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S. A. Mousa, L. O’Connor, D. Lincoln; Broad Spectrum Anti-Angiogenic Efficacy of OT-674 in Inhibiting Oxidative Stress and Pro-Angiogenic Growth Factor-Mediated Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3424.
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To determine the potential effect of the antioxidant OT-674 and its pro-drug OT-551 on the inhibition of angiogenesis induced by growth factors, cytokine, pro-inflammatory stimuli, and oxidative stress.
The efficacy of OT-674/OT-551 in inhibiting angiogenesis induced by various stimuli, including oxidative stress (H2O2), basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), angiotensin II, bradykinin, and endotoxin (LPS) was determined using the chick chorioallantoic membrane (CAM) model of angiogenesis.
Investigation by our and other laboratories has demonstrated that the pro-angiogenesis effects of bFGF are blocked by monoclonal antibodies directed toward bFGF or the integrin αvß3 antagonists and that the pro-angiogenesis effects of VEGF are blocked by specific VEGF antibodies, or other anti-VEGF strategies, in the CAM model. In this current investigation, the potential anti-angiogenesis effect of OT-674/OT-551 was evaluated in the CAM model, at doses ranging from 30 to 800 µg. Generation of new blood vessels from existing vessels was promoted two- to three-fold by H2O2, bFGF, VEGF, angiotensin II, bradykinin, or LPS. The pro-angiogenesis effect of these different mediators was significantly inhibited (P <0.01) by OT-674/OT-551 applied topically or by intravenous administration. Furthermore, an additive anti-angiogenesis efficacy was demonstrated between OT-674 and avastin or lucentis in inhibiting VEGF-induced angiogenesis.
These data indicate the broad potential efficacy of OT-674/OT-551 against the various stimuli used and its potential benefit, either alone or in combination with other single-mechanism-based anti-angiogenesis agents such as avastin or lucentis, in the prevention and treatment of angiogenesis associated with diabetic retinopathy, macular degeneration, and other ocular disorders.
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