Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors.
A few peptide residues in structurally important locations often determine biological functions of proteins implicated in the regulation of angiogenesis. We have shown recently that the short COOH-terminal segment PF-4(47-70) derived from platelet factor 4 (PF-4) is the smallest sequence that conserves potent antiangiogenic activity in vitro and in vivo. Here we show that modified COOH-terminal PF-4 peptides containing the sequence ELR (or related DLR), a critical domain present in proangiogenic chemokines, surprisingly elicit several times greater antiangiogenic potential than the original peptide. The modified peptides inhibit binding of iodinated vascular endothelial growth factor and fibroblast growth factor 2 to endothelial cell receptors, endothelial cell proliferation, migration, and microvessel assembly in the rat aortic ring model at lower doses than PF-4(47-70). On the differentiated chick chorioallantoic membrane, topical application of 40 micro g of modified peptides potently reduces capillary angiogenesis induced by vascular endothelial growth factor(165), a dose where peptide PF-4(47-70) was inactive. Established intracranial glioma in nude mice decreased significantly in size when treated locally with a total dose of 250 micro g of peptide PF-4(47-70)DLR (n = 10) compared with the same dose of the original PF-4(47-70) peptide (n = 10) or controls (n = 30). Tailored PF-4 peptides represent a new class of antiangiogenic agents with a defined mode of action and a strong in vivo activity.
Hagedorn
Martin
M
Institut National de la Santé et de la Recherche Médicale EMI 0113 Molecular Mechanisms of Angiogenesis, Université de Bordeaux I, 33405 Talence, France.
Zilberberg
Lior
L
Wilting
Jörg
J
Canron
Xavier
X
Carrabba
Giorgio
G
Giussani
Carlo
C
Pluderi
Mauro
M
Bello
Lorenzo
L
Bikfalvi
Andreas
A
D000482:Allantois / Q000098:blood supply; D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000254:growth & development; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010978:Platelet Factor 4 / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C423562:platelet factor 4 (47-70); D016222:Fibroblast Growth Factor 2; D010978:Platelet Factor 4