The aim of the present study was to identify specific alpha(v)beta(3)/alpha(v)beta(5) 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 pseuclopeptides. The results identified ST1646 as a high-affinity specific ligand for alpha(v)beta(3) and alpha(v)beta(5) integrins with negligible interacting with alpha(5)beta(1) 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 choriciallantoic 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)beta(3)/alpha(v)beta(5)-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)beta(3)-bound EMD121974. Accordingly, computer-docking studies indicated that the ST1646-003 integrin complex maintains the ligand-receptor distances and interactions observed in the crystalline EMD121974-alpha(v)beta(3) integrin complex. Taken together, these observations indicate that ST1646 represents a dual alpha(v)beta(3)/alpha(v)beta(5) integrin antagonist with interesting biochemical and biological features to be tested in cancer therapy.

Belvisi, L., Riccioni, T., Marcellini, M., Vesci, L., Chiarucci, I., Efrati, D., et al. (2005). Biological and molecular properties of a new alpha(v)beta(3)/alpha(v)beta(5) integrin antagonist. MOLECULAR CANCER THERAPEUTICS, 4(11), 1670-1680 [10.1158/1535-7163.MCT-05-0120].

Biological and molecular properties of a new alpha(v)beta(3)/alpha(v)beta(5) integrin antagonist

ORLANDI, AUGUSTO;
2005-01-01

Abstract

The aim of the present study was to identify specific alpha(v)beta(3)/alpha(v)beta(5) 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 pseuclopeptides. The results identified ST1646 as a high-affinity specific ligand for alpha(v)beta(3) and alpha(v)beta(5) integrins with negligible interacting with alpha(5)beta(1) 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 choriciallantoic 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)beta(3)/alpha(v)beta(5)-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)beta(3)-bound EMD121974. Accordingly, computer-docking studies indicated that the ST1646-003 integrin complex maintains the ligand-receptor distances and interactions observed in the crystalline EMD121974-alpha(v)beta(3) integrin complex. Taken together, these observations indicate that ST1646 represents a dual alpha(v)beta(3)/alpha(v)beta(5) integrin antagonist with interesting biochemical and biological features to be tested in cancer therapy.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/08 - Anatomia Patologica
English
matrix metalloproteinase-2 mmp-2; cyclic rgd peptides; alpha(v)beta(3) antagonists; vitronectin receptor; signal-transduction; improves survival; melanoma-cells; tumor-growth; in-vivo; beta 3
11
Belvisi, L., Riccioni, T., Marcellini, M., Vesci, L., Chiarucci, I., Efrati, D., et al. (2005). Biological and molecular properties of a new alpha(v)beta(3)/alpha(v)beta(5) integrin antagonist. MOLECULAR CANCER THERAPEUTICS, 4(11), 1670-1680 [10.1158/1535-7163.MCT-05-0120].
Belvisi, L; Riccioni, T; Marcellini, M; Vesci, L; Chiarucci, I; Efrati, D; Potenza, D; Scolastico, C; Manzoni, L; Lombardo, K; Stasi, M; Orlandi, A; Ciucci, A; Nico, B; Ribatti, D; Giannini, G; Presta, M; Carminati, P; Pisano, C
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/33744
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