title: Non-invasive monitoring of tumor-vessel infarction by retargeted truncated tissue factor tTF-NGR using multi-modal imaging.
abstract: The fusion protein tTF-NGR consists of the extracellular domain of the thrombogenic human tissue factor (truncated tissue factor, tTF) and the peptide GNGRAHA (NGR), a ligand of the surface protein CD13 (aminopeptidase N), upregulated on endothelial cells of tumor vessels. tTF-NGR preferentially activates blood coagulation within tumor vasculature, resulting in tumor vessel infarction and subsequent tumor growth retardation/regression. The anti-vascular mechanism of the tTF-NGR therapy approach was verified by quantifying the reduced tumor blood-perfusion with contrast-enhanced ultrasound, the reduced relative tumor blood volume by ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging, and by in vivo-evaluation of hemorrhagic bleeding with fluorescent biomarkers (AngioSense(680)) in fluorescence reflectance imaging. The accumulation of tTF-NGR within the tumor was proven by visualizing the distribution of the iodine-123-labelled protein by single-photon emission computed tomography. Use of these multi-modal vascular and molecular imaging tools helped to assess the therapeutic effect even at real time and to detect non-responding tumors directly after the first tTF-NGR treatment. This emphasizes the importance of imaging within clinical studies with tTF-NGR. The imaging techniques as used here have applicability within a wider scope of therapeutic regimes interfering with tumor vasculature. Some even are useful to obtain predictive biosignals in personalized cancer treatment.
authors.affiliation: Department of Clinical Radiology, University of Muenster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Persigehl
authors.forename: Janine
authors.initials: J
authors.lastname: Ring
authors.forename: Christoph
authors.initials: C
authors.lastname: Bremer
authors.forename: Walter
authors.initials: W
authors.lastname: Heindel
authors.forename: Richard
authors.initials: R
authors.lastname: Holtmeier
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Michael
authors.initials: M
authors.lastname: Claesener
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Caroline
authors.initials: C
authors.lastname: Zerbst
authors.forename: Christoph
authors.initials: C
authors.lastname: Schliemann
authors.forename: Rolf M
authors.initials: RM
authors.lastname: Mesters
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Christian
authors.initials: C
authors.lastname: Schwöppe
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007238:Infarction / Q000139:chemically induced / Q000000981:diagnostic imaging; D018810:Magnetic Resonance Angiography; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000000981:diagnostic imaging / Q000188:drug therapy; D011859:Radiography; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D013925:Thromboplastin / Q000235:genetics / Q000494:pharmacology*; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; D013925:Thromboplastin