Targeting hypoxia, a novel treatment for advanced retinoblastoma
Targeting hypoxia, a novel treatment for advanced retinoblastoma
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DOI：
10.1167/iovs.08-1751
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发表时间：
2008-07-01
影响因子：
4.4
通讯作者：
Cebulla, Colleen M.
中科院分区：
文献类型：
--
作者：
Boutrid, Hinda;Jockovich, Maria-Elena;Cebulla, Colleen M.
目的。本研究的目的是评估小鼠视网膜母细胞瘤中缺氧的存在和程度，以及以缺氧细胞为靶点作为一种新的治疗策略的可行性。方法：采用免疫组织化学方法检测LHBETA T-AG小鼠视网膜肿瘤的缺氧面积和血管面积。应用糖酵解抑制剂2-脱氧-D-葡萄糖(2-DG)检测靶向低氧细胞治疗视网膜母细胞瘤的效果。16周龄LHBETA T-AG小鼠注射生理盐水、卡铂(31.25mg20亩L)、2-DG(500 mg/kg)、卡铂(31.25mg20亩L)+2-DG(500 mg/kg)。卡铂通过两周一次的右眼结膜下注射给药，仅持续3周。2-DG腹腔注射，每周3次，连续5周。两种方法都注射生理盐水。结果：在大于3.28 mm的肿瘤中观察到缺氧区(2)。当2-DG与卡铂联合使用时，观察到肿瘤负担显著降低，这比单独给药时明显更明显。卡铂+2-DG(P<；0.01)和单独应用2-DG(P<；0.01)均能显著减少缺氧肿瘤细胞的数量，但单用卡铂不能显著减少缺氧肿瘤细胞的数量。结论糖酵解抑制剂作为化疗的辅助手段，可提高晚期视网膜母细胞瘤的化疗疗效。这种方法可能对患有这种疾病的儿童有好处，应该进行进一步的研究。
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. Hypoxic and vascular areas in LHBETA 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 LHBETA T-AG mice received injections of saline, carboplatin (31.25 mu g/20 mu L), 2-DG (500 mg/ kg), and carboplatin (31.25 mu g/20 mu L) + 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.