This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hagedorn, M. Articles by Bikfalvi, A. Search for Related Content PubMed PubMed Citation Articles by Hagedorn, M. Articles by Bikfalvi, A.

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.

This article has been cited by other articles:

				O. Benny, S.-K. Kim, K. Gvili, I. S. Radzishevsky, A. Mor, L. Verduzco, L. G. Menon, P. M. Black, M. Machluf, and R. S. Carroll In vivo fate and therapeutic efficacy of PF-4/CTF microspheres in an orthotopic human glioblastoma model FASEB J, February 1, 2008; 22(2): 488 - 499. [Abstract] [Full Text] [PDF]

				S. Struyf, M. D. Burdick, E. Peeters, K. Van den Broeck, C. Dillen, P. Proost, J. Van Damme, and R. M. Strieter Platelet Factor-4 Variant Chemokine CXCL4L1 Inhibits Melanoma and Lung Carcinoma Growth and Metastasis by Preventing Angiogenesis Cancer Res., June 15, 2007; 67(12): 5940 - 5948. [Abstract] [Full Text] [PDF]

				M. Kanamori, T. Kawaguchi, M. S. Berger, and R. O. Pieper Intracranial Microenvironment Reveals Independent Opposing Functions of Host {alpha}Vbeta3 Expression on Glioma Growth and Angiogenesis J. Biol. Chem., December 1, 2006; 281(48): 37256 - 37264. [Abstract] [Full Text] [PDF]

				T.-C. Liu, T. Zhang, H. Fukuhara, T. Kuroda, T. Todo, X. Canron, A. Bikfalvi, R. L. Martuza, A. Kurtz, and S. D. Rabkin Dominant-Negative Fibroblast Growth Factor Receptor Expression Enhances Antitumoral Potency of Oncolytic Herpes Simplex Virus in Neural Tumors. Clin. Cancer Res., November 15, 2006; 12(22): 6791 - 6799. [Abstract] [Full Text] [PDF]

				P. Nyberg, L. Xie, and R. Kalluri Endogenous Inhibitors of Angiogenesis Cancer Res., May 15, 2005; 65(10): 3967 - 3979. [Abstract] [Full Text] [PDF]

				T. A. Rege, C. Y. Fears, and C. L. Gladson Endogenous inhibitors of angiogenesis in malignant gliomas: Nature's antiangiogenic therapy Neuro-oncol, April 1, 2005; 7(2): 106 - 121. [Abstract] [PDF]

				M. Hagedorn, S. Javerzat, D. Gilges, A. Meyre, B. de Lafarge, A. Eichmann, and A. Bikfalvi Accessing key steps of human tumor progression in vivo by using an avian embryo model PNAS, February 1, 2005; 102(5): 1643 - 1648. [Abstract] [Full Text] [PDF]

				L. Bello, V. Lucini, F. Costa, M. Pluderi, C. Giussani, F. Acerbi, G. Carrabba, M. Pannacci, D. Caronzolo, S. Grosso, et al. Combinatorial Administration of Molecules That Simultaneously Inhibit Angiogenesis and Invasion Leads to Increased Therapeutic Efficacy in Mouse Models of Malignant Glioma Clin. Cancer Res., July 1, 2004; 10(13): 4527 - 4537. [Abstract] [Full Text] [PDF]

				L. Zilberberg, S. Shinkaruk, O. Lequin, B. Rousseau, M. Hagedorn, F. Costa, D. Caronzolo, M. Balke, X. Canron, O. Convert, et al. Structure and Inhibitory Effects on Angiogenesis and Tumor Development of a New Vascular Endothelial Growth Inhibitor J. Biol. Chem., September 12, 2003; 278(37): 35564 - 35573. [Abstract] [Full Text] [PDF]