dihydropyrimidine dehydrogenase
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2022 ◽  
pp. 194187442110689
Author(s):  
Rebecca Jules ◽  
Arushi Thaper ◽  
Ryan Foster ◽  
Pouya Ameli ◽  
Christopher Robinson ◽  
...  

5 fluorouracil (5-FU)-related neurotoxicity is a rare and severe complication of 5-FU administration. Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with an increased risk of serious adverse reactions due to its role in 5-FU metabolism. We report a case of acute reversible neurotoxicity with global areas of diffusion restriction in a patient with colorectal adenocarcinoma being treated with leucovorin calcium, 5-fluorouracil, and oxaliplatin (FOLFOX) without DPD deficiency following uridine triacetate administration.


Author(s):  
Jihyun Kang ◽  
Andrew HyoungJin Kim ◽  
Inseung Jeon ◽  
Jaeseong Oh ◽  
In‐Jin Jang ◽  
...  

2021 ◽  
Vol 01 (01) ◽  
pp. 72
Author(s):  
S. Crucitta ◽  
F. Sciandra ◽  
A. Cerbioni ◽  
F. Cucchiara ◽  
R. Arici ◽  
...  

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2036
Author(s):  
Paula Soria-Chacartegui ◽  
Gonzalo Villapalos-García ◽  
Luis A. López-Fernández ◽  
Marcos Navares-Gómez ◽  
Gina Mejía-Abril ◽  
...  

Among cancer patients treated with fluoropyrimidines, 10–40% develop severe toxicity. Polymorphism of the dihydropyrimidine dehydrogenase (DPYD) gene may reduce DPD function, the main enzyme responsible for the metabolism of fluoropyrimidines. This leads to drug accumulation and to an increased risk of toxicity. Routine genotyping of this gene, which usually includes DPYD *HapB3, *2A, *13 and c.2846A > T (D949V) variants, helps predict approximately 20–30% of toxicity cases. For DPD intermediate (IM) or poor (PM) metabolizers, a dose adjustment or drug switch is warranted to avoid toxicity, respectively. Societies such as the Spanish Society of Pharmacogenetics and Pharmacogenomics (SEFF), the Dutch Pharmacogenetics Working Group (DPWG) or the Clinical Pharmacogenetics Implementation Consortium (CPIC) and regulatory agencies (e.g., the Spanish Medicines Agency, AEMPS) already recommend DPYD routine genotyping. However, the predictive capacity of genotyping is currently still limited. This can be explained by the presence of unknown polymorphisms affecting the function of the enzyme. In this case-control work, 11 cases of severe fluoropyrimidine toxicity in patients who did not carry any of the four variants mentioned above were matched with 22 controls, who did not develop toxicity and did not carry any variant. The DPYD exome was sequenced (Sanger) in search of potentially pathogenic mutations. DPYD rs367619008 (c.187 A > G, p.Lys63Glu), rs200643089 (c.2324 T > G, p.Leu775Trp) and rs76387818 (c.1084G > A, p.Val362Ile) increased the percentage of explained toxicities to 38–48%. Moreover, there was an intronic variant considered potentially pathogenic: rs944174134 (c.322-63G > A). Further studies are needed to confirm its clinical relevance. The remaining variants were considered non-pathogenic.


2021 ◽  
Vol 6 (11) ◽  

Fluoropyrimidine is commonly used to treat unresectable cases of metastatic colorectal cancer or as an adjuvant therapy for colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) is an enzyme encoded by the DPYD gene, which is responsible for the rate-limiting step in pyrimidine catabolism and breaks down >80% of standard doses of 5-fluorouracil (5-FU). Reductions in DPD activity increase the half-life of 5-FU, resulting in excess 5-FU accumulation and toxicity, which can lead to life-threatening side effects. There have been several published case reports about DPD deficiency in colorectal cancer patients from Western countries. However, case reports of DPD deficiency in Japanese colorectal cancer patients are rare because the measurement of DPD activity is not covered by the public medical insurance system in Japan, and DPD activity is not currently measured in daily clinical practice. Furthermore, there have not been any reports about anticancer drug therapy for Japanese patients with DPD deficiency. In this report, we describe a case in which a Japanese patient with colorectal cancer was diagnosed with DPD deficiency. The DPD deficiency arose as a severe adverse effect of mFOLFOX6/CapOX treatment for recurrent colorectal cancer, and the patient was subsequently treated with TAS-102, without experiencing any severe adverse effects. We report this case along with a review of the literature.


2021 ◽  
pp. 107815522110491
Author(s):  
Charlotte W Ockeloen ◽  
Aron Raaijmakers ◽  
Manon Hijmans-van der Vegt ◽  
Jörgen Bierau ◽  
Judith de Vos-Geelen ◽  
...  

Decreased dihydropyrimidine dehydrogenase enzyme activity is associated with severe fluoropyrimidine-associated toxicity. Four clinically relevant variants in the DPYD gene are associated with decreased dihydropyrimidine dehydrogenase activity. However, only ∼25% of DPYD variant carriers show a decreased dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells. Objective To investigate if dihydropyrimidine dehydrogenase phenotyping has added value when combined with DPYD genotyping in predicting fluoropyrimidine-related toxicity. Methods Retrospective cohort study in which treatment and toxicity data were collected of 228 patients genotyped for four DPYD variants and phenotyped using an ex vivo peripheral blood mononuclear cell assay. Results Severe toxicity occurred in 25% of patients with a variant and normal dihydropyrimidine dehydrogenase activity, in 21% of patients without a variant and with decreased dihydropyrimidine dehydrogenase activity, and in 29% of patients without a variant and with normal dihydropyrimidine dehydrogenase activity (controls). The majority of patients with a variant or a decreased dihydropyrimidine dehydrogenase activity received an initial dose reduction (68% and 53% vs 19% in controls) and had a lower mean dose intensity (75% and 81% vs 91% in controls). Fifty percent of patients with a variant and decreased enzyme activity experienced severe toxicity, despite the lowest initial dose and whole treatment dose intensity. They also experienced more grade 4/5 toxicities. Conclusions Our results indicate that a combined genotype–phenotype approach could be useful to identify patients at increased risk for fluoropyrimidine-associated toxicity (e.g. patients with a variant and decreased dihydropyrimidine dehydrogenase activity). Because the group sizes are too small to demonstrate statistically significant differences, this warrants further research in a prospective study in a larger cohort.


Author(s):  
P. García-Alfonso ◽  
M. Saiz-Rodríguez ◽  
R. Mondéjar ◽  
J. Salazar ◽  
D. Páez ◽  
...  

Abstract5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines.


2021 ◽  
Author(s):  
Kelly E. Sullivan ◽  
Sheetal Kumar ◽  
Xin Liu ◽  
Ye Zhang ◽  
Emily Koning ◽  
...  

Abstract Pyrimidine catabolism is implicated in hepatic steatosis. Dihydropyrimidine Dehydrogenase (DPYD) is an enzyme responsible for uracil and thymine catabolism, and DPYD human genetic variability affects clinically observed toxicity following 5-Fluorouracil (5-FU) administration. In an in vitro model of diet-induced steatosis, the pharmacologic inhibition of DPYD resulted in protection from lipid accumulation. Additionally, a gain-of-function mutation of DPYD, created through clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR-Cas9) engineering, led to an increased lipid burden, which was associated with altered mitochondrial functionality in a hepatocarcionma cell line. The studies presented herein describe a novel role for DPYD in hepatocyte metabolic regulation as a modulator of hepatic steatosis.


Folia Medica ◽  
2021 ◽  
Vol 63 (5) ◽  
pp. 760-767
Author(s):  
Velko Minchev ◽  
Nadya Hristova-Avakumova ◽  
Kalina Kamenova ◽  
Liliya Atanasova ◽  
Marin Angelov ◽  
...  

Introduction: Colorectal cancer is the third most common cancer type worldwide. Fluoropyrimidines and their prodrug-based regimens are widely applied as primary medications. The main enzyme responsible for the rate-limiting step in pyrimidine and for the 5-fluorouracil catabolism is dihydropyrimidine dehydrogenase (DPD). Aim: We aimed to screen DPD level and the changes of plasma antioxidant capacity of colorectal cancer patients on 5-fluorouracil regimen.  Materials and methods: Human DPD Elisa Kit based on sandwich enzyme-linked immune-sorbent assay and spectrophotometric methods (FRAP and ABTS) were used in the study. Results: No statistically significant changes in plasma scavenging activity according to the results obtained in the ABTS system have been observed after evaluating all patients and considering DPD concentration. A decrease of the ferric reducing ability of patients’ plasma taken after the administered treatment was found. The increase of DPD level is accompanied by a decrease in the p values and therefore the statistical significance of the differences increases. Conclusions: Based on the aforementioned observations, it could be concluded that some aspects of plasma antioxidant capacity and individuals’ antioxidant status might be involved in the pathogenesis of the disease and could be altered by the activity of some enzymes. The cancer therapy in question, by the specificity of its mechanism of action, can modify patient’s oxidative status.


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