文章：

p53在决定放射治疗敏感性中的作用

The role of p53 in determining sensitivity to radiotherapy

原文发布日期：2003-02-01

DOI: 10.1038/nrc992

类型: Review Article

开放获取: 否

要点：

1. Ionizing radiation (IR) has proved to be a powerful tool in the treatment of cancer. However, it also has serious side effects for normal tissues. The overall sensitivity of a mammalian organism to IR is determined by the pathological alterations that occur in a few sensitive tissues.
2. Organisms that survive acute toxicity of radiation can suffer from long-term remote consequences, including radiation-induced carcinogenesis and fibrosis, which develop in exposed organs (such as the kidneys, liver or lungs) months and years after irradiation.
3. Cellular DNA is the main target of IR; it causes DNA damage (genotoxic stress) by direct and indirect (free-radical-based) mechanisms. All organisms maintain a DNA-repair system that is capable of effective recovery of radiation-damaged DNA; errors in the DNA-repair process might lead to mutations and an increased risk of cancer development.
4. At the molecular level, radiation-induced damage results in activation of DNA repair, coupled with arrest at cell-cycle checkpoints, which allows the cell to repair the damage before proceeding through mitosis. This mechanism is conserved in all eukaryotes.
5. Multicellular organisms have acquired additional response mechanisms to genotoxic stress, which involve activation of the transcription factor p53. p53 can induce growth arrest or apoptosis, and these responses maintain genomic stability. Failure of this system results in cancer development and genomic instability.
6. The ways in which cells respond to IR are tissue specific and vary greatly during embryogenesis. Cells with a high proliferative capacity tend to apoptose, whereas fibroblasts — the structural component of tissues — tend to growth arrest.
7. Tumours are generally highly sensitive to gamma-radiation — because of loss of negative growth regulation and genomic stability — and are treated with many local doses to reduce damage to normal tissues.
8. Apoptosis has a relatively modest role in the tumour response to radiation; most tumours lose the ability to apoptose. The antitumour effect of radiation is realized through mitotic catastrophe or in senescence-like irreversible growth arrest.
9. Radiation sensitivity involves both intrinsic mechanisms and bystander effects, in which the failure of a certain cell type within the complex mix of tumour and normal cells leads to a chain of reactions that results in tissue failure.
10. Facilitation of radiation therapy outcome can be achieved by modulating the molecular mechanisms of the DNA-damage response in normal tissues and in tumours. So, p53 inhibition can reduce normal tissue damage and sensitize tumour cells for treatment.

要点翻译：

1. 电离辐射（IR）已被证明是治疗癌症的有效手段。然而，它也会对正常组织产生严重副作用。哺乳动物对IR的整体敏感性取决于少数敏感组织中发生的病理改变。
2. 经受住辐射急性毒性的生物体可能遭受长期远期后果，包括辐射诱发的致癌作用和纤维化，这些变化在受照射器官（如肾脏、肝脏或肺部）于照射后数月甚至数年出现。
3. 细胞DNA是IR的主要靶标；它通过直接和间接（基于自由基的）机制引起DNA损伤（基因毒性应激）。所有生物体都拥有能够有效修复辐射损伤DNA的DNA修复系统；DNA修复过程中的错误可能导致突变并增加癌症发生风险。
4. 在分子水平上，辐射诱导的损伤会激活DNA修复，同时伴随细胞周期检查点的停滞，使细胞在进入有丝分裂前完成损伤修复。这一机制在所有真核生物中均保守存在。
5. 多细胞生物进化出了应对基因毒性应激的额外机制，涉及转录因子p53的激活。p53可诱导生长停滞或细胞凋亡，这些反应能维持基因组稳定性。该系统的失效会导致癌症发生和基因组不稳定性。
6. 细胞对IR的反应方式具有组织特异性，并在胚胎发生过程中呈现显著差异。高增殖能力的细胞倾向于发生凋亡，而作为组织结构成分的成纤维细胞则倾向于生长停滞。
7. 肿瘤通常对γ射线高度敏感——这是由于负向生长调控和基因组稳定性的缺失——临床采用多次局部照射以减轻对正常组织的损伤。
8. 凋亡在肿瘤辐射反应中的作用相对有限；大多数肿瘤丧失了凋亡能力。辐射的抗肿瘤效应主要通过有丝分裂灾难或衰老样不可逆生长停滞实现。
9. 辐射敏感性既涉及内在机制，也包含旁观者效应——在肿瘤与正常细胞混杂的复杂环境中，特定细胞类型的失效会引发连锁反应，最终导致组织功能衰竭。
10. 通过调控正常组织和肿瘤中DNA损伤反应的分子机制，可改善放疗效果。例如，抑制p53既能减轻正常组织损伤，又能增敏肿瘤细胞。

英文摘要：

Ionizing radiation (IR) has proven to be a powerful medical treatment in the fight against cancer. Rational and effective use of its killing power depends on understanding IR-mediated responses at the molecular, cellular and tissue levels. Tumour cells frequently acquire defects in the molecular regulatory mechanisms of the response to IR, which sensitizes them to radiation therapy. One of the key molecules involved in a cell's response to IR is p53. Understanding these mechanisms indicates new rational approaches to improving cancer treatment by IR.

摘要翻译： 

电离辐射（IR）已被证明是抗击癌症的有力医学治疗手段。要合理有效地利用其杀伤作用，需在分子、细胞和组织水平上理解IR介导的生物学反应。肿瘤细胞常常在IR应答的分子调控机制中存在缺陷，这使它们对放疗更为敏感。在细胞对IR的应答中，p53是关键分子之一。深入理解这些机制，可为通过IR改善癌症治疗提供新的理性策略。

原文链接：

The role of p53 in determining sensitivity to radiotherapy