title: A peptide derived from TIMP-3 inhibits multiple angiogenic growth factor receptors and tumour growth and inflammatory arthritis in mice.
abstract: The binding of vascular endothelial growth factor (VEGF) to VEGF receptor-2 (VEGFR-2) on the surface of vascular endothelial cells stimulates many steps in the angiogenic pathway. Inhibition of this interaction is proving of value in moderating the neovascularization accompanying age-related macular degeneration and in the treatment of cancer. Tissue inhibitor of metalloproteinases-3 (TIMP-3) has been shown to be a natural VEGFR-2 specific antagonist-an activity that is independent of its ability to inhibit metalloproteinases. In this investigation we localize this activity to the C-terminal domain of the TIMP-3 molecule and characterize a short peptide, corresponding to part of this domain, that not only inhibits all three VEGF-family receptors, but also fibroblast growth factor and platelet-derived growth factor receptors. This multiple-receptor inhibition may explain why the peptide was also seen to be a powerful inhibitor of tumour growth and also a partial inhibitor of arthritic joint inflammation in vivo.
authors.affiliation: Department of Oncology, Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.
authors.forename: Yung-Yi
authors.initials: YY
authors.lastname: Chen
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Brown
authors.forename: Rita
authors.initials: R
authors.lastname: Jones
authors.forename: Claire E
authors.initials: CE
authors.lastname: Lewis
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Mujamammi
authors.forename: Munitta
authors.initials: M
authors.lastname: Muthana
authors.forename: Michael P
authors.initials: MP
authors.lastname: Seed
authors.forename: Michael D
authors.initials: MD
authors.lastname: Barker
mesh_terms: D000818:Animals; D001168:Arthritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008268:Macular Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000737:chemistry / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010455:Peptides; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2