文章：

改进靶向药物放疗的策略

Strategies to improve radiotherapy with targeted drugs

原文发布日期：2011-03-24

DOI: 10.1038/nrc3007

类型: Review Article

开放获取: 否

要点：

1. Two complementary ways to improve radiotherapy are to increase the killing of tumour cells and to decrease damage to surrounding normal tissues. Central to success is finding and exploiting genetic or microenvironmental differences between normal and malignant tissues in each individual patient.
2. Modulating DNA repair: owing to genetic instability, tumours are often defective in one aspect of DNA repair but usually have backup pathways for accomplishing repair. Attacking these backup pathways can render the tumour radiosensitive while leaving the normal tissue relatively resistant. Increasing numbers of such examples are being discovered.
3. Modulating cell cycle checkpoints: tumours are often defective in one of the cell cycle checkpoints (such as the G1/S checkpoint). Inhibiting remaining checkpoints can leave tumours with less repair time, resulting in greater cell kill than in normal tissues.
4. Modulating signal transduction pathways: the PI3K–AKT, nuclear factor-κB (NF-κB), MAPK pathways and others, can all mediate radioresistance and are often aberrantly activated in tumours. Attacking these pathways with specific inhibitors is a promising avenue for increasing the radiosensitivity of tumours.
5. Modulating the microenvironment: tumours often contain radioresistant and chemoresistant hypoxic cells. Several methods are available to attack or exploit tumour hypoxia, leading to tumour-specific effects. Tumour vasculature can also be attacked in ways that increase the response to ionizing radiation.
6. Modulating normal tissue damage: a variety of strategies have shown promise in ameliorating ionizing radiation damage to normal tissues, including protection with radical scavengers, stimulating recovery with cytokines, modifying the p53 response, reducing the negative effects of inflammatory cascades and oxidative stress, and stem cell therapy.
7. The future: for any new strategies, it will be essential to define not only effects on the tumour but also effects on normal tissues. In addition, to realize personalized treatments, rapid and robust methods to assess deregulated pathways need to be developed. These then need to be combined with the development of a larger arsenal of agents inhibiting specific pathways, so that the most effective radiomodifying drug can be selected for each patient.

要点翻译：

1. 提高放疗效果的两种互补方法是增加肿瘤细胞的杀伤和减少对周围正常组织的损伤。成功的关键在于发现并利用每位患者正常组织与恶性肿瘤组织之间的遗传或微环境差异。
2. 调节DNA修复：由于遗传不稳定性，肿瘤通常在某一方面存在DNA修复缺陷，但通常拥有完成修复的备用途径。攻击这些备用途径可以使肿瘤对放射敏感，同时使正常组织相对耐受。此类例子正越来越多地被发现。
3. 调节细胞周期检查点：肿瘤通常在某一个细胞周期检查点（如G1/S检查点）存在缺陷。抑制剩余的检查点可以减少肿瘤的修复时间，从而导致比正常组织更大的细胞杀伤效果。
4. 调节信号转导通路：PI3K–AKT、核因子κB（NF-κB）、MAPK通路等均可介导放射抗性，且常在肿瘤中异常激活。使用特异性抑制剂攻击这些通路是提高肿瘤放射敏感性的有效途径。
5. 调节微环境：肿瘤常含有耐放射和耐化疗的缺氧细胞。现有多种方法可攻击或利用肿瘤缺氧，从而实现肿瘤特异性效应。肿瘤血管系统也可通过特定方式攻击，以增强对电离辐射的反应。
6. 调节正常组织损伤：多种策略在改善电离辐射对正常组织的损伤方面展现出潜力，包括使用自由基清除剂进行保护、用细胞因子刺激恢复、修饰p53反应、减轻炎症级联反应和氧化应激的负面影响，以及干细胞治疗。
7. 未来展望：对于任何新策略，不仅需明确其对肿瘤的影响，还需了解其对正常组织的作用。此外，为实现个性化治疗，需要开发快速可靠的方法来评估失调通路，并结合更多抑制特定通路的药物，从而为每位患者选择最有效的放射修饰药物。

英文摘要：

Radiotherapy is used to treat approximately 50% of all cancer patients, with varying success. The dose of ionizing radiation that can be given to the tumour is determined by the sensitivity of the surrounding normal tissues. Strategies to improve radiotherapy therefore aim to increase the effect on the tumour or to decrease the effects on normal tissues. These aims must be achieved without sensitizing the normal tissues in the first approach and without protecting the tumour in the second approach. Two factors have made such approaches feasible: namely, an improved understanding of the molecular response of cells and tissues to ionizing radiation and a new appreciation of the exploitable genetic alterations in tumours. These have led to the development of treatments combining pharmacological interventions with ionizing radiation that more specifically target either tumour or normal tissue, leading to improvements in efficacy.

摘要翻译： 

放射治疗被用于大约50%的癌症患者，但疗效不一。可给予肿瘤的离子辐射剂量取决于周围正常组织的敏感性。因此，改进放疗的策略旨在增强对肿瘤的效果或减少对正常组织的影响。在第一种方法中，必须确保不增加正常组织的敏感性；在第二种方法中，则不能保护肿瘤。有两个因素使这些方法成为可能：一是对细胞和组织对离子辐射分子反应机制的深入理解；二是对肿瘤中可利用的遗传变异的新认识。这些进展促成了药物干预与离子辐射相结合的治疗方式，可更特异性地靶向肿瘤或正常组织，从而提高疗效。

原文链接：

Strategies to improve radiotherapy with targeted drugs