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H. Boutrid, C. M. Cebulla, Y. Pina, M. E. Jockovich, T. J. Lampidis, T. G. Murray; Regional Hypoxia in LHBetaTag Murine Retinoblastoma: Implication for Novel Treatements. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1601.
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The purpose of this study was to evaluate the presence and extent of hypoxia in retinoblastoma tumors and the feasibility of targeting hypoxic cells as a novel therapeutic strategy. To this aim, hypoxic cells were labeled by immunohistochemistry and tumor control was assessed by using combination therapy of Carboplatin, a chemotherapeutic agent, and 2-Deoxy-d-Glucose (2-DG), a glycolytic inhibitor.
The study protocol was approved by the University of Miami, IACUC. All experiments were conducted in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Twenty four LHBetaTAG transgenic retinoblastoma mice were evaluated. Two 16-week-old LHBetaTAG mice received 60mg/kg of pimonidazole (10mg/ml) via tail vein injection. One 16-week LHBetaTAG wildtype mouse served as control receiving the same treatment. The animals were euthanized 2 hours post injection and eyes were harvested for histopathologic examination. Hypoxic areas were measured using immunohistochemistry. Twenty-one, 10-week-old LHBetaTAG mice were divided into 3 groups and received periocular injections of (a) saline, (b) carboplatin (31.25ug/20ul, subtherapeutic dose), and (c) carboplatin (31.25ug/20ul )+ 2-DG (500 mg/kg). Treatment was administered five times a week for 3 weeks via periocular injection to right eyes only. Eyes were enucleated at 16 weeks of age, stained with H&E and histopathologically examined for residual tumor volume.
Retinoblastoma tumors exhibited variable hypoxic areas. Large tumors exhibited definite hypoxic areas, while medium size tumors did not. Subtherapeutic carboplatin dosing did not have an effect in controlling tumor burden. Furthermore, 2-DG as adjuvant to carboplatin did not result in a significant reduction in tumor size. Conjunctival fibrosis was observed in the carboplatin + 2-DG combination group.
Regional hypoxia is present in large transgenic murine retinoblastoma tumors. The treatment of these eye tumors with both the glycolytic inhibitor 2-DG and carboplatin did not result in a significant reduction in tumor growth at the doses used. It is possible that treating advanced disease will result in enhanced tumor control since hypoxia was detected at this stage. Treatment of glycolytic inhibitors as adjuvants to vessel targeting has potential as a strategy to eliminate hypoxic regions while enhancing vascular targeting. This approach may have benefits for children with this disease and should be further investigated
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