Urokinase receptor antagonists inhibit angiogenesis and primary tumor growth in syngeneic mice.
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.
Min
H Y
HY
Chiron Corporation, Emeryville, California 94608, USA.
Doyle
L V
LV
Vitt
C R
CR
Zandonella
C L
CL
Stratton-Thomas
J R
JR
Shuman
M A
MA
Rosenberg
S
S
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003094:Collagen; D018076:DNA, Complementary / Q000235:genetics; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D000939:Epitopes / Q000737:chemistry / Q000235:genetics; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005803:Genes, Immunoglobulin; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics; D007797:Laminin; D008222:Lymphokines / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D017924:Nucleopolyhedroviruses / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D011509:Proteoglycans; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D018076:DNA, Complementary; D004338:Drug Combinations; D016228:Endothelial Growth Factors; D000939:Epitopes; D007074:Immunoglobulin G; D007797:Laminin; D008222:Lymphokines; C524898:PLAUR protein, human; D010446:Peptide Fragments; C524899:Plaur protein, mouse; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D003094:Collagen; D014568:Urokinase-Type Plasminogen Activator