Endogenous metabolic markers for predicting the activity of dihydropyrimidine dehydrogenase

Kang, Ji-Hyun; Kim, Andrew Hyoung Jin; Jeon, Inseung; Oh, Jaeseong; Jang, In‐Jin; Lee, SeungHwan; Cho, Joo Youn

doi:10.1111/cts.13203

Cited by 4 publications

(3 citation statements)

References 27 publications

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“…For instance, an increase in endogenous compounds potentially leading to DPD inhibition could be observed in the plasma of patients with renal impairment. 20 , 22 , 23 , 24 Nevertheless, a case of dialyzed patients who tolerated standard 5-FU doses despite high levels uracilemia has been observed, 10 questioning the uracilemia-based phenotype in this situation. In the case of ‘false’ hyperuracilemia, as a pre-therapeutic plasma value of U ≥ 16 ng/ml may lead to a decrease in the 5-FU dose prescribed in the first line, there is a risk of 5-FU underexposure.…”

Section: Discussionmentioning

confidence: 99%

Impact of renal impairment on dihydropyrimidine dehydrogenase (DPD) phenotyping

et al. 2023

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Section: Discussionmentioning

confidence: 99%

Impact of renal impairment on dihydropyrimidine dehydrogenase (DPD) phenotyping

et al. 2023

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“…It also inhibits the formation of 5-FU catabolites that either may exert toxicity or may interfere with the antitumor activity of 5-FU. It is reported that more than 80% of 5-FU is converted to FBAL, a neurotoxic catabolite. − The developed DPD inhibitor eniluracil has shown potent inhibitory activity with no significant neurotoxicity and cardiotoxicity. Thereby, this DPD inhibitor is a protective agent that may not only counter the 5-FU resistance but also reduce the toxicity induced by 5-FU. , In humans, neutropenia is the main side effect caused by eniluracil as observed with a 5-day schedule and diarrhea with a 28-day schedule .…”

Section: Strategies To Counter Dpd-mediated Resistance To 5-fumentioning

confidence: 99%

Dihydropyrimidine Dehydrogenase-Mediated Resistance to 5-Fluorouracil: Mechanistic Investigation and Solution

Verma

Narendra

Raju

et al. 2022

ACS Pharmacol. Transl. Sci.

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5-Fluorouracil (5-FU) is one of the most widely used chemotherapeutics for the treatment of cancers associated with the aerodigestive tract, breast, and colorectal system. The efficacy of 5-FU is majorly affected by dihydropyrimidine dehydrogenase (DPD) as it degrades more than 80% of administered 5-FU into an inactive metabolite, dihydrofluorouracil. Herein we discuss the molecular mechanism of this inactivation by analyzing the interaction pattern and electrostatic complementarity of the DPD–5-FU complex. The basis of DPD overexpression in cancer cell lines due to significantly distinct levels of the miRNAs (miR-134, miR-27b, and miR-27a) compared to normal cells has also been outlined. Additionally, some kinases including sphingosine kinase 2 (SphK2) have been reported to correlate with DPD expression. Currently, to address this problem various strategies are reported in the literature, including 5-FU analogues (bypass the DPD-mediated inactivation), DPD downregulators (regulate the DPD expression levels in tumors), inhibitors (as promising adjuvants), and formulation development loaded with 5-FU (liposomes, nanoparticles, nanogels, etc.), which are briefly discussed in this Review.

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“…However, the use of 5-fluorouracil (5-FU) and its oral pro-drug, capecitabine, are associated with a significant risk of toxicity. This toxicity could be enhanced in patients with dihydropyrimidine dehydrogenase (DPD) deficiency 1 2. For this reason, on June 2020, the Spanish Agency for Medicines and Health Products recommended genotype and/or phenotype testing in patients who are candidates for these therapies 3…”

Section: Introductionmentioning

confidence: 99%

Determination of plasma uracil as a screening for dihydropyrimidine dehydrogenase deficiency: clinical application in oncological treatments

2022

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AimsTreatment with dihydropyrimidines poses a significant risk of serious adverse reactions for patients with dihydropyrimidine dehydrogenase (DPD) deficiency. This study seeks to analyse the correlation between DPD deficiency and plasmatic uracil values in patients who are candidates for a fluoropyrimidine scheme. It also studies the incidence of adverse events (AEs) in patients with DPD deficiency established with plasmatic uracil determination.MethodsThis was a retrospective observational study conducted in a tertiary level establishment from September 2020 to April 2021. Patients included were diagnosed with gastrointestinal tumours, were of good status, and were initiated into a fluoropyrimidine-based regimen. The incidence and grade of AEs, according Common Terminology Criteria for Adverse Events (CTCAE), were collected and compared in patients with and without DPD deficiency.Results119 patients diagnosed with gastrointestinal cancer met the inclusion criteria. In 92 (77%) patients there was no DPD deficiency according to plasmatic uracil thresholds. In the group of patients without deficit, dose reductions oscillated between 10–25% (mean 17.4%). In the no DPD deficiency group, 43 (46%) patients experienced AEs. Patients who had a DPD deficiency according to plasmatic uracil measurements were started on a 5-fluorouracil (5-FU) regimen with a dose reduction of 15–50% (mean 35%). In this group, 12 patients (44%) experienced some AEs.ConclusionNew research is needed to clarify the correlation between plasma uracil values and DPD deficiency to achieve an optimal balance between clinical benefit and toxicity.

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Endogenous metabolic markers for predicting the activity of dihydropyrimidine dehydrogenase

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 4 publications

References 27 publications

Impact of renal impairment on dihydropyrimidine dehydrogenase (DPD) phenotyping

Impact of renal impairment on dihydropyrimidine dehydrogenase (DPD) phenotyping

Dihydropyrimidine Dehydrogenase-Mediated Resistance to 5-Fluorouracil: Mechanistic Investigation and Solution

Determination of plasma uracil as a screening for dihydropyrimidine dehydrogenase deficiency: clinical application in oncological treatments

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