Inhibition of tumor growth by RGD peptide-directed delivery of truncated tissue factor to the tumor vasculature.
Selective activation of blood coagulation in tumor vessels with subsequent tumor infarction is a promising anticancer strategy. To this end, a fusion protein consisting of the extracellular domain of tissue factor [truncated tissue factor (tTF)] was fused to the peptide GRGDSP selectively targeting alpha(v)-integrins on tumor endothelial cells. tTF-RGD retained its thrombogenic and integrin-binding activity in vitro. In vivo studies in mice bearing human adenocarcinomas (CCL185), melanoma (M21), and fibrosarcoma (HT1080) revealed that i.v. administration of tTF-RGD induced thrombotic occlusion of tumor vessels resulting in tumor growth retardation or regression in all three types of solid tumors. No apparent side effects, such as thrombosis, in other organs or other treatment-related toxicities were observed. Reduced tumor blood flow in tTF-RGD-treated animals as determined by contrast-enhanced magnetic resonance imaging underlines the proposed mechanism. In conclusion, we consider RGD peptide-directed delivery of tTF as alternative to previously used antibody fusion proteins. Small peptide-directed delivery of coaguligands does not cause immunologic side effects and those caused by accumulation in the reticuloendothelial system. This is the first report to describe the induction of selective thrombosis in tumor vessels by RGD peptide-directed delivery of tTF, which may be a promising strategy for the treatment of cancer.
Kessler
Torsten
T
Department of Medicine/Hematology and Oncology, University of Muenster, Muenster, Germany.
Bieker
Ralf
R
Padró
Teresa
T
Schwöppe
Christian
C
Persigehl
Thorsten
T
Bremer
Christoph
C
Kreuter
Michael
M
Berdel
Wolfgang E
WE
Mesters
Rolf M
RM
D000818:Animals; D001783:Blood Flow Velocity; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009842:Oligopeptides / Q000378:metabolism / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000627:therapeutic use*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*
D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; C526680:tTF-RGD peptide; D013925:Thromboplastin; C058161:glycyl-arginyl-glycyl-aspartyl-seryl-proline