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R. J. D'Amato, K. Christensen, D. Wigelsworth, R. Collier, M. Rogers; Mutant Anthrax Toxin B-Moiety (Protective Antigen) Inhibits Ocular Angiogenesis and Tumor Growth. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4455.
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© ARVO (1962-2015); The Authors (2016-present)
Bacillus anthracis protective antigen (PA), the B-subunit of the binary anthrax toxin, binds to the cellular receptors capillary morphogenesis gene protein 2 (CMG2) and tumor endothelial marker 8 (TEM8) with high affinity. Both CMG2 and TEM8 are expressed on endothelial cells during angiogenesis. We sought to determine whether one could inhibit ocular angiogenesis by interfering with the binding of these receptors to their endogenous ligands.
Wild-type PA and PA mutants were tested for their ability to inhibit angiogenesis in the corneal micropocket model and in the Lewis Lung carcinoma model of tumor growth.
We show that wild-type PA inhibits both VEGF-induced and bFGF-induced ocular angiogenesis at moderate but statistically significant levels. Structure-activity studies identified a PA mutant that exhibited markedly enhanced inhibition of ocular angiogenesis and also inhibited tumor growth in vivo. This mutant, PA-SSSR , is unable to undergo normal cellular processing and thus, remains bound to the surface receptor. Further mutation of PA-SSSR so that it does not bind to these cell surface receptors abolished its ability to inhibit angiogenesis.
High affinity anthrax receptor ligands, such as PA and PA-SSSR, are angiogenesis inhibitors. Thus anthrax toxin receptors are useful targets for anti-angiogenic therapy of ocular neovascularization. We are currently screening chemical libraries for small molecules with similar activity.
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