title: Anticancer therapy by tumor vessel infarction with polyethylene glycol conjugated retargeted tissue factor.
abstract: tTF-NGR consists of the extracellular domain of tissue factor and the peptide GNGRAHA, a ligand of the surface protein aminopeptidase N and of integrin αvβ3. Both surface proteins are upregulated on endothelial cells of tumor vessels. tTF-NGR shows antitumor activity in xenografts and inhibition of tumor blood flow in cancer patients. We performed random TMS(PEG)12 PEGylation of tTF-NGR to improve the antitumor profile of the molecule. PEGylation resulted in an approximately 2-log step decreased procoagulatory activity of the molecule. Pharmacokinetic studies in mice showed a more than 1-log step higher mean area under the curve. Comparison of the LD10 values for both compounds and their lowest effective antitumor dose against human tumor xenografts showed an improved therapeutic range (active/toxic dose in mg/kg body weight) of 1/5 mg/kg for tTF-NGR and 3/>160 mg/kg for TMS(PEG)12 tTF-NGR. Results demonstrate that PEGylation can significantly improve the therapeutic range of tTF-NGR.
authors.affiliation: Department of Medicine A, Hematology, Oncology and Pneumology, University of Muenster , Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany. christian.schwoeppe@uni-muenster.de
authors.forename: Christian
authors.initials: C
authors.lastname: Schwöppe
authors.forename: Caroline
authors.initials: C
authors.lastname: Zerbst
authors.forename: Max
authors.initials: M
authors.lastname: Fröhlich
authors.forename: Christoph
authors.initials: C
authors.lastname: Schliemann
authors.forename: Torsten
authors.initials: T
authors.lastname: Kessler
authors.forename: Ruediger
authors.initials: R
authors.lastname: Liersch
authors.forename: Laura
authors.initials: L
authors.lastname: Overkamp
authors.forename: Richard
authors.initials: R
authors.lastname: Holtmeier
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.forename: Alena
authors.initials: A
authors.lastname: Dreiling
authors.forename: Simone
authors.initials: S
authors.lastname: König
authors.forename: Carsten
authors.initials: C
authors.lastname: Höltke
authors.forename: Martin
authors.initials: M
authors.lastname: Lücke
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Rolf M
authors.initials: RM
authors.lastname: Mesters
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011487:Protein Conformation; D013925:Thromboplastin / Q000737:chemistry / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C526428:NGR peptide; D009842:Oligopeptides; D011092:Polyethylene Glycols; D013925:Thromboplastin