文章：

预防或减少放射治疗的晚期副作用：放射生物学与分子病理学的结合

Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology

原文发布日期：2006-09-01

DOI: 10.1038/nrc1950

类型: Review Article

开放获取: 否

要点：

1. Around 50% of patients with solid malignant tumours receive radiation therapy with curative or palliative intent at some point in the course of their disease. Early and late side effects limit radiation dose and might affect the long-term health-related quality of life of the patient.
2. The classical framework for discussing early and late side effects was the target-cell hypothesis: that the severity of side effects mainly reflected cell depletion as a result of the direct cell killing of a putative target cell leading to subsequent functional deficiency. This was the prevailing biological model until the mid 1990s.
3. Recent research in radiobiology and molecular pathology has caused a change of paradigm, particularly in the understanding of late effects: radiation induces a concerted biological response at the cell and tissue level effected by the early activation of cytokine cascades.
4. Fibrogenesis and excessive extracellular matrix and collagen deposition has a key role in the development and expression of many types of late effects. This can be seen as a wound-healing response gone wrong.
5. Transforming growth factor-β is a key fibrogenic cytokine. Its activation, signalling pathway and downstream effects are understood in some detail and offer a number of potential targets for therapeutic intervention in the pathogenic process. This 'bottom-up' approach has benefited from the translation of findings from molecular pathology studies of other diseases characterized by the excessive development of fibrosis.
6. Patient-to-patient variability in the response to radiotherapy represents a 'top-down' discovery strategy whereby clinical outcome data are linked with data from high-throughput assays.
7. Radiogenomics is the study of genetic variation as an explanation for inter-individual differences in radiotherapy response. Most of the research so far has concentrated on single-nucleotide polymorphisms (SNPs) in selected candidate genes, but genome-wide approaches seem to be within reach in the near future.
8. Advances in molecular radiation pathology combined with advances in clinical radiobiology, radiation therapy planning and delivery technology are likely to improve radiation therapy outcome within the next 5–10 years.

要点翻译：

1. 约50%的实体恶性肿瘤患者会在病程中的某个阶段接受以根治或姑息为目的的放射治疗。早期与晚期副作用限制了放疗剂量，并可能影响患者与健康相关的长期生活质量。
2. 讨论早期与晚期副作用的经典框架是靶细胞假说：该假说认为副作用严重程度主要反映了由于假想靶细胞直接死亡导致的细胞耗竭，继而引发功能缺陷。这一生物学模型在1990年代中期之前一直占据主导地位。
3. 放射生物学与分子病理学的最新研究引发了范式转变，特别是在对晚期效应的理解上：辐射通过早期激活细胞因子级联反应，在细胞和组织层面诱导出协同生物反应。
4. 纤维生成及过度的细胞外基质与胶原蛋白沉积在许多晚期效应的发生和表现中起关键作用。这可被视为一种失常的伤口愈合反应。
5. 转化生长因子-β是关键致纤维化细胞因子。其激活途径、信号转导及下游效应已得到较详细阐释，为针对这一致病过程的治疗干预提供了多个潜在靶点。这种"自下而上"的研究方法得益于从其他以过度纤维化为特征的疾病中获得的分子病理学发现。
6. 患者对放疗反应的个体差异构成了"自上而下"的发现策略，通过将临床结局数据与高通量检测数据相关联进行研究。
7. 放射基因组学致力于通过遗传变异解释个体间放疗反应的差异。目前大多数研究集中于选定候选基因的单核苷酸多态性，但全基因组研究方法在不久的将来有望实现。
8. 分子放射病理学的进展，结合临床放射生物学、放疗计划与实施技术的进步，有望在未来5-10年内显著提升放疗疗效。

英文摘要：

Radiation therapy has curative or palliative potential in roughly half of all incident solid tumours, and offers organ and function preservation in most cases. Unfortunately, early and late toxicity limits the deliverable intensity of radiotherapy, and might affect the long-term health-related quality of life of the patient. Recent progress in molecular pathology and normal-tissue radiobiology has improved the mechanistic understanding of late normal-tissue effects and shifted the focus from initial-damage induction to damage recognition and tissue remodelling. This stimulates research into new pharmacological strategies for preventing or reducing the side effects of radiation therapy.

摘要翻译： 

放射治疗在约半数实体瘤中具有根治或姑息潜力，并在大多数情况下可保留器官与功能。然而，早期和晚期毒性限制了放疗的可递送剂量，并可能影响患者的长期健康相关生活质量。分子病理学及正常组织放射生物学的最新进展，深化了对晚期正常组织损伤机制的理解，使研究重心从初始损伤诱导转向损伤识别与组织重塑。这推动了旨在预防或减轻放射治疗副作用的新药理学策略的研究。

原文链接：

Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology