Journal
BRITISH JOURNAL OF CANCER
Volume 100, Issue 5, Pages 747-757Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjc.6604939
Keywords
radiation therapy; tumour hypoxia; hypoxia-inducible factor-1; molecular imaging
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Funding
- R&D of Molecular Imaging Equipment for Malignant Tumor Therapy Support
- New Energy and Industrial Technology Development Organization (NEDO) Japan
- Scientific Research on Priority Areas (Cancer Research)
- Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan
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Hypoxia-inducible factor-1 (HIF-1) has been reported to promote tumour radioresistance; therefore, it is recognised as an excellent target during radiation therapy. However, the inhibition of HIF-1 in unsuitable timing can suppress rather than enhance the effect of radiation therapy because its anti-angiogenic effect increases the radioresistant hypoxic fraction. In this study, we imaged changes of HIF-1 activity after treatment with radiation and/or an HIF-1 inhibitor, YC-1, and optimised their combination. Hypoxic tumour cells were reoxygenated 6 h postirradiation, leading to von Hippel-Lindau (VHL)-dependent proteolysis of HIF-1a and a resultant decrease in HIF-1 activity. The activity then increased as HIF-1a accumulated in the reoxygenated regions 24 h postirradiation. Meanwhile, YC-1 temporarily but significantly suppressed HIF-1 activity, leading to a decrease in microvessel density and an increase in tumour hypoxia. On treatment with YC-1 and then radiation, the YC-1-mediated increase in tumour hypoxia suppressed the effect of radiation therapy, whereas on treatment in the reverse order, YC-1 suppressed the postirradiation upregulation of HIF-1 activity and consequently delayed tumour growth. These results indicate that treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the therapeutic effect of radiation, and the suppression of the postirradiation upregulation of HIF-1 activity is important for the best therapeutic benefit.
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