Focal, periocular delivery of 2-deoxy-d-glucose as adjuvant to chemotherapy for treatment of advanced retinoblastoma

PURPOSE. The aim of this study was to evaluate the changes in tumor burden and hypoxia in the LHBETATAG retinal tumors after treatment with a focal, single-modality, and combination therapy using periocular carboplatin and 2-deoxy-Dglucose (2-DG). METHODS. Seventeen-week-old LHBETATAG transgenic mice (n {box drawings double horizontal} 25) were treated with periocular injections of varying doses of 2-DG (62.5, 125, 250, 500 mg/kg) to obtain a dose response. Same-aged mice (n {box drawings double horizontal} 30) received periocular injections of saline, carboplatin, and 2-DG. Mice were divided into six groups: saline; carboplatin (31.25 μg/20 μL, subtherapeutic dose); 2-DG (250 mg/kg); 2-DG (500 mg/kg); carboplatin (31.25 μg/20 μL) and 2-DG (250 mg/kg); and carboplatin (31.25 μg/20 μL) and 2-DG (500 mg/kg). Injections were administered twice weekly for three consecutive weeks. Eyes were enucleated at 20 weeks of age, snap frozen, and analyzed for hypoxic regions and tumor volume. RESULTS. The difference in percentage of hypoxia after treatment with 500 mg/kg 2-DG was statistically significant from the other dose groups (P < 0.015). The difference in tumor burden was statistically significant from the 250 mg/kg dose (P < 0.015) and 500 mg/kg dose (P < 0.001). Highly significant differences were found between the treatment types for tumor burden, percentage of hypoxia, and pimonidazole intensity (P < 0.001). Tumor burden decreased significantly after all forms of treatment (P < 0.001); however, tumor burden became significantly more reduced after treatment with combination therapy of carboplatin and 2-DG than with either treatment alone (P < 0.001). The percentage of hypoxia and pimonidazole intensity decreased after treatment with 2-DG alone and in combination with carboplatin (P < 0.001) in all treatment groups using 2-DG regardless of the 2-DG dose used. There was no percentage reduction of hypoxia after treatment with carboplatin alone (P < 0.25). CONCLUSIONS. This study demonstrates the efficacy of focal, periocular 2-DG as an adjunct to carboplatin chemotherapy to decrease both intratumoral hypoxia and tumor burden. Hypoxia is increasingly present in advanced disease of LHBETATAG retinal tumors. The use of glycolytic inhibitors as a therapeutic strategy has the potential to enhance current retinoblastoma treatments.