48 poster: Treatment Regimen Determines Whether a HIF-1 Inhibitor Enhances or Inhibits the Effect of Radiation Therapy

Hypoxia-inducible factor-1 (HIF-1) has been reported to promote tumour radioresistance; therefore, it is recognised as an excellenttarget during radiation therapy. However, the inhibition of HIF-1 in unsuitable timing can suppress rather than enhance the effect ofradiation therapy because its anti-angiogenic effect increases the radioresistant hypoxic fraction. In this study, we imaged changes ofHIF-1 activity after treatment with radiation and/or an HIF-1 inhibitor, YC-1, and optimised their combination. Hypoxic tumour cellswere reoxygenated 6h postirradiation, leading to von Hippel-Lindau (VHL)-dependent proteolysis of HIF-1a and a resultantdecrease in HIF-1 activity. The activity then increased as HIF-1a accumulated in the reoxygenated regions 24h postirradiation.Meanwhile, YC-1 temporarily but significantly suppressed HIF-1 activity, leading to a decrease in microvessel density and an increasein tumour hypoxia. On treatment with YC-1 and then radiation, the YC-1-mediated increase in tumour hypoxia suppressedthe effect of radiation therapy, whereas on treatment in the reverse order, YC-1 suppressed the postirradiation upregulation ofHIF-1 activity and consequently delayed tumour growth. These results indicate that treatment regimen determines whether an HIF-1inhibitor enhances or inhibits the therapeutic effect of radiation, and the suppression of the postirradiation upregulation ofHIF-1 activity is important for the best therapeutic benefit.British Journal of Cancer (2009) 100, 747–757. doi:10.1038/sj.bjc.6604939 www.bjcancer.comPublished online 17 February 2009& 2009 Cancer Research UKKeywords: radiation therapy; tumour hypoxia; hypoxia-inducible factor-1; molecular imagingA tumour-specific microenvironment, hypoxia, is associated withresistance to radiation therapy because the depletion of oxygendisturbs radiolysis of H