TS-1 Enhances the Effect of Radiotherapy by Suppressing Radiation-induced HIF-1 Activation and inDuc

来源 :首届全球华人辐射研究大会 | 被引量 : 0次 | 上传用户:squallleo2009
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  Purpose: 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.Materials and methods: We identified hypoxia-inducible factor-1 (HIF-1) as one of the targets of TS-1 in chemoradiotherapy.A stable transfectant NCI-H441/5HRE-Luc cells was established, which express the luciferase gene under the control ofHIF-1.A suspension of H441/5HRE-Luc cells (1 × 106 cells/100 μl of PBS) was inoculated subcutaneously into the right hind leg of 6-week-old BALB/c nu/nu mice.TS-1 was administered orally daily for 5 consecutive days from day 0 to 4, and radiation therapy (RT) was given on day 2.On day 4, mice with subcutaneous tumor xenografts of H441/5HRE-Luc were i.p.inoculated with 200 μl of D-luciferin solution (10 mg/ml), and optical in vivo imaging experiments were performed 15 min later using an IVISTM 200 Imaging System.Immunohistochemical staining(HIF-1,CD31/TUNEL) was performed after tumor xenografts were excised surgically.Results: In growth delay assays using a tumor xenograft of H441, TS-1 treatment enhanced the therapeutic effect of single γ-ray radiotherapy (14 Gy) and significantly delayed tumor growth tripling time by 1.94-fold compared to radiotherapy alone (P < 0.01).An optical in vivo imaging experiment 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.radiotherapy alone) and a significant increase in apoptosis of tumor cells (P < 0.01; vs.radiotherapy alone) in tumor xenografts.Conclusions: 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 HIF-1 as a therapeutic target to enhance the effect of radiotherapy.
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