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Christina L. Decatur, Nikesh Shah, Yolanda Piña, Marcela Lonngi, Dien Pham, Samuel Houston, Timothy G. Murray; Use of AMP-kinase Activator 5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) in the Treatment of Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1875.
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The aim of the current study is to assess the impact of AICAR on tumor burden and hypoxia in the LHBETATAG transgenic animal model of retinoblastoma.
The study protocol was approved by the University of Miami Institutional Animal Care and Use Review Board Committee and the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. LHBETATAG transgenic mice received subconjunctival injections twice a week of AICAR (0.65 mg/20ul; 32.5 mg/ml) or saline control. In order to evaluate different time schedules of drug delivery, thirty-six animals were treated at different time points of tumor development. The animals were divided into three groups: (1) 12-week-old mice were treated for 3 weeks, (2) 12-week-old mice were treated for 7 weeks, and (3) 16-week-old mice were treated for 3 weeks. All animals were sacrificed and eyes were enucleated at one day following the last injection. At the time of enucleation, all eye samples were snap frozen and analyzed for tumor burden and hypoxia using immunohistochemical techniques. Average densities of the different groups were statistically analyzed using ANOVA.
There was no apparent toxicity associated with AICAR treatment. There was a 66% tumor burden reduction following 7 weeks of AICAR treatment at 12-weeks-of-age when compared to saline control treated eyes (p=0.008). There was no significant tumor burden reduction observed in the mice that were treated for 3 weeks at neither 12 nor 16-weeks-of-age (p>0.05). There was a 60% reduction of hypoxia following 7 weeks of AICAR treatment at 12-weeks-of-age when compared to saline control treated eyes (p=0.003). There was no significant hypoxia reduction observed in the mice that were treated for 3 weeks at neither 12 nor 16-weeks-of-age (p>0.05). Eyes treated with AICAR for 3 weeks at 16-weeks-of-age had a decrease in tumor burden and hypoxia, but were not statistically significant (p=0.43 and p=0.23, respectively).
AICAR treatment is most effective in medium-sized murine retinoblastoma tumors rather than advanced diseased tumors, with treatment administered over a longer period of time. In advanced retinal tumors, AICAR, combined with other therapies, may augment tumor control. The use of AICAR as a therapeutic strategy, due to its low toxicity, has the potential to enhance current retinoblastoma treatments.
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