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H. Boutrid, Y. Pina, M. E. Jockovich, C. C. Cebulla, T. J. Lampidis, T. G. Murray; Vascular Targeting Agent and Glycolytic Inhibitor Combination Therapy Decreases Tumor Burden in Advanced LHBETATAG Murine Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2043.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate changes in tumor burden and hypoxic regions of LHBETATAG murine retinal tumors following treatment with combination therapy of vessel targeting and glycolytic inhibitor agents. Tumors were treated with anecortave acetate (AA), a vessel targeting agent and 2-deoxy-D-glucose (2-DG), a glycolytic inhibitor. Hypoxic cells were labeled by immunohistochemistry.
The study protocol was approved by the IACUC and follows ARVO guidelines. Twenty 16 week old LHBetaTAG mice were evaluated. Mice were divided into 5 groups and received injections of (a) saline, (b) AA (300µg/20µl), (c) 2-DG (500mg/kg), (d) AA + 2-DG (administered 1 day post AA treatment), or (e) AA + 2-DG (administered 1 week post AA treatment). Treatment of AA was given once via periocular injection to right eyes only. Treatment of 2-DG was given intraperitoneally three times a week for five weeks. Eyes were enucleated at 21 weeks of age. To assess hypoxia, mice received 60 mg/kg of pimonidazole via intraperitoneal injection. Eyes were enucleated two hours post injection, placed in OCT, snap frozen in liquid nitrogen, and sectioned. Tumor sections were analyzed for hypoxia and tumor burden.
Tumor hypoxic regions decrease completely following treatment with AA and 2-DG. Eyes treated with 2-DG one day post AA injection show a 20% (p<0.05) decrease in tumor burden in comparison with the 2-DG alone group and a 60% (p<0.05) decrease in comparison with saline treated eyes. Eyes treated with 2-DG one week post AA injection show a 15% (p<0.05) decrease in tumor burden in comparison with 2-DG alone-treated eyes and a 57.5% (p<0.05) decrease in comparison with saline treated eyes. Eyes treated with AA alone do not show a significant decrease in tumor burden in comparison with saline treated eyes.
Transgenic retinoblastoma tumors decrease following the administration of a vessel targeting agent and a glycolytic inhibitor combination therapy. We propose that treatment of advanced disease with this combination therapy will result in enhanced tumor control as AA has been shown to increase hypoxic regions within the tumor and 2-DG has been shown to target hypoxic cells. This approach may have benefits for children with this disease and should be further investigated.
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