Purchase this article with an account.
M.I. Dorrell, E. Aguilar, P. Glidden, M. Friedlander; Synergistic Effects of Combination Therapies Utilizing Angiostatic Compounds With Distinct Mechanisms of Action . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1416.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Purpose: Despite promising pre–clinical studies, the results from clinical trials using angiostatic monotherapies to treat neovascular eye diseases have been disappointing. Angiogenesis is a complex process involving multiple mechanisms of activation. Thus, various compensatory mechanisms often become activated upon antagonism of a single angiogenesis pathway. Combination therapies using separate angiostatic compounds that target distinct angiogenic pathways may be required for effective angiostatic treatments. Here we demonstrate synergistic effects of combining a nucleotide VEGF antagonist, a small molecule αvß3 and αvß5 integrin antagonist, and T2–TrpRS. Methods: Neonatal BALB/c mice were injected with each individual compound, the various double combinations, and the triple combination at post–natal day 7 (P7). On P12, the retinas were analyzed for the angiostatic effects on the formation of the deep vascular plexus. The mouse model of OIR was also used to assess the effects of individual monotherapies, or various combination therapies on the formation of pathological neovascularization. Results: Strong synergistic effects were observed by combining the different angiostatic compounds. Even at maximum efficacy doses, >75% inhibition levels were only observed in 35% of the VEGF aptamer–treated retinas, in 25% of the integrin antagonist–treated retinas, and 45% of the T2–TrpRS treated retinas. In contrast, 93% of the triple combination–treated retinas exhibited >75% inhibition of neovascularization. At low doses where each monotherapy exhibited no angiostatic activity, complete inhibition of neovascularization was still observed in most of the triple combination–treated retinas. Similar synergistic effects were observed when the combination therapies were used to inhibit neovascular tuft formation in the mouse model of OIR. Conclusions: Synergism from combining angiostatic compounds with distinct mechanisms of action leads to a dramatic increase in the inhibition of neovascularization in vivo. Thus, combination therapies may represent a new paradigm for the treatment of neovascular eye diseases.
This PDF is available to Subscribers Only