文章：

急性淋巴细胞白血病：癌症治疗的药物基因组学模型

Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy

原文发布日期：2006-02-01

DOI: 10.1038/nrc1800

类型: Review Article

开放获取: 否

要点：

1. Germline polymorphisms are known to influence the pharmacokinetics and pharmacological effects of a growing number of anticancer agents.
2. Polymorphisms in the human thiopurine methyltransferase (TPMT) gene lead to loss of the functional protein and predispose with high penetrance to severe haematopoietic toxicity in TPMT-deficient patients, unless their dose of mercaptopurine is reduced by 90–95%.
3. Candidate-gene strategies have shown that germline polymorphisms in additional genes — such as the glutathione S-transferase genes, the uridine-5′-diphosphate-glucuronosyl-transferase genes and the thymidylate synthetase gene — are associated with the efficacy or toxicity of chemotherapy for acute lymphoblastic leukaemia (ALL).
4. Recently, distinct gene-expression profiles of primary ALL cells have been linked to the sensitivity of leukaemia cells to several antileukaemic agents in vitro, and these expression signatures also predicted treatment outcome.
5. These findings provide momentum for future genome-wide studies to identify additional genomic determinants of ALL- treatment responses. These will allow the development of polygenic models that can be used to optimize the treatment of ALL and other human cancers.

要点翻译：

1. 已知种系多态性可影响越来越多抗癌药物的药代动力学及药理作用。
2. 人类硫嘌呤甲基转移酶（TPMT）基因的多态性会导致功能性蛋白缺失，并具有高外显率，使得TPMT缺陷患者易发生严重造血系统毒性——除非将其巯嘌呤剂量降低90%-95%。
3. 候选基因策略研究表明，其他基因（如谷胱甘肽S-转移酶基因、尿苷-5′-二磷酸-葡萄糖醛酸转移酶基因和胸苷酸合成酶基因）的种系多态性与急性淋巴细胞白血病（ALL）化疗的疗效或毒性相关。
4. 近期研究发现，原代ALL细胞的独特基因表达谱与白血病细胞体外对多种抗白血病药物的敏感性相关，这些表达特征也能预测治疗结局。
5. 这些发现为未来开展全基因组研究提供了动力，以识别ALL治疗反应的其他基因组决定因素。这将促进多基因模型的开发，用于优化ALL及其他人类癌症的治疗方案。

英文摘要：

The use of combination chemotherapy to cure acute lymphoblastic leukaemia (ALL) in children emerged in the 1980s as a paradigm for curing any disseminated cancer, and many of the therapeutic principles were subsequently applied to the treatment of other disseminated human cancers. Similarly, elucidation of the pharmacogenomics of ALL and its translation into new chemotherapeutic approaches might serve as a model for optimizing the treatment of other human cancers. Germline polymorphisms and gene-expression patterns in ALL cells have been linked to the toxicity and efficacy of chemotherapy for ALL and are beginning to emerge as useful clinical diagnostics.

摘要翻译： 

联合化疗用于治愈儿童急性淋巴细胞白血病（ALL）始于20世纪80年代，为治愈任何播散性癌症树立了典范，其许多治疗原则随后被应用于其他播散性人类癌症的治疗。同样，阐明ALL的药物基因组学并将其转化为新的化疗方法，可能成为优化其他人类癌症治疗的典范。ALL细胞的遗传多态性和基因表达模式与ALL化疗的毒性和疗效相关，并开始成为有用的临床诊断手段。

原文链接：

Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy