MyVisionTest News Archive
Sep 21, 2010
anti-VEGF therapy impairs RPE function
VEGF antagonists, such as Avastin (bevacizumab) and Lucentis (ranibizumab), impair the barrier function of cultured retinal pigment epithelium (RPE) cells, according to a new study.
In spite of the favorable results of anti-VEGF therapies in the treatment of exudative age-related macular degeneration (AMD), several adverse incidents are related to their use, such as RPE tear and intraocular inflammation.
The mechanisms of these adverse drug effects are still a matter of speculation
Tight junctions between RPE cells function as the outer blood-retinal barrier, which restricts diffusion between the retina and choroid.
Because of adverse effects such as RPE tear and intraocular inflammatory reactions, it is possible that anti-VEGF treatment disturbs the barrier, perhaps by influencing RPE permeability.
Oxidative stress increases the permeability of cultured RPE cells. This is accompanied by redox imbalance with reduced glutathione (GSH), one of the most important antioxidant components in all animal cells. The increased permeability and redox imbalance can be prevented by triamcinolone acetonide (TA).
This study investigated the influence of Avastin (bevacizumab) and Lucentis (ranibizumab) on the permeability of cultured retinal pigment epithelium cells and on intracellular GSH levels and the effect of TA in combination with VEGF antagonists.
Methods and Results
Porcine RPE cells were cultured on six-well membrane inserts. The cells were exposed to bevacizumab (62.5 microg/mL) or ranibizumab (25 microg/mL) for 24 hours (short term) or 9 days (long term).
Transepithelial flux of FITC-dextran and intracellular levels of reduced glutathione (GSH) at normal and low-glucose conditions were investigated at different points in time. The influence of the addition of triamcinolone acetonide (TA) was investigated.
The effect of GSH depletion on RPE permeability was examined using L-buthionine sulfoximine (BSO), a gamma-glutamylcysteine synthethase inhibitor.
After short-term exposure, VEGF antagonists increased the transepithelial flux of FITC-dextran significantly on day 2. Bevacizumab, but not ranibizumab, increased permeability up to 9 days.
Under long-term exposure, both drugs enhanced permeability for 7 days; bevacizumab had the stronger effect. The addition of TA inhibited this increase.
At the ninth day of short- and long-term exposure, bevacizumab-exposed cells, but not ranibizumab-exposed cells, exhibited a significantly lower GSH level. In the low-glucose condition, both drugs accelerated the decrease of intracellular GSH for the first 48 hours. GSH depletion increased the permeability of retinal pigment epithelium. TA had no effect on BSO-induced GSH depletion.
Discussion and Conclusions
The present study shows that Avasatin and Lucentis induce increased permeability of cultured retinal pigment epithelium, with a stronger and longer lasting effect seen with Avastin, suggesting that these VEGF antagonists might decrease RPE barrier function.
Cells exposed for 24 hours to Lucentis returned to baseline at day 3, whereas Avastin-exposed cells exhibited elevated flux until day 9. In general, the effect seen with Avastin was more profound than with Lucentis.
The development of RPE tears has been reported as among the possible incidences to follow anti-VEGF treatment. The tear can occur in eyes regardless of the existence of pigment epithelial detachment (PED).
It is, however, clear that the incidence rate of RPE tear is significantly higher in eyes with PED. The researchers speculate that anti-VEGF treatment increases the natural risk for RPE tears.
Several potential mechanisms have been proposed, including rapid resorption of the sub-RPE fluid and contraction of the CNV. Additionally, the disturbance of RPE barrier function, suggested in this study, might be one of the participating mechanisms.
Most researchers report an incidence rate for RPE tear around 17% after Avastin treatment,
whereas with Lucentis, an incidence rate of 12.3% is presented.
The authors suggest that this rate is similar to the incidence rate in the natural course of PED (10%–12%) and that Lucentis injection might be associated with a lower tendency for inducing RPE tears compared with Avastin treatment.
If the hypothesis holds true that Avastin induces RPE tear at a higher rate than Lucentis, the difference between these two drugs presented in this study might be strongly related to the pathogenesis of RPE tear after anti-VEGF treatment.
Results from the concurrently performed intracellular GSH measurement suggested GSH consumption by VEGF antagonists.
Given that redox imbalance after oxidative stress is accompanied by increased permeability in RPE cells, the researchers believe that GSH consumption might be related to the decrease of RPE barrier after the exposure to Avastin and Lucentis.
TA stabilized RPE permeability, even in GSH-depleted conditions, indicating that TA has a protective effect on RPE junctions through the GSH-independent pathway. It is conceivable that TA might reduce the rate of RPE tear induced by anti-VEGF drugs.
Rebound or rapid reincrease of VEGF after anti-VEGF treatment, which might induce the recurrence of CNV or macular edema, could also be prevented by TA. Therefore, the administration of TA with anti-VEGF drugs is considered to be beneficial. Regarding the incident of RPE tear, however, its rate has not been studied thus far in any of the combination therapies tested.
The investigators conclude that Avastin and Lucentis may decrease RPE barrier function, with Avastin exhibiting a prolonged and more profound effect. Combination with TA is thought to be beneficial because of its protective effect on stabilizing RPE junctional integrity.
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Invest Ophthalmol Vis Sci. 2010 Sep;51(9):4848-55. Epub 2010 Apr 30
ncbi.nlm.nih.gov
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