Urokinase receptor antagonists inhibit angiogenesis and primary tumor growth in syngeneic mice

• Published in: Cancer research (Chicago, Ill.) Vol. 56; no. 10; pp. 2428 - 2433
• Main Authors: HYE YEONG MIN, DOYLE, L. V, VITT, C. R, ZANDONELLA, C. L, STRATTON-THOMAS, J. R, SHUMAN, M. A, ROSENBERG, S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.05.1996
• Subjects: Amino Acid Sequence; Animals; Antineoplastic agents; Base Sequence; Biological and medical sciences; Cells, Cultured; Cloning, Molecular; Collagen; DNA, Complementary - genetics; Drug Combinations; Endothelial Growth Factors - pharmacology; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Epitopes - chemistry; Epitopes - genetics; Female; Fibroblast Growth Factor 2 - pharmacology; General aspects; Genes, Immunoglobulin; Humans; Immunoglobulin G - genetics; Laminin; Lymphokines - pharmacology; Medical sciences; Melanoma, Experimental - drug therapy; Melanoma, Experimental - pathology; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Neovascularization, Pathologic - drug therapy; Nucleopolyhedrovirus - genetics; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - therapeutic use; Pharmacology. Drug treatments; Proteoglycans; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - genetics; Receptors, Urokinase Plasminogen Activator; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - therapeutic use; Urokinase-Type Plasminogen Activator - biosynthesis; Urokinase-Type Plasminogen Activator - chemistry; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - therapeutic use; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Antineoplastic agent; Cell proliferation; u-Plasminogen activator; Serine endopeptidases; Enzyme; Rodentia; IgG; In vitro; Angiogenesis; In vivo; Vertebrata; Mammalia; Fc-Fragment; Mouse; Animal; Hydrolases; Antagonist; Inhibition; Neovascularization; Recombinant protein; Fusion protein; Proteinases; Biological receptor
• ISSN: 0008-5472; 1538-7445

Urokinase plasminogen activator (uPA) and its receptor are key components of a cell surface proteolytic cascade used by tumor cells and capillary endothelial cells for basement membrane invasion, a process required for metastasis and angiogenesis. We have cloned, expressed, and purified the epidermal growth factor-like domain of murine uPA alone and fused it to the Fc portion of human IgG as high-affinity murine urokinase receptor antagonists. These molecules are potent inhibitors of murine urokinase binding to its receptor and inhibit angiogenesis in an in vitro model of capillary tube formation in fibrin gels. In vivo, basic fibroblast growth factor-induced neovascularization and B16 melanoma growth in syngeneic mice are also substantially suppressed by these molecules. Coupled with previous studies showing inhibition of metastasis, these findings suggest that urokinase receptor antagonists may be useful therapeutically as inhibitors of tumor progression.