Infarction of tumor vessels by NGR-peptide-directed targeting of tissue factor: experimental results and first-in-man experience.
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 alpha(v)beta(3) (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 histologic analysis. tTF-NGR, but not untargeted tTF, induced significant tumor growth retardation or regression in all 3 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 decreased 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.
Bieker
Ralf
R
Departments of Medicine/Hematology and Oncology, University of Muenster, Germany.
Kessler
Torsten
T
Schwöppe
Christian
C
Padró
Teresa
T
Persigehl
Thorsten
T
Bremer
Christoph
C
Dreischalück
Johannes
J
Kolkmeyer
Astrid
A
Heindel
Walter
W
Mesters
Rolf M
RM
Berdel
Wolfgang E
WE
D000328:Adult; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods; D004617:Embolism / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009842:Oligopeptides / Q000378:metabolism / Q000627:therapeutic use*; D016879:Salvage Therapy; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; C526428:NGR peptide; D009842:Oligopeptides; D013925:Thromboplastin