Hishinuma Eiji, Gutiérrez Rico Evelyn, Hiratsuka Masahiro
Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan.
J Clin Med. 2020 Jul 22;9(8):2342. doi: 10.3390/jcm9082342.
Fluoropyrimidine drugs (FPs), including 5-fluorouracil, tegafur, capecitabine, and doxifluridine, are among the most widely used anticancer agents in the treatment of solid tumors. However, severe toxicity occurs in approximately 30% of patients following FP administration, emphasizing the importance of predicting the risk of acute toxicity before treatment. Three metabolic enzymes, dihydropyrimidine dehydrogenase (DPD), dihydropyrimidinase (DHP), and β-ureidopropionase (β-UP), degrade FPs; hence, deficiencies in these enzymes, arising from genetic polymorphisms, are involved in severe FP-related toxicity, although the effect of these polymorphisms on in vivo enzymatic activity has not been clarified. Furthermore, the clinical usefulness of current methods for predicting in vivo activity, such as pyrimidine concentrations in blood or urine, is unknown. In vitro tests have been established as advantageous for predicting the in vivo activity of enzyme variants. This is due to several studies that evaluated FP activities after enzyme metabolism using transient expression systems in or mammalian cells; however, there are no comparative reports of these results. Thus, in this review, we summarized the results of in vitro analyses involving DPD, DHP, and β-UP in an attempt to encourage further comparative studies using these drug types and to aid in the elucidation of their underlying mechanisms.
氟嘧啶类药物（FPs），包括5-氟尿嘧啶、替加氟、卡培他滨和去氧氟尿苷，是治疗实体瘤时最广泛使用的抗癌药物之一。然而，约30%的患者在使用FPs后会出现严重毒性，这凸显了在治疗前预测急性毒性风险的重要性。三种代谢酶，二氢嘧啶脱氢酶（DPD）、二氢嘧啶酶（DHP）和β-脲基丙酸酶（β-UP）可降解FPs；因此，由基因多态性引起的这些酶的缺陷与严重的FPs相关毒性有关，尽管这些多态性对体内酶活性的影响尚未阐明。此外，目前用于预测体内活性的方法，如血液或尿液中的嘧啶浓度，其临床实用性尚不清楚。体外试验已被证实有利于预测酶变体的体内活性。这是因为有几项研究使用昆虫或哺乳动物细胞中的瞬时表达系统评估了酶代谢后的FPs活性；然而，尚无这些结果的比较报告。因此，在本综述中，我们总结了涉及DPD、DHP和β-UP的体外分析结果，以期鼓励使用这些药物类型进行进一步的比较研究，并有助于阐明其潜在机制。
