文章：

药物遗传学与癌症治疗

Pharmacogenetics and cancer therapy

原文发布日期：2001-11-01

DOI: 10.1038/35101056

类型: Review Article

开放获取: 否

要点：

1. The field of pharmacogenetics has gained increased attention, particularly with the recent evidence that essentially every human gene is polymorphic. Polymorphisms in gene products that affect cancer drug metabolism can affect the toxicity or efficacy of anticancer therapy.
2. The 10% of the population harbouring mutant alleles of thiopurine methyltransferase are at increased risk of toxicity and secondary tumours after treatment with thiopurine drugs.
3. Polymorphisms in dihydropyrimidine dehydrogenase can affect the toxicity, and variations in thymidylate synthase can affect the anticancer efficacy, of the drug 5-fluorouracil.
4. A glucuronosyltransferase gene has a variable number of TA repeats in its promoter, which affect the expression levels of the enzyme. An active metabolite of a drug used to treat colon cancer, irinotecan, causes side effects more frequently in patients who have low glucuronosyltransferase on the basis of their promoter TA repeat status.
5. Glutathione transferases, enzymes that detoxify many cancer drugs, are inactivated in up to 50% of some populations.
6. Because oestrogen-replacement therapy in women is associated with a higher risk of endometrial cancer in patients who have a specific genotype in a steroid-metabolizing cytochrome P450, such pharmacogenetic information might assist in prescribing practices for oestrogen medications.
7. The data so far implicating genetic polymorphisms in cancer therapy support a practice of incorporating pharmacogenetic studies in cancer clinical trials.

要点翻译：

1. 药物遗传学领域日益受到关注，尤其是最新证据表明几乎所有人類基因都存在多态性。影响癌症药物代谢的基因产物多态性可能影响抗癌治疗的毒性或疗效。
2. 人群中10%携带硫嘌呤甲基转移酶突变等位基因的个体，在使用硫嘌呤类药物后出现毒性和继发肿瘤的风险增高。
3. 二氢嘧啶脱氢酶的多态性会影响药物5-氟尿嘧啶的毒性，而胸苷酸合成酶的变异则会影响其抗癌效果。
4. 葡萄糖醛酸转移酶基因启动子区的TA重复序列数量存在变异，这种变异会影响酶的表达水平。用于治疗结肠癌的药物伊立替康的活性代谢物，在启动子TA重复序列导致葡萄糖醛酸转移酶活性较低的患者中更易引发副作用。
5. 谷胱甘肽转移酶（一种可解毒多种抗癌药物的酶）在某些人群中的失活率高达50%。
6. 由于女性雌激素替代疗法与类固醇代谢细胞色素P450特定基因型患者子宫内膜癌风险升高相关，此类药物遗传学信息可能有助于指导雌激素药物的临床应用。
7. 目前关于基因多态性影响癌症治疗的数据支持将药物遗传学研究纳入癌症临床试验的实践模式。

英文摘要：

Pharmacogenetics is the study of how genetic variations affect drug response. These variations can affect a patient's response to cancer drugs, for which there is usually a fine line between a dosage that has a therapeutic effect and one that produces toxicity. Gaining better insight into the genetic elements of both the patient and the tumour that affect drug efficacy will eventually allow for individualized dosage determination and fewer adverse effects.

摘要翻译： 

药物遗传学研究遗传变异如何影响药物反应。这些变异可能影响患者对癌症药物的反应，因为治疗剂量与产生毒性的剂量之间通常只有细微差别。更深入地了解患者和肿瘤中影响药物疗效的遗传因素，最终将有助于实现个体化剂量确定并减少不良反应。

原文链接：

Pharmacogenetics and cancer therapy