A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature.
A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature.
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DOI：
10.3390/jpm10030113
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发表时间：
2020-09-03
影响因子：
--
通讯作者：
Filippelli A
中科院分区：
文献类型：
--
作者：
Conti V;De Bellis E;Manzo V;Sabbatino F;Iannello F;Dal Piaz F;Izzo V;Charlier B;Stefanelli B;Torsiello M;Iannaccone T;Coglianese A;Colucci F;Pepe S;Filippelli A
氟嘧啶 (FP) 主要由 DPYD 基因编码的二氢嘧啶脱氢酶 (DPD) 代谢。建议使用 FP 药物遗传学，包括四种 DPYD 多态性 (DPYD-PGx) 来定制基于 FP 的化疗。这些多态性增加了严重毒性的风险；因此，DPYD-PGx 应在启动 FP 之前执行。其他因素影响 FP 安全性，因此表型分析方法，例如 5-氟尿嘧啶 (5-FU) 清除率和 DPD 活性的测量，可以补充 DPYD-PGx。我们描述了一系列患者的病例，我们对这些患者进行了 DPYD-PGx（通过实时 PCR）、5-FU 清除率和二氢尿嘧啶/尿嘧啶比率（作为表型分析）和连续临床监测。然后，已经经历过严重毒性的患者被确定为 DPYD 变体的携带者。血浆二氢尿嘧啶/尿嘧啶比率（通过高效液相色谱（HPLC）测定）在1.77和7.38之间。在 3/11 的患者中测量了 5-FU 清除率（通过超高效液相色谱法和串联质谱法）。其中之一是5-FU剂量减半后减少；在另一种情况下，尽管剂量大幅减少，但它仍然很高。此外，我们对用作 FP 安全性预测因素的基因分型/表型组合进行了系统评价。测量血浆 5-FU 清除率和/或二氢尿嘧啶/尿嘧啶 (UH2/U) 比率可以提高 DPYD-PGx 的预测潜力。前期 DPYD-PGx 结合临床监测和可行的表型分析方法对于优化基于 FP 的化疗至关重要。
Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.
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DOI：
10.1016/j.curtheres.2018.10.001
发表时间：
2019-01-01
影响因子：
1.9
作者：
Coenen, Marieke J. H.;Paulussen, Aimee D. C.;van den Bosch, Bianca J. C.
通讯作者：
van den Bosch, Bianca J. C.
影响因子：
9.3
作者：
Hamzic, Seid;Kummer, Dominic;Largiader, Carlo R.
通讯作者：
Largiader, Carlo R.
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
3.5
作者：
Jacobs, Bart A. W.;Deenen, Maarten J.;Huitema, Alwin D. R.
通讯作者：
Huitema, Alwin D. R.
影响因子：
3.4
作者：
Liu, Yong-Ping;Ling, Yang;Pan, Yao-Dong
通讯作者：
Pan, Yao-Dong