Sustained radiosensitization of hypoxic glioma cells after oxygen pretreatment in an animal model of glioblastoma and in vitro models of tumor hypoxia.
Sustained radiosensitization of hypoxic glioma cells after oxygen pretreatment in an animal model of glioblastoma and in vitro models of tumor hypoxia.
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DOI：
10.1371/journal.pone.0111199
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Lee KS
中科院分区：
文献类型：
--
作者：
Clarke RH;Moosa S;Anzivino M;Wang Y;Floyd DH;Purow BW;Lee KS
多形性胶质母细胞瘤（GBM）是最常见和致命的脑癌形式，这些肿瘤对化疗和放疗具有高度抗性。放射抗性被认为是由于缺氧肿瘤区域缺乏分子氧，导致DNA损伤减少和细胞防御机制增强。在放射治疗期间对抗肿瘤缺氧的努力受到健康脑组织对辐射的敏感性随之增加的限制。然而，在放射治疗过程中存在高水平的分子氧，虽然传统上被认为是辅助氧治疗使缺氧肿瘤组织敏感的关键，但实际上可能不是必需的。我们评估了这样的概念：在辐射暴露之前通过短暂提高组织氧合来预治疗肿瘤组织可以增加放疗的疗效，即使是在肿瘤组织氧恢复到缺氧基线水平后进行放疗。使用携带颅内U87-荧光素酶异种移植物的裸鼠和肿瘤缺氧的体外模型，测试氧预处理用于产生放射增敏的功效。在GBM异种移植物中观察到氧诱导的肿瘤组织放射增敏，如通过抑制肿瘤生长和增加存活所见。此外，啮齿动物和人类神经胶质瘤细胞，和人类神经胶质瘤干细胞，表现出长期增强的脆弱性，辐射后，氧预处理在体外，即使在缺氧条件下提供辐射。HIF-1α的过度表达降低了这种放射增敏作用，表明这种作用部分是通过HIF-1依赖性机制的改变介导的。重要的是，相同时间的短暂高氧暴露不会使正常人星形胶质细胞对体外辐射敏感。总之，这些结果表明，在放疗前用高水平的氧短暂预处理肿瘤可能代表了一种选择性靶向耐辐射缺氧癌细胞的方法，并且可以作为GBM患者放射治疗的安全有效的辅助治疗。
Glioblastoma multiforme (GBM) is the most common and lethal form of brain cancer and these tumors are highly resistant to chemo- and radiotherapy. Radioresistance is thought to result from a paucity of molecular oxygen in hypoxic tumor regions, resulting in reduced DNA damage and enhanced cellular defense mechanisms. Efforts to counteract tumor hypoxia during radiotherapy are limited by an attendant increase in the sensitivity of healthy brain tissue to radiation. However, the presence of heightened levels of molecular oxygen during radiotherapy, while conventionally deemed critical for adjuvant oxygen therapy to sensitize hypoxic tumor tissue, might not actually be necessary. We evaluated the concept that pre-treating tumor tissue by transiently elevating tissue oxygenation prior to radiation exposure could increase the efficacy of radiotherapy, even when radiotherapy is administered after the return of tumor tissue oxygen to hypoxic baseline levels. Using nude mice bearing intracranial U87-luciferase xenografts, and in vitro models of tumor hypoxia, the efficacy of oxygen pretreatment for producing radiosensitization was tested. Oxygen-induced radiosensitization of tumor tissue was observed in GBM xenografts, as seen by suppression of tumor growth and increased survival. Additionally, rodent and human glioma cells, and human glioma stem cells, exhibited prolonged enhanced vulnerability to radiation after oxygen pretreatment in vitro, even when radiation was delivered under hypoxic conditions. Over-expression of HIF-1α reduced this radiosensitization, indicating that this effect is mediated, in part, via a change in HIF-1-dependent mechanisms. Importantly, an identical duration of transient hyperoxic exposure does not sensitize normal human astrocytes to radiation in vitro. Taken together, these results indicate that briefly pre-treating tumors with elevated levels of oxygen prior to radiotherapy may represent a means for selectively targeting radiation-resistant hypoxic cancer cells, and could serve as a safe and effective adjuvant to radiation therapy for patients with GBM.
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