文章：

癌症耐药性：一个不断发展的范例

Cancer drug resistance: an evolving paradigm

原文发布日期：2013-09-24

DOI: 10.1038/nrc3599

类型: Review Article

开放获取: 否

要点：

1. Tumour resistance to chemotherapy and molecularly targeted therapies limits the effectiveness of current cancer therapies.
2. Toxicity to normal tissues limits the amount of drug that can be systemically administered, and pharmacokinetic effects (absorption, distribution, metabolism and elimination (ADME)) limit the amount of drug that reaches the tumour.
3. At the level of the tumour, various resistance mechanisms can operate, such as increased drug efflux, mutations of the drug target, DNA damage repair, activation of alternative signalling pathways and evasion of cell death.
4. Tumour resistance can be intrinsic (that is, present before treatment), or acquired during treatment by various therapy-induced adaptive responses.
5. Tumours are heterogeneous; therefore, resistance can also arise by positive selection of a drug-resistant tumour subpopulation.
6. High-throughput screening techniques and systems biology approaches have the power to identify novel mechanisms of drug resistance and molecular signatures and genotypes that predict tumour response.
7. Increasingly, predictive biomarkers will be used clinically to stratify patients to receive specific therapeutics.
8. Improved understanding of the molecular basis of resistance will inevitably lead to the clinical assessment of rational drug combinations in selected patient populations.

要点翻译：

1. 肿瘤对化疗及分子靶向治疗的耐药性限制了现有癌症疗法的疗效。
2. 对正常组织的毒性作用限制了可全身给药的药物剂量，而药代动力学因素（吸收、分布、代谢和排泄）则限制了抵达肿瘤部位的药物浓度。
3. 在肿瘤层面，多种耐药机制可能同时发挥作用，例如药物外排增加、药物靶点突变、DNA损伤修复、替代信号通路激活以及细胞死亡逃逸。
4. 肿瘤耐药性可分为内在耐药（即治疗前已存在）和治疗过程中通过多种疗法诱导的适应性反应产生的获得性耐药。
5. 肿瘤具有异质性，因此耐药性也可能源于耐药性肿瘤亚群的正向选择。
6. 高通量筛选技术和系统生物学方法能够识别新的耐药机制、预测肿瘤反应的分子特征及基因型。
7. 预测性生物标志物将日益广泛应用于临床，用于对患者进行分层以接受特异性治疗。
8. 对耐药分子机制的深入理解，必将推动基于理性药物组合的临床评估在特定患者群体中的开展。

英文摘要：

Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to therapies that are designed to be selective for specific molecular targets share many features, such as alterations in the drug target, activation of prosurvival pathways and ineffective induction of cell death. With the increasing arsenal of anticancer agents, improving preclinical models and the advent of powerful high-throughput screening techniques, there are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.

摘要翻译： 

对化疗和分子靶向治疗的耐药性是当前癌症研究面临的一个重大问题。对“经典”细胞毒化疗药物以及针对特定分子靶点设计的治疗产生耐药的机制具有许多共同特征，例如药物靶点的改变、促生存通路的激活以及细胞死亡的诱导无效。随着抗癌药物的不断增加、临床前模型的改进以及强大的高通量筛选技术的出现，现在通过评估合理的治疗药物组合以及使用预测性生物标志物实现患者分层，前所未有地提供了理解和克服耐药性的机会。

原文链接：

Cancer drug resistance: an evolving paradigm