PMID- 18823375
OWN - NLM
STAT- MEDLINE
DCOM- 20090123
LR  - 20131121
IS  - 1349-7006 (Electronic)
IS  - 1347-9032 (Linking)
VI  - 99
IP  - 11
DP  - 2008 Nov
TI  - TS-1 enhances the effect of radiotherapy by suppressing radiation-induced 
      hypoxia-inducible factor-1 activation and inducing endothelial cell apoptosis.
PG  - 2327-35
LID - 10.1111/j.1349-7006.2008.00943.x [doi]
AB  - 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.
FAU - Zeng, Lihua
AU  - Zeng L
AD  - Department of Radiation Oncology and Image-applied Therapy, Kyoto University 
      Graduate School of Medicine, Kyoto, Japan.
FAU - Ou, Guangfei
AU  - Ou G
FAU - Itasaka, Satoshi
AU  - Itasaka S
FAU - Harada, Hiroshi
AU  - Harada H
FAU - Xie, Xuejun
AU  - Xie X
FAU - Shibuya, Keiko
AU  - Shibuya K
FAU - Kizaka-Kondoh, Shinae
AU  - Kizaka-Kondoh S
FAU - Morinibu, Akiyo
AU  - Morinibu A
FAU - Shinomiya, Kazumi
AU  - Shinomiya K
FAU - Hiraoka, Masahiro
AU  - Hiraoka M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080922
PL  - England
TA  - Cancer Sci
JT  - Cancer science
JID - 101168776
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Drug Combinations)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 150863-82-4 (S 1 (combination))
RN  - 1548R74NSZ (Tegafur)
RN  - 5VT6420TIG (Oxonic Acid)
SB  - IM
MH  - Animals
MH  - Antimetabolites, Antineoplastic/*therapeutic use
MH  - *Apoptosis
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy/radiotherapy/*therapy
MH  - Cell Line, Tumor
MH  - Combined Modality Therapy
MH  - Drug Combinations
MH  - Endothelial Cells/metabolism/radiation effects
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*metabolism
MH  - Immunohistochemistry
MH  - Lung Neoplasms/drug therapy/radiotherapy/*therapy
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Oxonic Acid/*therapeutic use
MH  - Tegafur/*therapeutic use
MH  - Vascular Endothelial Growth Factor A/metabolism
EDAT- 2008/10/01 09:00
MHDA- 2009/01/24 09:00
CRDT- 2008/10/01 09:00
PHST- 2008/10/01 09:00 [pubmed]
PHST- 2009/01/24 09:00 [medline]
PHST- 2008/10/01 09:00 [entrez]
AID - CAS943 [pii]
AID - 10.1111/j.1349-7006.2008.00943.x [doi]
PST - ppublish
SO  - Cancer Sci. 2008 Nov;99(11):2327-35. doi: 10.1111/j.1349-7006.2008.00943.x. Epub 
      2008 Sep 22.