MTHFR c.665C>T guided fluoropyrimidine therapy in cancer: gender-dependent effect on dose requirements

Q2 Pharmacology, Toxicology and Pharmaceutics

Drug metabolism and personalized therapy Pub Date : 2022-03-11 DOI:10.1515/dmpt-2021-0219

Charalampia Ioannou, G. Ragia, I. Balgkouranidou, N. Xenidis, K. Amarantidis, T. Koukaki, E. Biziota, S. Kakolyris, V. Manolopoulos

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引用次数: 4

Abstract

Abstract Objectives The fluoropyrimidine derivatives 5-Fluorouracil and Capecitabine are widely used for the treatment of solid tumors. Fluoropyrimidine metabolism involves a cascade of different enzymes, including MTHFR enzyme. MTHFR c.665C>T polymorphism, leading to decreased MTHFR activity, is a potential pharmacogenomic marker for fluoropyrimidine drug response. The aim of the present study was to analyze the association of MTHFR c.665C>T polymorphism with fluoropyrimidine response in terms of therapy induced adverse events (AEs), requirement of dose reduction and delayed drug administration or therapy discontinuation. Methods The study group consisted of 313 fluoropyrimidine-treated cancer patients. PCR-RFLP was used to analyze MTHFR c.665C>T polymorphism. Results In female patients, MTHFR c.665 CT and TT genotypes were associated with dose reduction (p=0.029). In gender stratification, regression analysis adjusted for age of disease onset, body surface area and AE incidence, showed that MTHFR CT and TT genotypes increased both need for fluoropyrimidine dose reduction (OR 5.050, 95% CI 1.346–18.948, p=0.016) and percentage of dose reduction (β=3.318, 95% C.I. 1.056–5.580, p=0.004) in female patients. Such differences were not present in male patients. No other associations were found. Conclusions MTHFR c.665C>T polymorphism was associated with fluoropyrimidine dose reduction in female cancer patients. This gender*MTHFR interaction merits further investigation.

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MTHFR c.665C>T引导氟嘧啶治疗癌症:剂量需求的性别依赖效应

摘要目的氟嘧啶衍生物5-氟尿嘧啶和卡培他滨被广泛用于实体瘤的治疗。氟嘧啶代谢涉及一系列不同的酶，包括MTHFR酶。MTHFR c.665C>T多态性导致MTHFR活性降低，是氟嘧啶药物反应的潜在药物基因组学标志物。本研究的目的是分析MTHFR c.665C>T多态性与氟嘧啶反应在治疗引起的不良事件(ae)、减量要求和延迟给药或停药方面的关系。方法以313例氟嘧啶治疗的肿瘤患者为研究对象。PCR-RFLP分析MTHFR c.665C>T多态性。结果女性患者中MTHFR为c.665CT和TT基因型与剂量减少相关(p=0.029)。在性别分层中，校正发病年龄、体表面积和AE发生率的回归分析显示，MTHFR CT和TT基因型女性患者氟嘧啶减剂量需求(OR 5.050, 95% CI 1.346 ~ 18.948, p=0.016)和减剂量百分比(β=3.318, 95% CI 1.056 ~ 5.580, p=0.004)均增加。这种差异在男性患者中不存在。没有发现其他关联。结论MTHFR c.665C>T多态性与女性肿瘤患者氟嘧啶剂量减少有关。这种性别*MTHFR的相互作用值得进一步研究。

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来源期刊

Drug metabolism and personalized therapy Pharmacology, Toxicology and Pharmaceutics-Pharmacology, Toxicology and Pharmaceutics (all)

CiteScore

2.30

自引率

0.00%

发文量

期刊介绍： Drug Metabolism and Personalized Therapy (DMPT) is a peer-reviewed journal, and is abstracted/indexed in relevant major Abstracting Services. It provides up-to-date research articles, reviews and opinion papers in the wide field of drug metabolism research, covering established, new and potential drugs, environmentally toxic chemicals, the mechanisms by which drugs may interact with each other and with biological systems, and the pharmacological and toxicological consequences of these interactions and drug metabolism and excretion. Topics: drug metabolizing enzymes, pharmacogenetics and pharmacogenomics, biochemical pharmacology, molecular pathology, clinical pharmacology, pharmacokinetics and drug-drug interactions, immunopharmacology, neuropsychopharmacology.