TS-1 enhances the effect of radiotherapy by suppressing radiation-induced hypoxia-inducible factor-1 activation and inducing endothelial cell apoptosis

Cancer Sci. 2008 Nov;99(11):2327-35. doi: 10.1111/j.1349-7006.2008.00943.x. Epub 2008 Sep 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Apoptosis*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / radiotherapy
  • Carcinoma, Non-Small-Cell Lung / therapy*
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Drug Combinations
  • Endothelial Cells / metabolism
  • Endothelial Cells / radiation effects
  • Humans
  • Hypoxia-Inducible Factor 1 / metabolism*
  • Immunohistochemistry
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / radiotherapy
  • Lung Neoplasms / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Oxonic Acid / therapeutic use*
  • Tegafur / therapeutic use*
  • Vascular Endothelial Growth Factor A / metabolism


  • Antimetabolites, Antineoplastic
  • Drug Combinations
  • Hypoxia-Inducible Factor 1
  • Vascular Endothelial Growth Factor A
  • S 1 (combination)
  • Tegafur
  • Oxonic Acid