May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Acute and Chronic Effects of Fenretinide on RPE Loss and Growth Factor Regulation
Author Affiliations & Notes
  • C. Spee
    Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, California
  • P. G. Sreekumar
    Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, California
  • J. Zhou
    Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, California
  • S. J. Ryan
    Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, California
    Ophthalmology,
    University of Southern California, Keck School of Medicine, Los Angeles, California
  • R. Kannan
    Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, California
  • D. R. Hinton
    Arnold and Mabel Beckman Macular Research Center, Doheny Eye Institute, Los Angeles, California
    Pathology,
    University of Southern California, Keck School of Medicine, Los Angeles, California
  • Footnotes
    Commercial Relationships C. Spee, None; P.G. Sreekumar, None; J. Zhou, None; S.J. Ryan, None; R. Kannan, None; D.R. Hinton, None.
  • Footnotes
    Support NIH grants EY03040 and EY01545, RPB, and the Arnold and Mabel Beckman Foundation
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 3428. doi:https://doi.org/
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      C. Spee, P. G. Sreekumar, J. Zhou, S. J. Ryan, R. Kannan, D. R. Hinton; Acute and Chronic Effects of Fenretinide on RPE Loss and Growth Factor Regulation. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3428. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose:: Fenretinide (N-4-hydroxyphenyl retinamide; 4-HPR) is a retinoic acid derivative and an effective anticancer agent against neuroglial tumors. The aim of this study is to investigate the effect of fenretinide on RPE cell loss and growth factor regulation under acute (in vitro) and chronic (in vivo) conditions.

Methods:: Early passage confluent human RPE were treated with different doses of fenretinide (1-10 µM) for 24h. Apoptosis was monitored by TUNEL, and gene expression of VEGF and PEDF was determined by real-time PCR. Levels of VEGF in RPE cell lysates and secretion into the medium were determined in untreated and fenretinide-treated RPE by ELISA. Mice were administered fenretinide (0.4 mg or 1 mg/kg twice daily or vehicle, i.p.) for 7 and 14 days after laser-induced photocoagulation. Cytokeratin immunohistochemical staining was performed in tissue sections of drug-treated mice and controls. Staining for alpha B crystallin was also performed with a specific polyclonal antibody.

Results:: Fenretinide caused dose-dependent (1-10 µM) RPE apoptosis which correlated with an increase in VEGF and a decrease in PEDF as compared to controls. Intracellular VEGF concentration and secretion into medium were also significantly increased in fenretinide-treated vs untreated RPE. In experiments in vivo, a significant decrease was found in RPE encircling the laser lesion with fenretinide treatment, with cytokeratin staining on day 7 and day 14 as compared to untreated mice. Further, immunohistochemical staining with alphaB crystallin revealed a significant upregulation in fenretinide-treated mice vs controls on day 14.

Conclusions:: Our results show that fenretinide causes apoptosis in cultured RPE accompanied by upregulation of angiogenic (VEGF) and downregulation of antiangiogenic (PEDF) factors. Loss of RPE could also be demonstrated in areas encircling laser lesions in vivo. The increased expression of the small heat shock protein alphaB crystallin may protect the retina by counteracting the damaging effect of the drug on proteins.

Keywords: choroid: neovascularization • age-related macular degeneration • drug toxicity/drug effects 
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