Buchumschlag

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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Hauptverfasser: Dreischalück, Johannes (VerfasserIn) , Schwöppe, Christian (VerfasserIn) , Spieker, Tilmann (VerfasserIn) , Kessler, Torsten (VerfasserIn) , Tiemann, Klaus (VerfasserIn) , Liersch, Ruediger (VerfasserIn) , Schliemann, Christoph (VerfasserIn) , Kreuter, Michael (VerfasserIn) , Kolkmeyer, Astrid (VerfasserIn) , Hintelmann, Heike (VerfasserIn) , Mesters, Rolf M. (VerfasserIn) , Berdel, Wolfgang E. (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: December 1, 2010
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
Volltext
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
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 16.02.2023
Beschreibung:Online Resource
ISSN:1791-2423
DOI:10.3892/ijo_00000790

Ähnliche Einträge