Novel retinoblastoma treatment avoids chemotherapy: the effect of optimally timed combination therapy with angiogenic and glycolytic inhibitors on LHBETA TAG retinoblastoma tumors
Novel retinoblastoma treatment avoids chemotherapy: the effect of optimally timed combination therapy with angiogenic and glycolytic inhibitors on LHBETA TAG retinoblastoma tumors
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DOI：
10.2147/opth.s15179
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发表时间：
2011-01-01
影响因子：
2.2
通讯作者：
Lampidis, Ted J.
中科院分区：
文献类型：
--
作者：
Houston, Samuel K.;Pina, Yolanda;Lampidis, Ted J.
目的：本研究的目的是评估血管生成和糖酵解抑制剂的最佳时机联合治疗对晚期视网膜母细胞瘤肿瘤负荷、缺氧和血管生成的影响。方法：对30只LH β T AG小鼠进行评价。将小鼠分为5组（n = 6），于16周龄（晚期肿瘤）注射a)生理盐水，b)醋酸anecortave acetate (AA), c) 2-脱氧葡萄糖（2-DG）， d) AA + 2-DG （AA治疗后1天），或e) AA + 2-DG （AA治疗后1周）。21周时摘除眼球，分析肿瘤切片缺氧、血管生成和肿瘤负荷。结果：aa注射后1天用2-DG治疗的眼睛，肿瘤负荷比单独用2-DG治疗的眼睛减少23% (P = 0.03)，比用盐水治疗的眼睛减少61% （P, 0.001）。注射aa后1周，用2-DG治疗的眼睛与单独用2-DG治疗的眼睛相比，肿瘤负荷没有显著降低（P = 0.21），与用盐水治疗的眼睛相比，肿瘤负荷降低了56% （P < 0.001）。与生理盐水对照组相比，2-DG显著降低肿瘤新生血管总密度44% (P < 0.001)，但不影响成熟血管的密度。结论：血管生成抑制剂和糖酵解抑制剂联合治疗可显著增强肿瘤控制。协同效应显示依赖于治疗的时间过程，强调最佳时机。2-DG可降低新生血管密度，在体内具有抗血管生成作用。因此，血管生成和糖酵解抑制剂可能有很大的潜力作为治疗儿童视网膜母细胞瘤的替代疗法。
Purpose: The purpose of this study was to evaluate the effect of optimally timed combination treatment with angiogenic and glycolytic inhibitors on tumor burden, hypoxia, and angiogenesis in advanced retinoblastoma tumors.Methods: LH BETA T AG mice (n = 30) were evaluated. Mice were divided into 5 groups (n = 6) and received injections at 16 weeks of age (advanced tumors) with a) saline, b) anecortave acetate (AA), c) 2-deoxyglucose (2-DG), d) AA + 2-DG (1 day post-AA treatment), or e) AA + 2-DG (1 week post-AA treatment). Eyes were enucleated at 21 weeks and tumor sections were analyzed for hypoxia, angiogenesis, and tumor burden.Results: Eyes treated with 2-DG 1 day post-AA injection showed a 23% (P = 0.03) reduction in tumor burden compared with 2-DG alone and a 61% (P, 0.001) reduction compared with saline-treated eyes. Eyes treated with 2-DG 1 week post-AA injection showed no significant decrease in tumor burden compared with 2-DG alone (P = 0.21) and a 56% (P < 0.001) decrease in comparison with saline-treated eyes. 2-DG significantly reduced the total density of new blood vessels in tumors by 44% compared to saline controls (P < 0.001), but did not affect the density of mature vasculature.Conclusions: Combination therapy with angiogenic and glycolytic inhibitors significantly enhanced tumor control. Synergistic effects were shown to be dependent on the temporal course of treatment, emphasizing optimal timing. 2-DG was shown to reduce the density of neovessels, demonstrating an antiangiogenic effect in vivo. As a result, angiogenic and glycolytic inhibitors may have significant potential as alternative therapies for treating children with retinoblastoma.