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D. Sherris, N. S. Bora, P. S. Bora, P. McGuire, A. Das, C. Perruzzi, J. Varnau, L. Benjamin; Palomid 529, a Non-Steroidal Small Molecule Anti-Angiogenic Agent Inhibits Retinal and Subretinal Neovascularization by Inhibiting the Akt/mtor Pathway. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3766.
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© ARVO (1962-2015); The Authors (2016-present)
Characterize small molecule drug inhibitor of anti-angiogenesis in a variety of in vitro models and in vivo models of retinal and subretinal neovascularization.
in vitro endothelial cell assays including pro-angiogenic cytokine stimulation, apoptosis, signal transduction mediator responses and matrix metalloproteinase activity. in vivo murine laser-induced neovascularization and murine retinopathy of prematurity models, rabbit retinal detachment models and Evans blue permeability model.
Retinal diseases of neovasculature create aberrant vessels which induce ocular pathologies initiated by a host of pro-angiogenic factors. Palomid 529, the lead analog for the clinic, broadly inhibits angiogenic cytokine signalling as it inhibits two very different signalling pathways of both VEGF and bFGF induced endothelial cell proliferation with IC50s of 0.02 and 0.2 µM respectively. Palomid 529 further stimulates endothelial cell apoptosis and inhibits matrix metalloproteinase activity, inhibits both endogenous and VEGF induced Akt phosphorylation in endothelial cells showing it as an inhibitor of the PI3/Akt/mTor pathway. Palomid 529 also inhibits VEGF induced angiogenesis in vivo as well as VEGF induced vascular permeability through the Evans blue dye assay. In a both a murine laser-induced retinopathy model and a murine retinopathy of prematurity (ROP) model, Palomid 529 was able to inhibit neovascularization by 65%. Particularly interesting, Palomid 529 was not only able to inhibit aberrant angiogenesis in the ROP model but allow normal angiogenesis to occur. Palomid 529 has extended benefit in a subretinal neovascularization model for at least 28 days after intravitreal administration. Palomid 529 was examined in a rabbit model of retinal detachment which showed a reduction of the presence of glial cells at the site of detachment and elimination of retinal scar formation.
Results described here show that Palomid 529 inhibits both in vitro and in vivo models of angiogenesis through inhibition of the Akt/mTor signal transduction pathway.
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