Application of Pharmacometrics of 5-Fluorouracil to Personalized Medicine: A Tool for Predicting Pharmacokinetic–Pharmacodynamic/Toxicodynamic Responses

Kobuchi, Shinji; Ito, Yoshiaki

doi:10.21873/anticanres.14683

Cited by 14 publications

(9 citation statements)

References 42 publications

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“…5-FU is phosphorylated and activated intracellularly, causing inhibition of DNA synthesis and RNA dysfunction ( Wigmore et al, 2010 ). Although 5-FU is a key drug used to treat many solid tumors, including gastric, colorectal, and breast cancers, it causes severe side effects, such as neutropenia, thrombocytopenia, mucositis, diarrhea, and hand-foot syndrome, in 10%–30% of patients treated with 5-FU ( Wigmore et al, 2010 ; Kobuchi and Ito, 2020 ). More than 80% of administered 5-FU is excreted through a three-step metabolic pathway involving DPD ( Figure 1 ) ( Heggie et al, 1987 ; Kunicka et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Importance of Rare DPYD Genetic Polymorphisms for 5-Fluorouracil Therapy in the Japanese Population

et al. 2022

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Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the rate-limiting enzyme in 5-fluorouracil (5-FU) degradation. In Caucasians, four DPYD risk variants are recognized to be responsible for interindividual variations in the development of 5-FU toxicity. However, these risk variants have not been identified in Asian populations. Recently, 41 DPYD allelic variants, including 15 novel single nucleotide variants, were identified in 3,554 Japanese individuals by analyzing their whole-genome sequences; however, the effects of these variants on DPD enzymatic activity remain unknown. In the present study, an in vitro analysis was performed on 41 DPD allelic variants and three DPD risk variants to elucidate the changes in enzymatic activity. Wild-type and 44 DPD-variant proteins were heterologously expressed in 293FT cells. DPD expression levels and dimerization of DPD were determined by immunoblotting after SDS-PAGE and blue native PAGE, respectively. The enzymatic activity of DPD was evaluated by quantification of dihydro-5-FU, a metabolite of 5-FU, using high-performance liquid chromatography-tandem mass spectrometry. Moreover, we used 3D simulation modeling to analyze the effect of amino acid substitutions on the conformation of DPD. Among the 41 DPD variants, seven exhibited drastically decreased intrinsic clearance (CLint) compared to the wild-type protein. Moreover, R353C and G926V exhibited no enzymatic activity, and the band patterns observed in the immunoblots after blue native PAGE indicated that DPD dimerization is required for its enzymatic activity. Our data suggest that these variants may contribute to the significant inter-individual variability observed in the pharmacokinetics and pharmacodynamics of 5-FU. In our study, nine DPD variants exhibited drastically decreased or no enzymatic activity due to dimerization inhibition or conformational changes in each domain. Especially, the rare DPYD variants, although at very low frequencies, may serve as important pharmacogenomic markers associated with the severe 5-FU toxicity in Japanese population.

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Section: Introductionmentioning

confidence: 99%

Importance of Rare DPYD Genetic Polymorphisms for 5-Fluorouracil Therapy in the Japanese Population

et al. 2022

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“…The drug 5-fluorouracil (5-FU) is used in chemotherapy for various forms of cancer, including those presenting with solid tumors in the gastrointestinal tract, breast, head, and neck (Wigmore et al, 2010;Kobuchi and Ito, 2020). It is an antimetabolite that works by preventing cell proliferation and is used in combination with other agents or as a single-drug treatment (Wigmore et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Once the agent reaches the circulatory system, most of the administered 5-FU (more than 80%) is metabolized to dihydro-5-FU (FUH 2 ) in the liver by the enzyme dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2). (Heggie et al, 1987;Kunicka et al, 2016;Kobuchi and Ito, 2020). Dihydropyrimidinase (DHPase; EC 3.5.2.2) then This article has not been copyedited and formatted.…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization of 12 Dihydropyrimidinase Allelic Variants in Japanese Individuals for the Prediction of 5-Fluorouracil Treatment-Related Toxicity

et al. 2022

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The drug 5-fluorouracil (5-FU) is the first-choice chemotherapeutic agent against advanced-stage cancers. However, 10-30% of treated patients experience grade 3-4 toxicity. The deficiency of dihydropyrimidinase (DHPase), which catalyzes the second step of the 5-FU degradation pathway, is correlated with the risk of developing toxicity. Thus, genetic polymorphisms within DPYS, the DHPase-encoding gene, could potentially serve as predictors of severe 5-FU-related toxicity. We identified 12 novel DPYS variants in 3,554 Japanese individuals, but the effects of these mutations on function remain unknown. In the current study, we performed in vitro enzymatic analyses of the 12 newly identified DHPase variants. Dihydrouracil or dihydro-5-FU hydrolytic ring-opening kinetic parameters, K m and V max , and intrinsic clearance (CL int = V max /K m ) of the wild-type DHPase and eight variants were measured. Five of these variants (R118Q, H295R, T418I, Y448H, and T513A) showed significantly reduced CL int compared with that in the wild-type. The parameters for the remaining four variants (V59F, D81H, T136M, and R490H) could not be determined as dihydrouracil and dihydro-5-FU hydrolytic ring-opening activity was undetectable. We also determined DHPase variant protein stability using cycloheximide and bortezomib. The mechanism underlying the observed changes in the kinetic parameters was clarified

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patients with gastric (Arjmandi et al, 2022), breast, head, neck and other cancers (Grem, 2000). 5-FU has still remained the cornerstone for colorectal cancer chemotherapy (Kobuchi et al, 2020). However, serious side effects and drug resistance phenomenon have limited its clinical use (Ciaffaglione et al, 2021).

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confidence: 99%

Protective Effect of Adenosine Triphosphate against 5-Fluorouracil-Induced Oxidative Ovarian Damage in vivo

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Altuner

et al. 2023

Asian Pac J Cancer Prev

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patients with gastric (Arjmandi et al., 2022), breast, head, neck and other cancers (Grem, 2000). 5-FU has still remained the cornerstone for colorectal cancer chemotherapy (Kobuchi et al., 2020). However, serious side effects and drug resistance phenomenon have limited its clinical use (Ciaffaglione et al., 2021). Serious cardiac side effects including cardiomyopathy, angina pectoris, ventricular tachycardia, heart failure, acute myocardial infarction and cardiogenic shock have been reported in patients treated with 5-FU (Zhang et al., 2018) . Nausea, diarrhea, vomiting, oral and intestinal mucositis, mouth ulcers, anorexia, neutropenia and thrombocytopenia are

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Application of Pharmacometrics of 5-Fluorouracil to Personalized Medicine: A Tool for Predicting Pharmacokinetic–Pharmacodynamic/Toxicodynamic Responses

Cited by 14 publications

References 42 publications

Importance of Rare DPYD Genetic Polymorphisms for 5-Fluorouracil Therapy in the Japanese Population

Importance of Rare DPYD Genetic Polymorphisms for 5-Fluorouracil Therapy in the Japanese Population

Functional Characterization of 12 Dihydropyrimidinase Allelic Variants in Japanese Individuals for the Prediction of 5-Fluorouracil Treatment-Related Toxicity

Protective Effect of Adenosine Triphosphate against 5-Fluorouracil-Induced Oxidative Ovarian Damage in vivo

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