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TG Murray, EM Escalona, BC Hayden, N Cicciarelli, E Hernandez, W Feuer, JJ Windle; Combretastatin A4 Prodrug: Subconjunctival delivery of an angiogenesis Inhibitor in the Treatment of a Murine Model of Retinoblastoma . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3917.
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Purpose:To investigate the vascular response and tumor control efficacy of Combretastatin A4, a novel anti-angiogenic agent, in the subconjunctival treatment of murine transgenic retinoblastoma. Methods:Ninety-six, 12 week-old SV40 Tag positive mice were treated with subconjunctival Combretastatin A4 to the right eye only. Group A: Forty-eight mice received a single 2 mg/20 µl injection. Eight additional mice received a single subconjunctival injection of balanced salt solution (BSS); left eyes served as untreated controls. Eyes were enucleated at 1, 3, 7, 14, 21 and 28 days post-treatment. Group B: Forty-eight mice received serial injections at doses of 2000, 200, 20, 2, or 0.2 µg/20 µl twice a week for 3 weeks. Eight additional mice received serial subconjunctival injections of balanced salt solution; left eyes served as untreated controls. Eyes were enucleated at 16 weeks of age. All eyes were stained with haematoxylin & eosin, PAS, and histopathologically examined for intratumoral vascularity and residual tumor volume. Results:Histological assessment of intratumoral vascularity documented an 80% reduction in eyes receiving a single injection (Group A) in comparison to fellow control eyes and BSS controls (p=0.03). Tumor vascular reduction was noted as early as 24 hours after a single injection and peaked at day 7. Tumor volume reduction after a single injection was noted at 25% of the fellow control eye at day 7. Serial injection (Group B) documented a dose-dependent inhibition of both tumor vascularity and tumor volume. By 28 days post institution of therapy no intratumoral vascularity was present at treatment dose levels ≥ 200 µg/ 20µl. No evidence of toxicity was noted at any time point or treatment dose. Conclusion:Subconjunctival delivery of Combretastatin A4 prodrug inhibits tumor vasculature and is associated with tumor inhibition in a dose-dependent fashion in this murine model of retinoblastoma. Combretastatin A4, an antiangiogenic agent, may represent a novel therapy in the treatment of pediatric retinoblastoma.
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