Focal, periocular delivery of 2-deoxy-D-glucose as adjuvant to chemotherapy for treatment of advanced retinoblastoma.
Focal, periocular delivery of 2-deoxy-D-glucose as adjuvant to chemotherapy for treatment of advanced retinoblastoma.
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DOI：
10.1167/iovs.09-5033
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发表时间：
2010-12
影响因子：
4.4
通讯作者：
Y. Piña;S. Houston;T. Murray;H. Boutrid;M. Celdran;W. Feuer;W. Shi;E. Hernandez;T. Lampidis
中科院分区：
文献类型：
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作者：
Y. Piña;S. Houston;T. Murray;H. Boutrid;M. Celdran;W. Feuer;W. Shi;E. Hernandez;T. Lampidis
本研究的目的是评估使用眼周卡铂和2-脱氧-d-葡萄糖（2-DG）进行局灶性、单一模式和联合治疗后LH（BETA）T（AG）视网膜肿瘤的肿瘤负荷和缺氧变化。方法17周龄LH（BETA）T（AG）转基因小鼠（n = 25）眼周注射不同剂量的2-DG（62.5，125，250，500 mg/kg），观察剂量反应。相同年龄的小鼠（n = 30）接受眼周注射生理盐水，卡铂，和2-DG。将小鼠分为六组：生理盐水;卡铂（31.25 μg/20 μL，亚治疗剂量）; 2-DG（250 mg/kg）; 2-DG（500 mg/kg）;卡铂（31.25 μg/20 μL）和2-DG（250 mg/kg）;以及卡铂（31.25 μg/20 μL）和2-DG（500 mg/kg）。每周注射两次，连续三周。在20周龄时摘除眼睛，快速冷冻，并分析缺氧区域和肿瘤体积。结果2-DG 500 mg/kg组缺氧百分率与其他剂量组比较差异有统计学意义（P < 0.015）。250 mg/kg剂量（P < 0.015）和500 mg/kg剂量（P < 0.001）的肿瘤负荷差异具有统计学显著性。肿瘤负荷、缺氧百分比和哌莫硝唑强度在治疗类型之间存在高度显著性差异（P < 0.001）。所有治疗形式后肿瘤负荷均显著降低（P < 0.001）;然而，卡铂和2-DG联合治疗后肿瘤负荷的降低程度显著高于单独治疗（P < 0.001）。无论2-DG的剂量如何，所有2-DG治疗组在单独使用2-DG和与卡铂联合使用2-DG后，缺氧百分比和哌莫硝唑强度均降低（P < 0.001）。单独使用卡铂治疗后，缺氧百分比没有降低（P = 0.25）。结论：本研究证明了眼周局部2-DG作为卡铂化疗的辅助治疗，可有效降低肿瘤内缺氧和肿瘤负荷。缺氧越来越多地出现在晚期LH（BETA）T（AG）视网膜肿瘤中。使用糖酵解抑制剂作为治疗策略有可能提高目前视网膜母细胞瘤的治疗。
PURPOSE The aim of this study was to evaluate the changes in tumor burden and hypoxia in the LH(BETA)T(AG) retinal tumors after treatment with a focal, single-modality, and combination therapy using periocular carboplatin and 2-deoxy-d-glucose (2-DG). METHODS Seventeen-week-old LH(BETA)T(AG) transgenic mice (n = 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 = 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 LH(BETA)T(AG) retinal tumors. The use of glycolytic inhibitors as a therapeutic strategy has the potential to enhance current retinoblastoma treatments.