title: Nonpeptide somatostatin receptor agonists specifically target ocular neovascularization via the somatostatin type 2 receptor.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida 32610-0267, USA.
authors.forename: Stela S
authors.initials: SS
authors.lastname: Palii
authors.forename: Aqeela
authors.initials: A
authors.lastname: Afzal
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Shaw
authors.forename: Hao
authors.initials: H
authors.lastname: Pan
authors.forename: Sergio
authors.initials: S
authors.lastname: Caballero
authors.forename: Rehae C
authors.initials: RC
authors.lastname: Miller
authors.forename: Simona
authors.initials: S
authors.lastname: Jurczyk
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Yufei
authors.initials: Y
authors.lastname: Tan
authors.forename: Guenther
authors.initials: G
authors.lastname: Hochhaus
authors.forename: Henry
authors.initials: H
authors.lastname: Edelhauser
authors.forename: Dayle
authors.initials: D
authors.lastname: Geroski
authors.forename: Gideon
authors.initials: G
authors.lastname: Shapiro
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D001345:Autoradiography; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D048289:Imidazolidines / Q000819:agonists*; D007267:Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D015282:Octreotide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D009883:Ophthalmic Solutions; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D011817:Rabbits; D017481:Receptors, Somatostatin / Q000235:genetics* / Q000378:metabolism; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012590:Sclera; D016896:Treatment Outcome; D014822:Vitreous Body
chemical_list: D020533:Angiogenesis Inhibitors; D018931:Antineoplastic Agents, Hormonal; D048289:Imidazolidines; D009883:Ophthalmic Solutions; D017481:Receptors, Somatostatin; C514490:imidazolidine-2,4-dione; D012313:RNA; C093733:somatostatin receptor 2; D015282:Octreotide