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T.G. Murray; Combined Anti–angiogenic and Peri–ocular Chemotherapy utilizing Anecortave Acetate and Carboplatin in the Treatment of Retinal Tumorsin the LHBETATAG Murine Transgenic Model of Retinoblastoma . Invest. Ophthalmol. Vis. Sci. 2004;45(13):3362.
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Purpose: To investigate tumor control efficacy and determine optimal drug delivery scheduling for the combined treatment of murine transgenic retinoblastoma using peri–ocular Anecortave Acetate, an angiostatic cortisene, and Carboplatin chemotherapy. Methods: Sixty 10 week–old LHBETATAG mice (six mice per group) were treated with subtherapeutic doses of Anecortave Acetate and Carboplatin via subconjunctival injections to the right eye only; left eyes served as untreated controls. Carboplatin was delivered by six serial subconjunctival injections of 125µg/20µl and Anecortave Acetate by single subconjunctival injections of 150µg/20µl, 300µg/20µl, or 600µg/20µl delivered after two or six Carboplatin injections. Twenty–four mice (six per group) received either six injections of 125µg/20µl Carboplatin or single injection of 150µg/20µl, 300µg/20µl, or 600µg/20µl Anecortave Acetate. Six control mice received BSS. Eyes were enucleated at 16 weeks of age, stained with Haematoxylin & Eosin and histopathologically examined for residual tumor volume. Results: Histological assessment of tumor volume suggests a dose and drug delivery schedule dependent tumor response to the combined treatment. Combined treatments were more effective in reducing tumor volume than treatments with single agents. Delivery of 150, 300 or 600µg Anecortave Acetate after two Carboplatin injections resulted in a 60 to 80% dose dependent decrease in tumor burden with respect to untreated controls (p<0.01). Delivery of 150, 300 or 600µg of Anecortave Acetate after six Carboplatin injections resulted in an 80 to greater than 90% dose dependent decrease in tumor burden with respect to untreated controls (p<0.01). No evidence of toxicity was noted with the combined treatment. Conclusions:Peri–ocular delivery of Anecortave Acetate combined with Carboplatin effectively inhibits intraocular tumor burden in a dose and delivery schedule–dependent fashion in the LHBETATAG model of retinoblastoma. This treatment allows for significant reduction in focal chemotherapy dose requirements while maintaining enhanced local tumor control. This combined treatment affords the dual benefit of closing intratumoral blood flow while increasing intratumoral drug concentration by effectively inhibiting one route of drug egress. This treatment modality may represent a novel strategy for the treatment of pediatric retinoblastoma.
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