Purchase this article with an account.
V. Poulaki, N. Mitsiades, E. Iliaki, C.S. Mitsiades, E.S. Gragoudas, J.W. Miller; Geldanamycin Treatment Reduces Choroidal Neovascularization In A Murine Model . Invest. Ophthalmol. Vis. Sci. 2006;47(13):371.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
To investigate the anti–angiogenic effects of geldanamycin (GA) in a rat model of laser–induced choroidal neovascularization (CNV). Heat–shock protein (hsp)90 is the central component of a ubiquitous molecular chaperone complex that interacts with a variety of intracellular client proteins to facilitate their proper folding, prevent misfolding and preserve their 3–dimensional conformation to a functionally competent state. Hsp90 inhibitors, such as GA and other members of the ansamycin family, constitute promising investigational agents, as they have been recently shown to exhibit anti–neoplastic and anti–angiogenic activity in a variety of models.
CNV was induced in the eyes of Brown–Norway rats using Argon/Dye laser, followed by continuous administration via pump of either geldanamycin or vehicle at a total dose of 5mg/kg. Verterporfin photodynamic therapy (PDT) was performed 14 days after CNV induction using a verterporfin dose of 3 mg/m2, irradiance of 600 mW/cm2 and fluence of 25 J/cm2. CNV closure was assessed using fluorescein angiography masked grading 24 hours and 7 days after PDT using angiographic. Retinal levels of p38 and p42/44 MAPK, HIF–1α, NF–ΚB, VEGF, and endostatin were assessed with a modified ELISA method.
Continuous subcutaneous GA administration increased the efficacy of verteporfin PDT CNV closure. GA decreased the PDT–induced upregulation of HIF–1α and NF–ΚB activation and the upregulation of VEGF protein levels. GA treatment also had a synergistic effect with PDT in increasing the retinal endostatin levels.
GA treatment potentiated the efficacy of verterporfin PDT for CNV closure and suppressed the HIF–1α– and NF–ΚB–mediated expression of angiogenic factors, such as VEGF. GA increased anti–angiogenic factors, such as endostatin. GA and its analogs, such as 17–AAG, appear to be promising therapeutic agents for choroidal neovascularizaiton and other disorders.
This PDF is available to Subscribers Only