Abstract

DO.02.06

If VEGF-inhibition reaches its limit: Rapamycin and other alternatives

Hansjürgen Agostini, Andreas Stahl
Universitäts-Augenklinik Freiburg

Objective: The therapeutic manipulation of receptor-ligand systems can be achieved on an extracellular level, at the membrane bound receptors or the intracellular pathway. The current clinical approach of antiangiogenic therapy in ophthalmology focuses on reducing the active levels of ligands, especially VEGF. Rapamycin is an immunosuppressive agend, which inactivates a central regulatory kinase (mTOR) if bound as a complex.
Methods: A novel in vitro-model for RPE-induced, spheroidal endothelial cell sprouting was used to compare the antiangiogenic effect of rapamycin, compared to standard clinical drugs and Ly294002, an unspecific inhibitor of PI3K/Akt. The sprout length of endothelial cells was quantified as well as cell survival and rate of apoptosis. In addition, the effect of rapamycin on the expression of VEGF in RPE-cells was determined.
Results: Rapamycin inhibits REP-induced sprouting of endothelial cells. Inhibition is significant even if cell growth is not mediated by VEGF. In addition, rapamycin reduces the expression of VEGF in RPE-cells. Compared to Ly294002 the inhibition of sprouting is associated with a low rate of apoptosis. Beside VEGF, FGF2 could be identified as a strong growth factor for RPE-induced cell proliferation in vitro.
Conclusions: Inhibitors of the intracellular signal transduction offer possibilities to supplement current angioinhibitory treatment regimes if sole anti-VEGF-therapy proved ineffective. The low rate of rapamycin-induced apoptosis in endothelial cells indicates good tissue compatibility, also discussed in preliminary phase-I results with rapamycin in ocular disease.

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