Purpose: Endostatin, a peptide derived from proteolysis of collagen XVIII, is an endogenous inhibitor of angiogenesis and tumor growth. We have synthesized five peptide fragments designed to cover the whole length of the endostatin molecule (containing 40–50 amino acids each) with the aim of exploring the possibility that a specific sequence within the molecule might be responsible for its antiangiogenic effects. Experimental Design: The five peptide sequences, termed fragments I, II, III, IV, and IVox, the latter bearing the original disulfide bond Cys135-Cys165, were investigated for their effects on cultured endothelial cells, on enzyme activities related to angiogenesis, on tube formation in threedimensional gel matrices, in vivo in the avascular rabbit cornea assay, and in an experimental tumor burden paradigm. Results: Both the fragment covering the COOH-terminal endostatin region, fragment IV, and particularly fragment IVox, retained the angioinhibitory effects of endostatin. Fragment IVox strongly inhibited endothelial cell migration and proliferation, in vitro tube formation, and in vivo angiogenesis, displaying a potency comparable with that of endostatin. When tested in vivo on tumor growth, fragment IVox demonstrated to be more effective than fulllength endostatin. Unexpectedly, fragment III exhibited proangiogenic activity, increasing endothelial cell migration, producing neovascularization to an extent similar to that of vascular endothelial growth factor, and enhancing the angiogenic response to vascular endothelial growth factor in the cornea assay. Peptides encompassing the NH2-terminal region of endostatin (fragments I and II) had negligible effects on angiogenesis. Conclusions: In view of these results, which show strikingly distinct profiles of endostatin fragments, we propose that the amino acid sequence of endostatin contains both angiosuppressive and angiostimulatory domains.
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|Titolo:||Angiosuppressive and angiostimulatory effects exerted by synthetic partial sequences of endostatin|
|Citazione:||Morbidelli, L., Donnini, S., F., C., A., G., & Ziche, M. (2003). Angiosuppressive and angiostimulatory effects exerted by synthetic partial sequences of endostatin. CLINICAL CANCER RESEARCH, 9(14), 5358-5369.|
|Appare nelle tipologie:||1.1 Articolo in rivista|