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K. Poesen, T. Janssens, D. Lambrechts, P. Carmeliet, E. M. Conway; Advantages of the Vegf Inhibitor, Macugen: A More Favourable Toxicity Profile. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3412.
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Since anti-VEGF therapies in other diseases have recognized systemic side effects, we assessed the toxicity profile of Macugen in mouse models of human disease.
Mice were treated with Macugen, vehicle alone, with the potent kinase inhibitor of VEGFR-2 (SU5416), or with the VEGFR-2 neutralizing antibody (DC101). Effects on hemostatic system activation, myocardial function, tracheal vessel pruning, and motoneuron degeneration were quantified.
Mice treated for 3 weeks with Macugen (50 mg/kg i.p., MWF) exhibited no alterations (versus vehicle alone) in hemostatic system activity or tracheal vessel pruning. In contrast, mice treated with DC101 (750 ug ip, MWF) exhibited a significant increase in plasma levels of the hemostatic marker, plasminogen activator inhibitor (PAI)-1 (p<0.001) (10.1 + 2.0, 2.6 + 0.3, 2.4 + 0.2 ng/ml for DC101, Macugen, vehicle), and a significant decrease (p<0.05) in the number of capillaries in the neonatal trachea (6.0 + 0.4, 7.4+ 0.6, 7.5 + 0.5 capillaries/mm for DC101, Macugen, vehicle). Direct measures of heart rate, ventricular pressures (systolic, diastolic, end diastolic), and pressure gradients (dP/dt max and min) were not affected by systemic administration of Macugen over a 2 week period. Since low VEGF levels are linked to neurodegeneration, we assessed the effects over a 60-day period, of systemic administration of Macugen, SU5416 or DC101 in SOD1G93A mice, which spontaneously develop an ALS-like syndrome. SU5416 induced the most significant deterioration in neurologic function measured by rotarod performance. DC101 induced an intermediate effect, while Macugen elicited the least deleterious effect (p=NS versus vehicle). SU5416 and DC101 reduced survival by 14 and 9 days, respectively, while Macugen reduced survival only by 7 days.
Although Macugen is an inhibitor of VEGF, its specific activity against the VEGF165 isoform may explain why it appears in these mouse models, to be safer than VEGFR-2 inhibitors.
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