Inhibition of Tumor Growth by RGD Peptide–Directed Delivery of Truncated Tissue Factor to the Tumor Vasculature

• Published in: Clinical cancer research Vol. 11; no. 17; pp. 6317 - 6324
• Main Authors: KESSLER, Torsten, BIEKER, Ralf, PADRO, Teresa, SCHWÖPPE, Christian, PERSIGEHL, Thorsten, BREMER, Christoph, KREUTER, Michael, BERDEL, Wolfgang E, MESTERS, Rolf M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2005
• Subjects: Angiogenesis; Animals; Antineoplastic agents; Biological and medical sciences; Blood Flow Velocity; cancer; coaguligands; Endothelium, Vascular - metabolism; General aspects; Humans; Immunoenzyme Techniques; Integrin alphaVbeta3 - metabolism; integrins; Magnetic Resonance Imaging; Male; Medical sciences; metastasis; Mice; Mice, Inbred BALB C; Neoplasms, Experimental - blood supply; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Neovascularization, Pathologic - drug therapy; Oligopeptides - metabolism; Oligopeptides - therapeutic use; Pharmacology. Drug treatments; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - therapeutic use; Thromboplastin - genetics; Thromboplastin - metabolism; Thromboplastin - therapeutic use; tissue factor; tumor-homing peptides; vascular targeting; Antineoplastic agent; Targeting; RGD peptide; Tissue factor; Cardiovascular disease; Malignant tumor; Thrombosis; Vascularization; Vascular disease; Integrin; Tumor growth; Inhibitor; Inhibition; Fusion protein
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0389

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 α 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.