Circadian variation of dihydropyrimidine dehydrogenase mRNA expression in leukocytes and serum cortisol levels in patients with advanced gastrointestinal carcinomas compared to healthy controls

Raida, Martin; Ko, Kliche; Schwabe, Wolfgang; Häusler, Peter; Clement, Joachim H.; D, Behnke; Höffken, K.

doi:10.1007/s00432-001-0309-y

Cited by 23 publications

(1 citation statement)

References 11 publications

(12 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 16 Several reports indicated that DPD enzyme activity is partly determined by circadian rhythm, 20 although this circadian expression seems to be abolished in patients with gastrointestinal carcinomas. 21 In addition, it is not unlikely that comedication can influence the expression of DPD enzyme. Studies have indicated that oxaliplatin (an often used anticancer agent) results in a reduced DPD activity.…”

Section: Discussionmentioning

confidence: 99%

Evolution of Dihydropyrimidine Dehydrogenase Diagnostic Testing in a Single Center during an 8-Year Period of Time

Coenen¹,

Paulussen

Breuer

et al. 2019

Current Therapeutic Research

View full text Add to dashboard Cite

ObjectiveFluoropyrimidine treatment can be optimized based on dihydropyrimidine dehydrogenase (DPD) activity. DPD dysfunction leads to increased exposure to active metabolites, which can result in severe or even fatal toxicity.MethodsWe provide an overview of 8 years of DPD diagnostic testing (n = 1194).ResultsWithin the study period, our diagnostic test evolved from a single-enzyme measurement using first a radiochemical and then a nonradiochemical assay by ultra HPLC-MS in peripheral blood mononuclear cells with uracil, to a combined enzymatic and genetic test (ie, polymerase chain reaction) followed by Sanger sequence analysis of 4 variants of the DPYD gene (ie, DPYD*2A, DPYD*13, c.2846A>T, and 1129-5923C>G; allele frequencies 0.58%, 0.03%, 0.29%, and 1.35%, respectively). Patients who have 1 of the 4 variants tested (n = 814) have lower enzyme activity than the overall patient group. The majority of patients with the DPYD*2A variant (83%) consistently showed decreased enzyme activity. Only 24 (25.3%) of 95 patients (tested for 4 variants) with low enzyme activity carried a variant. Complete DPYD sequencing in a subgroup with low enzyme activity and without DPYD*2A variant (n = 47) revealed 10 genetic variants, of which 4 have not been described previously. We did not observe a strong link between DPYD genotype and enzyme activity.ConclusionsPrevious studies have shown that DPD status should be determined before treatment with fluoropyrimidine agents to prevent unnecessary side effects with possible fatal consequences. Our study in combination with literature shows that there is a discrepancy between the DPD enzyme activity and the presence of clinically relevant single nucleotide polymorphisms. At this moment, a combination of a genetic and enzyme test is preferable for diagnostic testing. (Curr Ther Res Clin Exp. 2018; 79:XXX–XXX).

show abstract

Section: Discussionmentioning

confidence: 99%

Evolution of Dihydropyrimidine Dehydrogenase Diagnostic Testing in a Single Center during an 8-Year Period of Time

Coenen¹,

Paulussen

Breuer

et al. 2019

Current Therapeutic Research

View full text Add to dashboard Cite

show abstract

Personalized Chronomodulated 5‐Fluorouracil Treatment: A Physiologically‐Based Pharmacokinetic Precision Dosing Approach for Optimizing Cancer Therapy

Marok,

Wojtyniak,

Selzer

et al. 2024

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

The discovery of circadian clock genes greatly amplified the study of diurnal variations impacting cancer therapy, transforming it into a rapidly growing field of research. Especially, use of chronomodulated treatment with 5‐fluorouracil (5‐FU) has gained significance. Studies indicate high interindividual variability (IIV) in diurnal variations in dihydropyrimidine dehydrogenase (DPD) activity – a key enzyme for 5‐FU metabolism. However, the influence of individual DPD chronotypes on chronomodulated therapy remains unclear and warrants further investigation. To optimize precision dosing of chronomodulated 5‐FU, this study aims to: (i) build physiologically‐based pharmacokinetic (PBPK) models for 5‐FU, uracil, and their metabolites, (ii) assess the impact of diurnal variation on DPD activity, (iii) estimate individual DPD chronotypes, and (iv) personalize chronomodulated 5‐FU infusion rates based on a patient's DPD chronotype. Whole‐body PBPK models were developed with PK‐Sim(R) and MoBi(R). Sinusoidal functions were used to incorporate variations in enzyme activity and chronomodulated infusion rates as well as to estimate individual DPD chronotypes from DPYD mRNA expression or DPD enzymatic activity. Four whole‐body PBPK models for 5‐FU, uracil, and their metabolites were established utilizing data from 41 5‐FU and 10 publicly available uracil studies. IIV in DPD chronotypes was assessed and personalized chronomodulated administrations were developed to achieve (i) comparable 5‐FU peak plasma concentrations, (ii) comparable 5‐FU exposure, and (iii) constant 5‐FU plasma levels via “noise cancellation” chronomodulated infusion. The developed PBPK models capture the extent of diurnal variations in DPD activity and can help investigate individualized chronomodulated 5‐FU therapy through testing alternative personalized dosing strategies.

show abstract

Dihydropyrimidine dehydrogenase mRNA expression in peripheral blood of rectal cancer patients is significantly associated with residual tumor and distant metastases following resection

Hoffmann

Brabender

Metzger

et al. 2009

Journal of Surgical Oncology

View full text Add to dashboard Cite

show abstract

Circadian variation of dihydropyrimidine dehydrogenase mRNA expression in leukocytes and serum cortisol levels in patients with advanced gastrointestinal carcinomas compared to healthy controls

Cited by 23 publications

References 11 publications

Evolution of Dihydropyrimidine Dehydrogenase Diagnostic Testing in a Single Center during an 8-Year Period of Time

Evolution of Dihydropyrimidine Dehydrogenase Diagnostic Testing in a Single Center during an 8-Year Period of Time

Personalized Chronomodulated 5‐Fluorouracil Treatment: A Physiologically‐Based Pharmacokinetic Precision Dosing Approach for Optimizing Cancer Therapy

Dihydropyrimidine dehydrogenase mRNA expression in peripheral blood of rectal cancer patients is significantly associated with residual tumor and distant metastases following resection

Contact Info

Product

Resources

About