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

Stela S. Palii, Aqeela Afzal, Lynn C. Shaw, Hao Pan, Sergio Caballero, Rehae C. Miller, Simona Jurczyk, Jean Claude Reubi, Yufei Tan, Guenther Hochhaus, Henry Edelhauser, Dayle Geroski, Gideon Shapiro, Maria B. Grant

Research output: Contribution to journalArticle

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Abstract

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 (IC50, 0.1-1.0 μM) 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.

Original languageEnglish (US)
Pages (from-to)5094-5102
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume49
Issue number11
DOIs
StatePublished - Nov 2008
Externally publishedYes

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Somatostatin Receptors
Octreotide
Choroidal Neovascularization
Retinal Neovascularization
Oxygen
imidazolidine-2,4-dione
somatostatin receptor 2
Eye Diseases
Chemotaxis
Somatostatin
Growth Hormone
Inhibitory Concentration 50
Permeability
Intercellular Signaling Peptides and Proteins
Lasers
Pharmacology
Peptides

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

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.

In: Investigative Ophthalmology and Visual Science, Vol. 49, No. 11, 11.2008, p. 5094-5102.

Research output: Contribution to journalArticle

Palii, SS, Afzal, A, Shaw, LC, Pan, H, Caballero, S, Miller, RC, Jurczyk, S, Reubi, JC, Tan, Y, Hochhaus, G, Edelhauser, H, Geroski, D, Shapiro, G & Grant, MB 2008, 'Nonpeptide somatostatin receptor agonists specifically target ocular neovascularization via the somatostatin type 2 receptor', Investigative Ophthalmology and Visual Science, vol. 49, no. 11, pp. 5094-5102. https://doi.org/10.1167/iovs.08-2289
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. / Nonpeptide somatostatin receptor agonists specifically target ocular neovascularization via the somatostatin type 2 receptor. In: Investigative Ophthalmology and Visual Science. 2008 ; Vol. 49, No. 11. pp. 5094-5102.
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abstract = "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 (IC50, 0.1-1.0 μM) 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.",
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T1 - Nonpeptide somatostatin receptor agonists specifically target ocular neovascularization via the somatostatin type 2 receptor

AU - Palii, Stela S.

AU - Afzal, Aqeela

AU - Shaw, Lynn C.

AU - Pan, Hao

AU - Caballero, Sergio

AU - Miller, Rehae C.

AU - Jurczyk, Simona

AU - Reubi, Jean Claude

AU - Tan, Yufei

AU - Hochhaus, Guenther

AU - Edelhauser, Henry

AU - Geroski, Dayle

AU - Shapiro, Gideon

AU - Grant, Maria B.

PY - 2008/11

Y1 - 2008/11

N2 - 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 (IC50, 0.1-1.0 μM) 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.

AB - 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 (IC50, 0.1-1.0 μM) 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.

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