Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides: activity and toxicity profile
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 fo...
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| Hauptverfasser: | , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
December 1, 2010
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| In: |
International journal of oncology
Year: 2010, Jahrgang: 37, Heft: 6, Pages: 1389-1397 |
| ISSN: | 1791-2423 |
| DOI: | 10.3892/ijo_00000790 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3892/ijo_00000790 Verlag, lizenzpflichtig, Volltext: https://www.spandidos-publications.com/10.3892/ijo_00000790 
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| Verfasserangaben: | Johannes Dreischalück, Christian Schwöppe, Tilmann Spieker, Torsten Kessler, Klaus Tiemann, Ruediger Liersch, Christoph Schliemann, Michael Kreuter, Astrid Kolkmeyer, Heike Hintelmann, Rolf M. Mesters and Wolfgang E. Berdel |
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| 245 | 1 | 0 | |a Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides |b activity and toxicity profile |c Johannes Dreischalück, Christian Schwöppe, Tilmann Spieker, Torsten Kessler, Klaus Tiemann, Ruediger Liersch, Christoph Schliemann, Michael Kreuter, Astrid Kolkmeyer, Heike Hintelmann, Rolf M. Mesters and Wolfgang E. Berdel |
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| 520 | |a 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. | ||
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