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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
11
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pubmed:dateCreated |
2005-11-8
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pubmed:abstractText |
The aim of the present study was to identify specific alpha(v)beta3/alpha(v)beta5 integrin antagonists active on tumor-induced angiogenesis. To this purpose, in vitro integrin-binding assays were used to screen a library of conformationally constrained bicyclic lactam Arg-Gly-Asp-containing pseudopeptides. The results identified ST1646 as a high-affinity specific ligand for alpha(v)beta3 and alpha(v)beta5 integrins with negligible interacting with alpha5beta1 integrin. In all the assays, ST1646 was equipotent to or more potent than the well-characterized integrin antagonists c(RGDfV) and cyclo(Arg-Gly-Asp-d-Phe-[NMe]Val) (EMD121974). In the chorioallantoic membrane assay, topical administration of ST1646 was able to prevent the angiogenic responses elicited by recombinant fibroblast growth factor-2 or vascular endothelial growth factor. In addition, systemic administration of ST1646 in mice exerted a significant antiangiogenic activity on neovascularization triggered by mammary carcinoma MDA-MB435 cells implanted s.c. in a dorsal air sac via a (Millipore Filter Corporation, Bedford, MA) chamber. Moreover, ST1646 delivery via an osmotic pump inhibited the growth and vascularization of tumor xenografts originating from the injection of alpha(v)beta3/alpha(v)beta5-expressing human ovarian carcinoma cells in nude mice. In agreement with the biochemical and pharmacologic studies, Monte Carlo/Stochastic Dynamics simulation showed that the bicyclic scaffold in ST1646 forced the compound to assume a preferred conformation superimposable to the X-ray conformation of alpha(v)beta3-bound EMD121974. Accordingly, computer-docking studies indicated that the ST1646-alpha(v)beta3 integrin complex maintains the ligand-receptor distances and interactions observed in the crystalline EMD121974-alpha(v)beta3 integrin complex. Taken together, these observations indicate that ST1646 represents a dual alpha(v)beta3/alpha(v)beta5 integrin antagonist with interesting biochemical and biological features to be tested in cancer therapy.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Arginine,
http://linkedlifedata.com/resource/pubmed/chemical/Aspartic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Fibroblast Growth Factor 2,
http://linkedlifedata.com/resource/pubmed/chemical/Glycine,
http://linkedlifedata.com/resource/pubmed/chemical/Integrin alphaVbeta3,
http://linkedlifedata.com/resource/pubmed/chemical/Integrins,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Oligopeptides,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides, Cyclic,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Vitronectin,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Vascular Endothelial Growth Factor A,
http://linkedlifedata.com/resource/pubmed/chemical/Vitronectin,
http://linkedlifedata.com/resource/pubmed/chemical/arginyl-glycyl-aspartic acid,
http://linkedlifedata.com/resource/pubmed/chemical/integrin alphaVbeta5
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
1535-7163
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pubmed:author |
pubmed-author:BelvisiLauraL,
pubmed-author:CarminatiPaoloP,
pubmed-author:ChiarucciIlariaI,
pubmed-author:CiucciAlessandroA,
pubmed-author:EfratiDanielaD,
pubmed-author:GianniniGiuseppeG,
pubmed-author:LombardoKatiaK,
pubmed-author:ManzoniLeonardoL,
pubmed-author:MarcelliniMarcellaM,
pubmed-author:NicoBeatriceB,
pubmed-author:OrlandiAugustoA,
pubmed-author:PisanoClaudioC,
pubmed-author:PotenzaDonatellaD,
pubmed-author:PrestaMarcoM,
pubmed-author:RibattiDomenicoD,
pubmed-author:RiccioniTeresaT,
pubmed-author:ScolasticoCarloC,
pubmed-author:StasiM AntoniettaMA,
pubmed-author:VesciLoredanaL
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pubmed:issnType |
Print
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pubmed:volume |
4
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1670-80
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:16275988-Animals,
pubmed-meshheading:16275988-Antineoplastic Agents,
pubmed-meshheading:16275988-Arginine,
pubmed-meshheading:16275988-Aspartic Acid,
pubmed-meshheading:16275988-Cattle,
pubmed-meshheading:16275988-Cell Adhesion,
pubmed-meshheading:16275988-Cell Line, Tumor,
pubmed-meshheading:16275988-Cell Proliferation,
pubmed-meshheading:16275988-Chickens,
pubmed-meshheading:16275988-Crystallography, X-Ray,
pubmed-meshheading:16275988-Dose-Response Relationship, Drug,
pubmed-meshheading:16275988-Endothelium, Vascular,
pubmed-meshheading:16275988-Fibroblast Growth Factor 2,
pubmed-meshheading:16275988-Glycine,
pubmed-meshheading:16275988-Guinea Pigs,
pubmed-meshheading:16275988-Humans,
pubmed-meshheading:16275988-Inhibitory Concentration 50,
pubmed-meshheading:16275988-Integrin alphaVbeta3,
pubmed-meshheading:16275988-Integrins,
pubmed-meshheading:16275988-Ligands,
pubmed-meshheading:16275988-Mice,
pubmed-meshheading:16275988-Mice, Nude,
pubmed-meshheading:16275988-Microcirculation,
pubmed-meshheading:16275988-Models, Chemical,
pubmed-meshheading:16275988-Models, Molecular,
pubmed-meshheading:16275988-Molecular Conformation,
pubmed-meshheading:16275988-Monte Carlo Method,
pubmed-meshheading:16275988-Neoplasm Transplantation,
pubmed-meshheading:16275988-Neovascularization, Pathologic,
pubmed-meshheading:16275988-Oligopeptides,
pubmed-meshheading:16275988-Peptides, Cyclic,
pubmed-meshheading:16275988-Platelet Aggregation,
pubmed-meshheading:16275988-Protein Binding,
pubmed-meshheading:16275988-Protein Conformation,
pubmed-meshheading:16275988-Receptors, Vitronectin,
pubmed-meshheading:16275988-Recombinant Proteins,
pubmed-meshheading:16275988-Stochastic Processes,
pubmed-meshheading:16275988-Vascular Endothelial Growth Factor A,
pubmed-meshheading:16275988-Vitronectin
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pubmed:year |
2005
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pubmed:articleTitle |
Biological and molecular properties of a new alpha(v)beta3/alpha(v)beta5 integrin antagonist.
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