplastin - chemistry; Tumors; Xenograft Model Antitumor Assays; Targeting; Infarct; Peptides; Subcutaneous; Toxicity; Tumoral tissue; Tissue factor; Malignant tumor; subcutaneous therapy; vascular targeting; truncated tissue factor; Biological activity; tumor-homing peptides; Cancerology; Treatment; Blood vessel; Truncated shape; Homing phenomenon; Circulatory system; Subcutaneous tissue; Cancer
• ISSN: 1019-6439; 1791-2423
• 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.