Nonpeptide somatostatin receptor agonists specifically target ocular neovascularization via the somatostatin type 2 receptor

Palii, Stela S; Afzal, Aqeela; Shaw, Lynn C; Pan, Hao; Caballero, Sergio; Miller, Rehae C; Jurczyk, Simona; Reubi, Jean-Claude; Tan, Yufei; Hochhaus, Guenther; Edelhauser, Henry; Geroski, Dayle; Shapiro, Gideon; Grant, Maria B (2008). Nonpeptide somatostatin receptor agonists specifically target ocular neovascularization via the somatostatin type 2 receptor. Investigative ophthalmology & visual science, 49(11), pp. 5094-102. Hagerstown, Md.: Association for Research in Vision and Ophthalmology 10.1167/iovs.08-2289

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PURPOSE: To define the molecular pharmacology underlying the antiangiogenic effects of nonpeptide imidazolidine-2,4-dione somatostatin receptor agonists (NISAs) and evaluate the efficacy of NISA in ocular versus systemic delivery routes in ocular disease models. METHODS: Functional inhibitory effects of the NISAs and the somatostatin peptide analogue octreotide were evaluated in vitro by chemotaxis, proliferation, and tube-formation assays. The oxygen-induced retinopathy (OIR) model and the laser model of choroidal neovascularization (CNV) were used to test the in vivo efficacy of NISAs. Transscleral permeability of a candidate NISA was also measured. RESULTS: NISAs inhibited growth factor-induced HREC proliferation, migration and tube formation with submicromolar potencies (IC(50), 0.1-1.0 microM) comparable to octreotide. In the OIR model, systemic administration of the NISAs RFE-007 and RFE-011 inhibited retinal neovascularization in a dose-dependent manner, comparable to octreotide. In the CNV model, intravitreal RFE-011 resulted in a 56% reduction (P < 0.01) in CNV lesion area, whereas systemic administration resulted in a 35% reduction (P < 0.05) in lesion area. RFE-011 demonstrated transscleral penetration. CONCLUSIONS: Micromolar concentrations of octreotide and NISAs are necessary for antiangiogenic effects, whereas nanomolar concentrations are effective for endocrine inhibition. This suggests that the antiangiogenic activity of NISAs and octreotide is mediated by an overall much less efficient downstream coupling mechanism than is growth hormone release. As a result, the intravitreal or transscleral route of administration should be seriously considered for future clinical studies of SSTR2 agonists used for treatment of ocular neovascularization to ensure efficacious concentrations in the target retinal and choroidal tissue.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Reubi-Kattenbusch, Jean-Claude

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0146-0404

ISBN:

18599562

Publisher:

Association for Research in Vision and Ophthalmology

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:02

Last Modified:

15 Oct 2019 12:17

Publisher DOI:

10.1167/iovs.08-2289

PubMed ID:

18599562

Web of Science ID:

000260502200055

URI:

https://boris.unibe.ch/id/eprint/27062 (FactScience: 101620)

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