Targeting hypoxia, a novel treatment for advanced retinoblastoma.
OBJECTIVE
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
Hypoxic and vascular areas in LH(BETA)T(AG) 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. Sixteen-week-old LH(BETA)T(AG) mice received injections of saline, carboplatin (31.25 microg/20 microL), 2-DG (500 mg/kg), and carboplatin (31.25 microg/20 microL) + 2-DG (500 mg/kg). Carboplatin was administered through biweekly subconjunctival injections to right eyes only for 3 weeks. 2-DG was administered through intraperitoneal injection three times a week for 5 weeks. Saline was administered using both methods. Eyes were enucleated at 21 weeks of age and examined for residual tumor.


RESULTS
Hypoxic regions were observed in tumors larger than 3.28 mm(2). When 2-DG was combined with carboplatin, a marked decrease in tumor burden was observed that 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) and 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 with glycolytic inhibitors as adjuvants to chemotherapy has the 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.
Boutrid
Hinda
H
Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida 33101, USA.
Jockovich
Maria-Elena
ME
Murray
Timothy G
TG
Piña
Yolanda
Y
Feuer
William J
WJ
Lampidis
Theodore J
TJ
Cebulla
Colleen M
CM
D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D003847:Deoxyglucose / Q000627:therapeutic use*; D018450:Disease Progression; D004338:Drug Combinations; D004357:Drug Synergism; D005240:Feasibility Studies; D006019:Glycolysis / Q000187:drug effects; D000860:Hypoxia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D019572:Retinal Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D012171:Retinal Vessels / Q000473:pathology; D012175:Retinoblastoma / Q000150:complications / Q000188:drug therapy* / Q000473:pathology
D000963:Antimetabolites; D000970:Antineoplastic Agents; D004338:Drug Combinations; D003847:Deoxyglucose; D016190:Carboplatin