Infarction of tumor vessels by NGR-peptide directed targeting of tissue factor. Experimental results and first-in-man experience.
2009, Blood. 2009 Jan 28. [Epub ahead of print]
Bieker R, Kessler T, Schwoppe C, Padro T, Persigehl T, Bremer C, Dreischaluck J, Kolkmeyer A, Heindel W, Mesters RM, Berdel WE.
Autors del centre relacionats: Padró Teresa.
Bieker R, Kessler T, Schwoppe C, Padro T, Persigehl T, Bremer C, Dreischaluck J, Kolkmeyer A, Heindel W, Mesters RM, Berdel WE.
Autors del centre relacionats: Padró Teresa.
Department of Medicine / Hematology and Oncology, University of Muenster, Muenster, Germany.
We induced thrombosis of blood vessels in solid tumors in mice by a fusion protein consisting of the extracellular domain of tissue factor (truncated tissue factor, tTF) and the peptide GNGRAHA, targeting aminopeptidase N (CD13) and the integrin alphavbeta3 (CD51/CD61) on tumor vascular endothelium. The designed fusion protein tTF-NGR retained its thrombogenic activity as demonstrated by coagulation assays. In vivo studies in mice bearing established human adenocarcinoma (A549), melanoma (M21) and fibrosarcoma (HT1080) revealed that systemic administration of tTF-NGR induced partial or complete thrombotic occlusion of tumor vessels as shown by histological analysis. tTF-NGR but not untargeted tTF induced significant tumor growth retardation or regression in all three types of solid tumors. Thrombosis induction in tumor vessels by tTF-NGR was also shown by contrast enhanced magnetic resonance imaging (MRI). In the human fibrosarcoma xenograft model MRI revealed a significant reduction of tumor perfusion by administration of tTF-NGR. Clinical first-in-man application of low dosages of this targeted coagulation factor revealed good tolerability and decrease of tumor perfusion as measured by MRI. Targeted thrombosis in the tumor vasculature induced by tTF-NGR may be a promising strategy for the treatment of cancer.
We induced thrombosis of blood vessels in solid tumors in mice by a fusion protein consisting of the extracellular domain of tissue factor (truncated tissue factor, tTF) and the peptide GNGRAHA, targeting aminopeptidase N (CD13) and the integrin alphavbeta3 (CD51/CD61) on tumor vascular endothelium. The designed fusion protein tTF-NGR retained its thrombogenic activity as demonstrated by coagulation assays. In vivo studies in mice bearing established human adenocarcinoma (A549), melanoma (M21) and fibrosarcoma (HT1080) revealed that systemic administration of tTF-NGR induced partial or complete thrombotic occlusion of tumor vessels as shown by histological analysis. tTF-NGR but not untargeted tTF induced significant tumor growth retardation or regression in all three types of solid tumors. Thrombosis induction in tumor vessels by tTF-NGR was also shown by contrast enhanced magnetic resonance imaging (MRI). In the human fibrosarcoma xenograft model MRI revealed a significant reduction of tumor perfusion by administration of tTF-NGR. Clinical first-in-man application of low dosages of this targeted coagulation factor revealed good tolerability and decrease of tumor perfusion as measured by MRI. Targeted thrombosis in the tumor vasculature induced by tTF-NGR may be a promising strategy for the treatment of cancer.
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