Combination angiostatic therapies: targeting multiple angiogenic pathways.

The multiplicity of signaling pathways for new blood vessel formation is suggested by the modest antiangiogenic effects achieved when any single pathway or molecular step is blocked. In an experimental model of neovascularization in newborn mice, highly significant improvements in an antiangiogenic effect are achieved when inhibitors of different pathways of new vessel formation are combined. In this model, neovascularization can be completely inhibited in the majority of animals when at least three pathways are inhibited. When only two pathways are blocked, complete inhibition of neovascularization is less commonly observed but still far more common than when a single pathway is inhibited. For the prevention of new blood vessel formation in neovascular eye diseases like age-related macular degeneration, the experimental evidence supports combination therapies that inhibit more than one molecular pathway.