TS-1 enhances the effect of radiotherapy by suppressing radiation-induced hypoxia-inducible factor-1 activation and inducing endothelial cell apoptosis
TS-1 enhances the effect of radiotherapy by suppressing radiation-induced hypoxia-inducible factor-1 activation and inducing endothelial cell apoptosis
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DOI：
10.1111/j.1349-7006.2008.00943.x
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发表时间：
2008-11-01
期刊：
影响因子：
5.7
通讯作者：
Hiraoka, Masahiro
中科院分区：
文献类型：
--
作者：
Zeng, Lihua;Ou, Guangfei;Hiraoka, Masahiro
TS-1同步放化疗的治疗效果已在多种实体瘤中得到证实；然而，详细的作用机制尚未完全阐明。在本研究中，我们将缺氧诱导因子-1 (HIF-1) 确定为放化疗中 TS-1 的靶标之一。在使用非小细胞肺癌肿瘤异种移植物的生长延迟测定中，H441、TS-1治疗增强了单次伽马射线放疗（14Gy）的治疗效果，与单独放疗相比，显着延迟了肿瘤生长1.58倍（P < 0.01）。使用 HIF-1 依赖性 5HRE-luc 报告基因进行的光学体内成像实验表明，TS-1 治疗可抑制肿瘤异种移植物中辐射诱导的 HIF-1 激活。这种抑制导致内皮细胞凋亡，从而导致肿瘤异种移植物中微血管密度显着降低（P < 0.05；与单独放射治疗相比），并且肿瘤细胞凋亡显着增加（P < 0.01；与单独放射治疗相比）。所有这些结果表明，TS-1通过抑制HIF-1活性来增强辐射诱导的内皮细胞凋亡，导致肿瘤细胞的放射敏感性增加。我们的研究结果强调了 HIF-1 及其下游基因（例如血管内皮细胞生长因子）作为增强放射治疗效果的治疗靶点的重要性。 （癌症科学 2008 年；99：2327-2335）。
The therapeutic effect of concurrent chemoradiotherapy with TS-1 has been confirmed in various solid tumors; however, the detailed mechanism of action has not yet been fully elucidated. In the present study, we identified hypoxia-inducible factor-1 (HIF-1) as one of the targets of TS-1 in chemoradiotherapy. In growth delay assays using a tumor xenograft of non-small-cell lung carcinoma, H441, TS-1 treatment enhanced the therapeutic effect of single gamma-ray radiotherapy (14 Gy) and significantly delayed tumor growth by 1.58-fold compared to radiotherapy alone (P < 0.01). An optical in vivo imaging experiment using a HIF-1-dependent 5HRE-luc reporter gene revealed that TS-1 treatment suppressed radiation-induced activation of HIF-1 in the tumor xenografts. The suppression led to apoptosis of endothelial cells resulting in both a significant decrease in microvessel density (P < 0.05; vs radiation therapy alone) and a significant increase in apoptosis of tumor cells (P < 0.01; vs radiation therapy alone) in tumor xenografts. All of these results indicate that TS-1 enhances radiation-induced apoptosis of endothelial cells by suppressing HIF-1 activity, resulting in an increase in radiosensitivity of the tumor cells. Our findings strengthen the importance of both HIF-1 and its downstream gene, such as vascular endothelial cell growth factor, as therapeutic targets to enhance the effect of radiotherapy. (Cancer Sci 2008; 99: 2327-2335).