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H. Boutrid, M.-E. Jockovich, C. Cebulla, T. J. Lampidis, T. G. Murray; Vascular Targeting Agent and Cytotoxic Chemotherapy Increase Hypoxia in LHBETATAG Murine Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2008;49(13):21.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the changes in hypoxic regions of LHBETATAG murine retinal tumors following treatment with vessel targeting and chemotherapy agents. Tumors were treated with carboplatin, a chemotherapeutic agent, and anecortave acetate, a vessel targeting agent and hypoxic cells were labeled by immunohistochemistry.
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. Seventy LHBetaTAG transgenic retinoblastoma mice were evaluated. The mice were divided into 3 groups and received periocular injections of (a) saline, (b) carboplatin (62.5µg/20µl), or (c) anecortave acetate (300µg/20µl). Treatment was administered once via periocular injection to right eyes only. Eyes were enucleated one day, one week and one month post injection. 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.
Levels of hypoxia significantly increase following treatment with anecortave acetate and carboplatin. Eyes treated with anecortave acetate show a 63% (p=0.01) increase in hypoxic regions in comparison with the saline-treated control group one day post injection and a 35% (p=0.01) increase one week post injection. Eyes treated with carboplatin, a DNA damaging agent that specifically targets proliferating cells, show a 70% (p=0.01) increase in hypoxic regions in comparison with the control group one day post injection and a 45% (p=0.01) increase one week post injection. Hypoxic regions are located in the tumor centers, not in the leading edges.
Hypoxic regions within the transgenic retinoblastoma tumors increase following the administration of a vessel targeting agent and cytotoxic chemotherapy. These results suggest that changes in the tumor microenvironment are evident as early as one day post treatment. We propose that treatment of advanced disease with glycolytic inhibitors as adjuvants to vessel targeting and chemotherapeutic agents will result in enhanced tumor control since glycolytic inhibitors have been shown to specifically target hypoxic cells. This approach may have benefits for children with this disease and should be further investigated.
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