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Yolanda Pina, Christina Decatur, Samuel Houston, Ludimilla Cavalcante, Theodore Lampidis, Timothy Murray; Mammalian Target Of Rapamycin In Combination With Chemotherapy: Upstream Regulation Of Anaerobic Glycolysis To Target The Chemoresistant Cell Population In Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2484.
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© ARVO (1962-2015); The Authors (2016-present)
To assess the efficacy of the combination therapy utilizing carboplatin chemotherapy and rapamycin as a mammalian target of rapamycin (mTOR) inhibitor, and its effect on tumor burden, hypoxia, and blood vessels in the LHBETATAG transgenic mouse model of retinoblastoma.
The study protocol was approved by the University of Miami Institutional Animal Care and Use Review Board Committee and conformed to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. 12-week-old (n=62) LHBETATAG transgenic mice were treated with the chemotherapeutic agent carboplatin, the m-TOR inhibitor rapamycin, or both. Animals were treated with subconjunctival injections twice a week and received treatment for either 1 week or 3 weeks. All animals were sacrificed at 1 day post-last injection and eyes were enucleated. At the time of enucleation, all eye samples were snap frozen and analyzed for tumor burden, hypoxia, new blood vessels, and mature blood vessels using histopathology and immunohistochemistry. Data were statistically analyzed using ANOVA.
Mice that received treatment for 1 week had a tumor reduction of 23.8%, 49.3%, and 60.6% when treated with carboplatin, rapamycin, and carboplatin + rapamycin, respectively (p<0.05). Mice that received treatment for 3 weeks had a tumor reduction of 71.4%, 79.5%, and 78.2% when treated with carboplatin (p=0.0147), rapamycin (p=0.0229), and carboplatin + rapamycin (p=0.0160), respectively. Hypoxia was significantly present in the advanced disease group. There was a significant reduction of hypoxia for both groups treated with rapamycin (p<0.001). Mice that received treatment for 1 week had a reduction of new blood vessels following treatment with carboplatin (54%), rapamycin (75%), and carboplatin + rapamycin (68%), and a reduction of mature blood vessels following treatment with rapamycin (45%) and carboplatin + rapamycin (9%) only. Mice that received treatment for 3 weeks had a reduction of new and mature blood vessels following treatment with carboplatin (30% and 49%), rapamycin (77% and 95%), and carboplatin + rapamycin (41% and 82%).
Combination therapy of carboplatin chemotherapy and mTOR inhibition using rapamycin significantly reduces tumor burden, hypoxia, and vasculature in the LHBETATAG transgenic mouse model of retinoblastoma. The modulation of the upstream mTOR appears to have a role in combination with chemotherapy to enhance retinoblastoma tumor control.
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