Open Access

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

  • Authors:
    • Johannes Dreischalück
    • Christian Schwöppe
    • Tilmann Spieker
    • Torsten Kessler
    • Klaus Tiemann
    • Ruediger Liersch
    • Christoph Schliemann
    • Michael Kreuter
    • Astrid Kolkmeyer
    • Heike Hintelmann
    • Rolf M. Mesters
    • Wolfgang E. Berdel
  • View Affiliations

  • Published online on: December 1, 2010     https://doi.org/10.3892/ijo_00000790
  • Pages: 1389-1397
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Abstract

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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December 2010
Volume 37 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Dreischalück J, Schwöppe C, Spieker T, Kessler T, Tiemann K, Liersch R, Schliemann C, Kreuter M, Kolkmeyer A, Hintelmann H, Hintelmann H, et al: Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides: Activity and toxicity profile. Int J Oncol 37: 1389-1397, 2010.
APA
Dreischalück, J., Schwöppe, C., Spieker, T., Kessler, T., Tiemann, K., Liersch, R. ... Berdel, W.E. (2010). Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides: Activity and toxicity profile. International Journal of Oncology, 37, 1389-1397. https://doi.org/10.3892/ijo_00000790
MLA
Dreischalück, J., Schwöppe, C., Spieker, T., Kessler, T., Tiemann, K., Liersch, R., Schliemann, C., Kreuter, M., Kolkmeyer, A., Hintelmann, H., Mesters, R. M., Berdel, W. E."Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides: Activity and toxicity profile". International Journal of Oncology 37.6 (2010): 1389-1397.
Chicago
Dreischalück, J., Schwöppe, C., Spieker, T., Kessler, T., Tiemann, K., Liersch, R., Schliemann, C., Kreuter, M., Kolkmeyer, A., Hintelmann, H., Mesters, R. M., Berdel, W. E."Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides: Activity and toxicity profile". International Journal of Oncology 37, no. 6 (2010): 1389-1397. https://doi.org/10.3892/ijo_00000790