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T. G. Murray, Y. Piña, S. Houston, E. Hernandez, M. Celdran, W. Feuer, T. Lampidis; Retinoblastoma Tumor Burden Control: Periocular m-TOR Inhibitor Rapamycin Decreases Tumor Burden in Advanced LHBETATAG Murine Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2067.
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The purpose of this study was to evaluate changes in tumor burden and hypoxic regions of LHBETATAG murine retinal tumors following treatment with the m-TOR inhibitor agent rapamycin.
The study protocol was approved by the IACUC and follows ARVO guidelines. 17-week-old LHBETATAG retinal tumor eyes (n=50) were evaluated. Mice were divided into 6 groups and received periocular injections for three consecutive weeks of: (a) saline, (b) rapamycin (33.25mg/kg), (c) rapamycin (66.5mg/kg), (d) rapamycin (133mg/kg), (e) rapamycin (266mg/kg), and (f) rapamycin (267mg/kg) + 2-DG (500mg/kg). Treatment of rapamycin was given once a week and treatment of 2-DG was given bi-weekly. Eyes were enucleated at 20 weeks of age. To assess hypoxia, mice received 60mg/kg of pimonidazole via intraperitoneal injection. Eyes were enucleated and tumor sections were analyzed for hypoxia and tumor burden.
Eyes treated with rapamycin alone showed a significant decrease in tumor burden (p<0.001, two-tailed t-test) in comparison with the saline control group in all treatment groups. There is a dose response of tumor burden reduction in the eyes treated with rapamycin alone (p<0.001, two-way analysis of variance, ANOVA). Tumor burden and levels of hypoxia significantly decreased following treatment with the combination therapy of rapamycin and 2-DG. Comparison between eyes treated with rapamycin alone and eyes treated with a combination therapy of rapamycin and 2-DG showed a significant reduction of both hypoxia regions and tumor burden (p<0.001).
This is the first report of LHBETATAG transgenic retinoblastoma tumors decreasing following the administration of the m-TOR inhibitor rapamycin administered alone or in combination with the glycolytic inhibitor 2-DG. This unique approach, utilizing cellular targeting of hypoxic pathways, may have benefits for children with retinoblastoma and warrants further translational investigation.
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