Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy.
Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy.
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DOI：
10.1038/sj.bjc.6604939
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发表时间：
2009-03-10
影响因子：
8.8
通讯作者：
Hiraoka, M.
中科院分区：
文献类型：
--
作者：
Harada, H.;Itasaka, S.;Zhu, Y.;Zeng, L.;Xie, X.;Morinibu, A.;Shinomiya, K.;Hiraoka, M.
据报道，缺氧诱导因子 - 1（HIF - 1）可促进肿瘤的放射抗性；因此，它被认为是放射治疗过程中的一个极佳靶点。然而，在不恰当的时机抑制HIF - 1可能会抑制而非增强放射治疗的效果，因为其抗血管生成作用会增加具有放射抗性的缺氧部分。在本研究中，我们对使用放射和/或一种HIF - 1抑制剂YC - 1治疗后HIF - 1活性的变化进行了成像，并优化了它们的组合。缺氧肿瘤细胞在照射后6小时复氧，导致HIF - 1α发生冯·希佩尔 - 林道（VHL）依赖性的蛋白水解，从而使HIF - 1活性降低。然后，随着HIF - 1α在照射后24小时在复氧区域积累，其活性又升高。同时，YC - 1暂时但显著地抑制了HIF - 1活性，导致微血管密度降低和肿瘤缺氧增加。先使用YC - 1然后进行放射治疗时，YC - 1介导的肿瘤缺氧增加抑制了放射治疗的效果，而顺序相反时，YC - 1抑制了照射后HIF - 1活性的上调，从而延缓了肿瘤生长。这些结果表明，治疗方案决定了HIF - 1抑制剂是增强还是抑制放射治疗效果，并且抑制照射后HIF - 1活性的上调对于获得最佳治疗效益非常重要。
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-1α and a resultant decrease in HIF-1 activity. The activity then increased as HIF-1α 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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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
3.5
作者：
Harada, Hiroshi;Kizaka-Kondoh, Shinae;Hiraoka, Masahiro
通讯作者：
Hiraoka, Masahiro
某些人类肺癌的组织学结构以及对放射疗法的可能影响。
影响因子：
8.8
作者：
THOMLINSON, R H;GRAY, L H
通讯作者：
GRAY, L H
DOI：
10.1016/s0360-3016(96)00539-1
发表时间：
1997-03-01
影响因子：
7
作者：
Kennedy, AS;Raleigh, JA;Varia, MA
通讯作者：
Varia, MA
影响因子：
8.8
作者：
Liu, J.;Harada, H.;Ogura, M.;Shibata, T.;Hiraoka, M.
通讯作者：
Hiraoka, M.