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首页> 外文期刊>Anticancer Research: International Journal of Cancer Research and Treatment >Molecular basis of 5-fluorouracil-related toxicity: lessons from clinical practice.
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Molecular basis of 5-fluorouracil-related toxicity: lessons from clinical practice.

机译：5-氟尿嘧啶相关毒性的分子基础：来自临床实践的经验教训。

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We aim to present a comprehensive review of the molecular basis of 5-fluorouracil (5-FU) toxicity, of which dihydropyrimidine dehydrogenase (DYPD) deficiency is a well-known mechanism. The prevalence of partial DYPD deficiency is fairly common, ranging between 3-5% in the general population, whereas it can be as high as 12% in African-American females. More than 50 genetic polymorphisms have been described as being associated with decreased enzymatic activity, whereas the c.1905+1G>A point mutation is the most commonly found (52% of cases), with a prevalence of heterozygosity in the general population ranging between 1-2%. Several methods have been utilized to identify reduced DYPD activity; functional tests are expensive and only available in specialized centers. Genotyping alone is not reliable enough, as some of the polymorphisms may not result in significantly reduced DYPD activity. The rate of cardiotoxicity associated with 5-FU or capecitabine does not seem to be related to DYPD deficiency, and has been estimated to range between 1.2-8%. Several pathophysiological mechanisms seem to contribute to 5-FU cardiotoxicity, including coronary spasm, increased endothelial thrombogenicity and myocardial inflammation. Tegafur/uracil and raltitrexed may be alternative options for patients with partial DYPD deficiency and previous manifested 5-FU cardiotoxicity, respectively. Pharmacogenetics is expected to further identify and clarify the mechanisms associated with 5-FU-related toxicity, thus aiding the oncology societies to formulate specific guidance on pre-treatment testing.
机译：我们旨在对5-氟尿嘧啶（5-FU）毒性的分子基础进行全面综述，其中二氢嘧啶脱氢酶（DYPD）缺乏是众所周知的机制。 DYPD部分缺乏症的患病率相当普遍，在一般人群中为3-5％，而在非洲裔美国女性中则高达12％。已有50多种基因多态性与酶活性降低相关，而c.1905 + 1G> A点突变是最常见的（52％的病例），杂合性在普通人群中普遍存在。 1-2％。已经采用了几种方法来鉴定降低的DYPD活性。功能测试价格昂贵，并且只能在专业中心使用。单靠基因分型还不够可靠，因为某些多态性可能不会导致DYPD活性大大降低。与5-FU或卡培他滨相关的心脏毒性发生率似乎与DYPD缺乏症无关，据估计在1.2-8％之间。几种病理生理机制似乎与5-FU心脏毒性有关，包括冠脉痉挛，内皮血栓形成增加和心肌炎症。对于部分DYPD缺乏症和先前表现出的5-FU心脏毒性的患者，替加氟/尿嘧啶和raltitrexed可能是替代选择。预期药物遗传学将进一步鉴定和阐明与5-FU相关毒性有关的机制，从而帮助肿瘤学协会就治疗前检测制定具体指南。

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