Vascular infarction by subcutaneous application of tissue factor targeted to tumor vessels with NGR-peptides: activity and toxicity profile.
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.
Department of Medicine A, University of Muenster, D-48129 Muenster, Germany.
Johannes
J
Dreischalück
Christian
C
Schwöppe
Tilmann
T
Spieker
Torsten
T
Kessler
Klaus
K
Tiemann
Ruediger
R
Liersch
Christoph
C
Schliemann
Michael
M
Kreuter
Astrid
A
Kolkmeyer
Heike
H
Hintelmann
Rolf M
RM
Mesters
Wolfgang E
WE
Berdel
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007238:Infarction / Q000139:chemically induced*; D007279:Injections, Subcutaneous; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D009842:Oligopeptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D013925:Thromboplastin / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; C526428:NGR peptide; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; D013925:Thromboplastin