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Amirfarbod Yazdanyar, Charles Cai, Ahmad Taimur, Eric shrier, Douglas R Lazzaro, Gloria Valencia, Jacob Aranda, Kay Beharry; Comparative Effects of Bevacizumab and Aflibercept on VEGF and IGF Signaling in Human Retinal Endothelial Cells Exposed to Hyperoxia and Intermittent Hypoxia. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3358.
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© ARVO (1962-2015); The Authors (2016-present)
Vascular endothelial growth factor (VEGF) inhibitors are mainstays of treatment in retinal vasculature abnormalities in adults and in part, in premature infants. Bevacizumab (Avastin) has long been used and studied in various clinical scenarios; however, literature is naïve with respect to the safety and efficacy of newer anti-VEGF agents such as Aflibercept (Eylea).Here we examined and compared the effects of Avastin and Eylea on VEGF and IGF-I signaling pathway in human retinal endothelial cells (HREC) exposed to hyperoxia, intermittent hypoxia (IH) and normoxia (Nx)
HREC were treated with Avastin (0.2 µg/mL); low-dose Aflibercept (Lo-AFC, 0.2 µg/mL); or high-dose Aflibercept (Hi-AFC, 0.4 µg/mL) and exposed to normoxia (Nx), hyperoxia (50% O2), or IH (50% O2 with 10% O2, 8 IH episodes/day) for 24, 48 or 72 hrs. VEGF (pg/mL), sVEGFR-1 (pg/mL), IGF-I (ng/mL) levels were determined in the media. Cells were stained for HIF1α, VEGF, IGF-I, and soluble VEGF (sVEGFR) and IGF receptors. Lipid peroxidation, and cell migration and tube-forming capacities were also determined.
At any given time point, Eylea was superior to Avastin for suppression of VEGF and thus, significantly increased sVEGFR-1, the endogenous VEGF trap. However, at 72 h time point, higher expression of receptors were detected in the Avastin treated cells which is most likely due to the shorter half-life of Avastin. Additionally, Eylea treated cells under IH expressed highest levels of sVEGFR-1 as opposed to other oxygen conditions in the same group or Avastin treated group. Surprisingly, the IGF-1 levels in the Avastin group were low, while levels in the Eylea treated group were significantly higher across different time points or oxygen conditions, and correlated with sVEGFR-1 levels. Under IH, Avastin decreased migration and tube formation more effectively than Eylea, however in normoxia the effect was opposite. Both Avastin and Eylea induced lipid peroxidation, but the effect was more substantial in the Eylea group under IH.
Eylea appears to have a more rapid and predominant suppressive effect on VEGF than Avastin. The metabolic effect of both drugs on HRECs seems to be diverse based on the oxygen environment. The effects of Eylea are highly potentiated by IH. Further investigation of the long term safety profile of both drugs is warranted.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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