文章：

癌症药物遗传学：多态性、途径及其他

Cancer pharmacogenetics: polymorphisms, pathways and beyond

原文发布日期：2003-12-01

DOI: 10.1038/nrc1233

类型: Review Article

开放获取: 否

要点：

1. The field of pharmacogenetics attempts to use genetic information to predict an individual's drug response. It is especially important in cancer chemotherapy given the narrow therapeutic index of these drugs.
2. So far, pharmacogenetic research has largely focused on the effect of single candidate polymorphisms. However, many of the genetic variants that are associated with extreme drug toxicity are rare and explain only a small portion of the variation seen in drug response.
3. Understanding the interactions of genetic variants within a biological or pharmacological pathway will allow for an improved ability to predict drug response.
4. Folate metabolism — a target of antifolate chemotherapeutic agents and thymidylate-synthase inhibitors — is a biological pathway of substantial interest to pharmacogenetic researchers.
5. Pharmacological pathways are being constructed for the systematic evaluation of the genes that regulate variation in the toxicity and efficacy of anticancer agents.
6. Mouse models show promise in identifying key enzymes in pharmacogenetic pathways and will allow study of genetic variation in these pathways.

要点翻译：

1. 药物遗传学领域试图利用遗传信息预测个体对药物的反应。鉴于抗癌药物的治疗窗狭窄，这在癌症化疗中尤为重要。
2. 迄今为止，药物遗传学研究主要集中于单个候选多态性的影响。然而，许多与严重药物毒性相关的遗传变异较为罕见，仅能解释药物反应中观察到的一小部分变异。
3. 理解遗传变异在生物学或药理学通路中的相互作用，将有助于提高预测药物反应的能力。
4. 叶酸代谢——作为抗叶酸化疗药物和胸苷酸合成酶抑制剂的作用靶点——是药物遗传学研究者高度关注的生物学通路。
5. 目前正在构建药理学通路，以系统评估调控抗癌药物毒性和疗效变异的相关基因。
6. 小鼠模型在识别药物遗传通路关键酶方面展现出潜力，并将有助于研究这些通路中的遗传变异。

英文摘要：

Inherited genetic variations can affect a patient's response to chemotherapeutic agents given for cancer. Pharmacogenetics aims to use knowledge of these variations to 'tailor' therapy for improved response and reduced toxicity. Most research so far has focused on single polymorphisms. A more comprehensive approach to predict treatment response will be to consider genetic variation in entire biological and pharmacological pathways. Of particular relevance to cancer chemotherapy is folate metabolism, which is the target of methotrexate and 5-fluorouracil. Furthermore, efforts have begun to construct pathways of genes that have pharmacological relevance for individual chemotherapeutic agents. Together, these pathway strategies offer a higher likelihood of achieving the promise of genetically guided cancer therapy.

摘要翻译： 

遗传变异可影响癌症患者对化疗药物的反应。药物基因组学旨在利用这些变异知识“量身定制”治疗方案，以提高疗效并降低毒性。目前大多数研究聚焦于单个多态性；更全面的预测治疗反应策略是考虑整个生物学及药理学通路中的遗传变异。叶酸代谢通路因系甲氨蝶呤和5-氟尿嘧啶的作用靶点，与癌症化疗尤为相关。此外，研究者已开始构建针对特定化疗药物具有药理学意义的基因通路。综合这些通路策略，将更有可能实现基因指导的癌症治疗前景。

原文链接：

Cancer pharmacogenetics: polymorphisms, pathways and beyond