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Abstract：
Fluoropyrimidine-based chemotherapies are widely used to treat gastrointestinal tract, head and neck, and breast carcinomas. Severe toxicities mostly impact rapidly dividing cell lines and can occur due to the partial or complete deficiency in dihydropyrimidine dehydrogenase (DPD) catabolism. Since April 2020, the European Medicines Agency (EMA) recommends DPD testing before any fluoropyrimidine-based treatment. Currently, different assays are used to predict DPD deficiency; the two main approaches consist of either phenotyping the enzyme activity (directly or indirectly) or genotyping the four main deficiency-related polymorphisms associated with 5-fluorouracil (5-FU) toxicity. In this review, we focused on the advantages and limitations of these diagnostic methods: direct phenotyping by evaluation of peripheral mononuclear cell DPD activity (PBMC-DPD activity), indirect phenotyping assessed by uracil levels or UH2/U ratio, and genotyping DPD of four variants directly associated with 5-FU toxicity. The risk of 5-FU toxicity increases with uracil concentration. Having a pyrimidine-related structure, 5-FU is catabolised by the same physiological pathway. By assessing uracil concentration in plasma, indirect phenotyping of DPD is then measured. With this approach, in France, a decreased 5-FU dose is systematically recommended at a uracil concentration of 16 ng/ml, which may lead to chemotherapy under-exposure as uracil concentration is a continuous variable and the association between uracil levels and DPD activity is not clear. We aim herein to describe the different available strategies developed to improve fluoropyrimidine-based chemotherapy safety, how they are implemented in routine clinical practice, and the possible relationship with inefficacy mechanisms.
摘要：
基于氟嘧啶的化疗广泛用于治疗胃肠道，头部和颈部,和乳腺癌。严重的毒性主要影响快速分裂的细胞系，并且可能由于二氢嘧啶脱氢酶（DPD）分解代谢的部分或完全缺乏而发生。自2020年4月以来，欧洲药品管理局（EMA）建议在任何基于氟嘧啶的治疗之前进行DPD测试。目前,使用不同的方法来预测DPD缺乏症;两种主要方法包括对酶活性进行表型分型（直接或间接）或对与5-氟尿嘧啶（5-FU）毒性相关的四种主要缺陷相关多态性进行基因分型。在这次审查中,我们专注于这些诊断方法的优点和局限性：通过评估外周单核细胞DPD活性（PBMC-DPD活性）进行直接表型分析，通过尿嘧啶水平或UH2/U比评估的间接表型，并对与5-FU毒性直接相关的四种变体的DPD进行基因分型。5-FU毒性的风险随尿嘧啶浓度而增加。具有嘧啶相关结构，5-FU通过相同的生理途径分解代谢。通过评估血浆中尿嘧啶的浓度，然后测量DPD的间接表型。通过这种方法，在法国,在尿嘧啶浓度为16ng/ml时，系统地建议减少5-FU剂量，这可能导致化疗暴露不足,因为尿嘧啶浓度是一个连续变量,尿嘧啶水平与DPD活性之间的关联尚不清楚.我们在此旨在描述开发的不同可用策略，以提高基于氟嘧啶的化疗安全性，它们是如何在常规临床实践中实施的，以及与无效机制的可能关系。
