TARGETING HYPOXIA, A NOVEL TREATMENT FOR ADVANCED RETINOBLASTOMA
Hinda Boutrid 1,
Maria-Elena Jockovich 2*,
Timothy Murray 1,
Yolanda Pina 1,
William J. Feuer 1,
Theodore J. Lampidis 3,
and
Colleen Cebulla 1
1 Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
2 Ophthalmology, Bascom Palmer Eye Institute, 1638 NW 10th Avenue, Miami, Florida, 33136, United States
3 Cell Biology and Anatomy, Univesity of Miami Miller School of Medicine, Miami, Florida, United States
* To whom correspondence should be addressed. E-mail: mjockovich{at}med.miami.edu.
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Abstract |
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Purpose: The purpose of this study was to evaluate the presence and extent of hypoxia in murine retinoblastoma tumors and the feasibility of targeting hypoxic cells as a novel therapeutic strategy.
Methods: Experiments were conducted in accordance with the ARVO statement for the use of Animals in Ophthalmic and Vision Research. Hypoxic and vascular areas in LHBETATAG mouse retinal tumors were measured using immunohistochemistry. The glycolytic inhibitor 2-Deoxy-D-Glucose (2-DG) was used to test the efficacy of targeting hypoxic cells in retinoblastoma. Ten week-old LHBETATAG mice received periocular injections of (a) saline, (b) carboplatin (31.25µg/20µl), (c) 2-DG (500 mg/kg), and (d) carboplatin (31.25µg/20µl) + 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 and examined for residual tumor.
Results: Hypoxic regions were observed in tumors larger than 3.28 mm2. When 2-DG was combined with a carboplatin, a marked decrease in tumor burden was observed, which was significantly more pronounced than when either agent was given alone. The hypoxic tumor cell population as measured by pimonidazole was markedly reduced by carboplatin + 2-DG (p<0.01) as well as by 2-DG alone (p<0.01), but not by carboplatin alone, indicating that 2-DG effectively killed hypoxic retinoblastoma cells, in vivo.
Conclusions: Treatment of glycolytic inhibitors as adjuvants to chemotherapy has potential to increase the efficacy of chemotherapy in advanced retinoblastoma. This approach may have benefits for children with this disease and should be further investigated.
Key Words:
hypoxia, retinoblastoma, transgenic animals
