Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity
Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity
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DOI：
10.1016/j.ccr.2005.06.016
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发表时间：
2005-08-01
期刊：
影响因子：
50.3
通讯作者：
Dewhirst, MW
中科院分区：
文献类型：
--
作者：
Moeller, BJ;Dreher, MR;Dewhirst, MW
我们以前已经表明，辐射增加肿瘤中HIF-1的活性，导致肿瘤血管系统的显着辐射保护。然而，HIF-1激活对整体肿瘤放射敏感性的影响尚不清楚。我们在这里揭示，HIF-1通过调节四个不同的过程在决定肿瘤放射反应性中起着重要作用。通过促进ATP代谢、增殖和p53活化，HIF-1对肿瘤具有放射增敏作用。通过刺激内皮细胞存活，HIF-1促进肿瘤的放射抗性。因此，HIF-11阻断对肿瘤放射反应性的净效应高度依赖于治疗顺序，“放射优先”策略比替代方案显著更有效。这些数据为寻求HIF-1阻断和常规治疗的序列特异性组合提供了强有力的理论基础。
We have previously shown that radiation increases HIF-1 activity in tumors, causing significant radioprotection of the tumor vasculature. The impact that HIF-1 activation has on overall tumor radiosensitivity, however, is unknown. We reveal here that HIF-1 plays an important role in determining tumor radioresponsiveness through regulating four distinct processes. By promoting ATP metabolism, proliferation, and p53 activation, HIF-1 has a radiosensitizing effect on tumors. Through stimulating endothelial cell survival, HIF-1 promotes tumor radioresistance. As a result, the net effect of HIF-11 blockade on tumor radioresponsiveness is highly dependent on treatment sequencing, with "radiation first" strategies being significantly more effective than the alternative. These data provide a strong rationale for pursuing sequence-specific combinations of HIF-1 blockade and conventional therapeutics.