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Domain Swapping in a COOH-terminal Fragment of Platelet Factor 4 Generates Potent Angiogenesis Inhibitors¹

Institut National de la Santé et de la Recherche Médicale EMI 0113 Molecular Mechanisms of Angiogenesis, Université de Bordeaux I, 33405 Talence, France [M. H., L. Z., X. C., A. B.]; Department of Neurosurgery, Department of Neurological Sciences, University of Milano, Ospedale Maggiore Policlinico, Istituto di Ricovero e Cura a Carattere Scientifico, 20122 Milan, Italy [G. C., C. G., M. P., L. B.]; and Universitätskinderklinik Göttingen, Abteilung Pädiatrie I, 37570 Göttingen, Germany [J. W.]

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 µg of modified peptides potently reduces capillary angiogenesis induced by vascular endothelial growth factor₁₆₅, 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 µg of peptide PF-4^47–70DLR (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.

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