The Dihydropyrimidine Dehydrogenase Deficiency Lab of Robert B. Diasio, M.D., at Mayo Clinic is investigating mechanisms that control the expression of genes that are necessary for metabolizing 5-FU.
5-Fluorouracil (5-FU) and its orally administered prodrug, capecitabine, are fluoropyrimidine-based chemotherapeutic agents that are widely used for the treatment of colorectal cancer and other solid tumors.. The dihydropyrimidine dehydrogenase (DPYD) gene encodes the rate-limiting enzyme for fluoropyrimidine catabolism and eliminates over 80% of administered 5-FU. Dihydropyrimidine dehydrogenase (DPYD) activity is subject to wide variability, mainly due to genetic variation. This results in a broad range of enzymatic deficiency from partial (3%-5% of population) to complete loss (0.2% of population) of enzyme activity.(2,3) Patients who are deficient in DPYD are at an increased risk for side effects and toxicity when undergoing 5-FU treatment.(4) In addition, pathogenic homozygous or compound heterozygous variants within DPYD are associated with dihydropyrimidine dehydrogenase (DPD) deficiency. DPD deficiency shows large phenotypic variability, ranging from no symptoms to a convulsive disorder ...
Dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) is the rate-limiting enzyme in the uracil catabolic pathway and has a pivotal role in the pharmacokinetics of the commonly prescribed anti-cancer drug 5-fluorouracil (5-FU). Deficiency of DPD, whether due to inadequate expression or deleterious variants in DPYD, has been linked to severe toxic responses to 5-FU. Little is known about the mechanisms governing DPD expression in the liver. In this report, we show increased accumulation of RNA induced silencing complex (RISC) proteins on DPYD mRNA in cells overexpressing the highly homologous microRNAs miR-27a and miR-27b. These microRNAs were shown to repress DPD expression through two conserved recognition sites in DPYD. The IC50 of 5-FU for HCT116 cells over-expressing miR-27a or miR-27b was 4.4 µM (both), significantly lower than that for cells expressing a non-targeting (scramble) control microRNA (14.3 µM; P=3.3×10-5 and P=1.5×10-7, respectively). Mouse liver DPD enzyme activity was ...
In this study, we have evaluated the role of a partial DPD deficiency in the etiology of unexpected severe 5FU toxicity encountered in 37 cancer patients. DPD is generally considered to be the rate-limiting step in the catabolism of the pyrimidine bases uracil, thymine, and the thymine analogue 5FU. Under normal conditions, a low DPD activity is still sufficient to maintain uracil homeostasis because obligate heterozygotes do not excrete elevated levels of pyrimidine bases (20) . After the loading of these patients with uracil or thymine, however, the accumulation of pyrimidine bases in plasma and urine increased compared with normal individuals, indicating a decreased capacity in heterozygotes to degrade the pyrimidine bases (20) . We have recently demonstrated that in a patient heterozygous for a mutant DPD allele, the AUC of 5FU in plasma was strongly increased compared with controls.3 To date, a number of patients with a partial DPD deficiency have been reported to suffer from severe ...
Dihydropyrimidine dehydrogenase (DPD) is a major determinant of the efficacy and toxicity of 5-fluorouracil in various cancer therapies. Single nucleotide polymorphisms (SNPs) within DPYD have been studied extensively for years. However, known SNPs do not explain most cases of altered DPD activity and response to 5-FU. Furthermore, variations of DPYD expression in cancer patients have been reported; however, the underlying molecular mechanism is unclear. This suggests that regulation of DPYD expression may be an additional mechanism to control DPD activity. In this study, we focused on epigenetic regulation of DPD and specifically investigated the role of histone methylation on DPYD expression. Inhibition of the H3K27 methyl-transferase Ezh2 by either GSK-126 or a dominant-negative histone H3 mutant significantly increased DPYD expression in various cell lines. The expression of thymidylate synthetase, a major target of 5-fluorouracil toxicity, was not altered. Consistent with elevated DPYD ...
1GTH: Crystal Structure of the Productive Ternary Complex of Dihydropyrimidine Dehydrogenase with Nadph and 5-Iodouracil. Implications for Mechanism of Inhibition and Electron Transfer
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S-1 is an oral 5-fluorouracil (5-FU) prodrug, which is designed to improve the antitumor activity of 5-FU by inhibiting dihydropyrimidine dehydrogenase, the key enzyme of 5-FU catabolism. Recently, two important studies on the clinical use of S-1 for pancreatic cancer have been reported .... ...
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For the last few years, my mother has been battling colorectal cancer. In 2012, the primary tumor was removed, all lymph nodes appeared clear, and the pathologist, surgeon, and oncologist all agreed it looked like an early stage II tumor and therefore didnt insist on chemo. Given the Clostridium difficile infection she picked up during…
3998 DPD gene polymorphism may lead to dramatic systemic overexposure to 5-FU with subsequent sharp increase in related-toxicities, and possible fatal outcome in patients treated with standard dosage of drug. Actual implication rate of DPD deficiency in iatrogeny of fluoropyrimidines remains to be determined, since usually, little investigation on DPD status is routinely carried out in patients presenting with such severe toxicities. Beside this, impact of DPD gene polymorphism in widely prescribed capecitabine (Xeloda®) toxic profile remains unclear. The aim of the present work was to validate clinically an alternative, simplified method for indexing patients regarding their DPD status, as an attempt to detect next those at risk with fluoropyrimidine drugs. In this study, we performed a retrospective investigation in 35 patients presenting with unanticipated, severe toxicities, including 2 lethal ones, after 5-FU continuous infusion (n=33) and capecitabine intake (n=2). DPD status was ...
Complete information for DPYSL2 gene (Protein Coding), Dihydropyrimidinase Like 2, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
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Affinity-purified antibodies that recognize Thymidylate Synthase (TS), Dihydropyrimidine Dehydrogenase (DPD), and Orotate Phosphoribosyltransferase (OPRT) that can be used for Western blot or immunohistochemistry
Affinity-purified antibodies that recognize Thymidylate Synthase (TS), Dihydropyrimidine Dehydrogenase (DPD), and Orotate Phosphoribosyltransferase (OPRT) that can be used for Western blot or immunohistochemistry
Dihydropyrimidine dehydrogenase catalyzes the first and rate-limiting reaction in pyrimidine catabolism. The enzyme contains one FMN, one FAD and four Fe-S clusters per subunit of 1025 amino acids as prosthetic groups. It is also the major determinant of bioavailability and toxicity of 5-fluorouracil, a chemotherapeutic agent widely used in the treatment of solid tumors. Crystals of this enzyme diffracting to at least 2.5 A have been obtained by the hanging-drop vapour-diffusion method and belong to space group P2(1) (unit-cell parameters a = 82.0, b = 159.3, c = 163.6 A, beta = 96.1 degrees ), with two homodimers per asymmetric unit.. ...
BACKGROUND: Inherited genetic variants may influence response to, and side-effects from, chemotherapy. We sought to generate a comprehensive inherited pharmacogenetic profile for oxaliplatin and 5FU/capecitabine therapy in advanced colorectal cancer (aCRC). METHODS: We analysed more than 200 potentially functional, common, inherited variants in genes within the 5FU, capecitabine, oxaliplatin and DNA repair pathways, together with four rare dihydropyrimidine dehydrogenase (DPYD) variants, in 2183 aCRC patients treated with oxaliplatin-fluoropyrimidine chemotherapy with, or without, cetuximab (from MRC COIN and COIN-B trials). Primary end-points were response, any toxicity and peripheral neuropathy. We had |85% power to detect odds ratios (ORs) = 1.3 for variants with minor allele frequencies |20%. RESULTS: Variants in DNA repair genes (Asn279Ser in EXO1 and Arg399Gln in XRCC1) were most associated with response (OR 1.9, 95% confidence interval [CI] 1.2-2.9, P = 0.004, and OR 0.7, 95% CI 0.5-0.9, P = 0
Title:Fluoropyrimidine-associated Toxicities in Colorectal Cancer Patients: The Epigenetic Point of View. VOLUME: 4 ISSUE: 2. Author(s):Laura Bertolaso* and Milena Gusella. Affiliation:Department of Oncology, Laboratory of Pharmacology and Molecular Biology, AULSS 5 Polesana, Rovigo, Department of Oncology, Unit of Medical Oncology, AULSS 5 Polesana, Rovigo. Keywords:Colorectal cancer, 5-fluorouracil, fluoropyrimidine, toxicity, epigenetics, miRNA, dihydropyridine dehydrogenase, chemosensitivity.. Abstract:Background: Fluoropyrimidines (FPs) have been used for a long time as first-line treatment for colorectal cancer and continue to represent the backbone of combination chemotherapy in both the adjuvant and metastatic disease settings. In a consistent percentage of patients (10-40%) FPs induce severe to life-threatening toxicity. On this basis, markers of tolerance to treatment need to be found. Dihydropyrimidine dehydrogenase (DPYD) pharmacogenetic screening is a useful tool to identify ...
In the "precision medicine" era, chemotherapy still remains the backbone for the treatment of many cancers, but no affordable predictors of response to the chemodrugs are available in clinical practice. Single nucleotide polymorphisms (SNPs) are gene sequence variations occurring in more than 1% of the full population, and account for approximately 80% of inter-individual genomic heterogeneity. A number of studies have investigated the predictive role of SNPs of genes enrolled in both pharmacodynamics and pharmacokinetics of chemotherapeutics, but the clinical implementation of related results has been modest so far. Among the examined germline polymorphic variants, several SNPs of dihydropyrimidine dehydrogenase (DPYD) and uridine diphosphate glucuronosyltransferases (UGT) have shown a robust role as predictors of toxicity following fluoropyrimidine- and/or irinotecan-based treatments respectively, and a few guidelines are mandatory in their detection before therapy initiation. Contrasting ...
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Synonyms for acyl CoA dehydrogenase deficiency in Free Thesaurus. Antonyms for acyl CoA dehydrogenase deficiency. 1 synonym for acyl: acyl group. What are synonyms for acyl CoA dehydrogenase deficiency?
2) 5,6-dihydrothymine + NAD+ = thymine + NADH + H+. For diagram of reaction click here.. Other name(s): dihydropyrimidine dehydrogenase; dihydrothymine dehydrogenase; pyrimidine reductase; thymine reductase; uracil reductase; dihydrouracil dehydrogenase (NAD+). Systematic name: 5,6-dihydropyrimidine:NAD+ oxidoreductase. Comments: An iron-sulfur flavoenzyme. The enzyme was originally discovered in the uracil-fermenting bacterium, Clostridium uracilicum, which utilizes uracil and thymine as nitrogen and carbon sources for growth [1]. Since then the enzyme was found in additional organisms including Alcaligenes eutrophus [2], Pseudomonas strains [3,4] and Escherichia coli [5,6].. Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 9026-89-5. References:. 1. Campbell, L.L. Reductive degradation of pyrimidines. III. Purificaion and properties of dihydrouracil dehydrogenase. J. Biol. Chem. 227 (1957) 693-700. [PMID: 13462991]. 2. Schmitt, U., Jahnke, K., Rosenbaum, K., Cook, ...
Identification of the molecular determinants of 5-fluorouracil (5-FU) and irinotecan (CPT-11) efficacy and toxicity is critically important for the development of more efficient and less toxic treatment strategies for patients with colon cancer. We have identified molecular predictors of response to chemotherapy with 5-FU and survival in patients with advanced colorectal cancer. Low gene expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) are associated with response and survival. Preliminary data suggest that gene expression levels of topoisomerase I, p21, bcl-2, and ICE may be predictive of response to therapy with CPT-11. Increased toxicity seen in patients treated with CPT-11 may be explained by polymorphism in the UGT1A1 gene, which is responsible for glucuronidation of the active metabolite of CPT-11. ...
PRIMARY OBJECTIVES:. I. Determine the antitumor activity of capecitabine in patients with persistent or recurrent non-squamous cell carcinoma of the cervix who have failed higher priority treatment protocols.. II. Determine the nature and degree of toxicity of this drug in these patients. III. Determine whether the mRNA tumor expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) at baseline are potential predictors of clinical outcomes (response and survival) in patients treated with this drug.. IV. Determine whether the serum level of TP is a potential prognostic indicator of clinical outcomes (response and survival) in patients treated with this drug.. V. Determine whether the TS promoter polymorphism in peripheral blood is a potential prognostic indicator of clinical outcomes (response and survival) in patients treated with this drug.. VI. Determine the associations among the various measures of TS, DPD, and TP and clinical ...
Carmofur (INN) or HCFU (1-hexylcarbamoyl-5-fluorouracil) is a pyrimidine analogue used as an antineoplastic agent. It is a derivative of fluorouracil, being a lypophilic-masked analog of 5-FU that can be administered orally. Carmofur prodrug is ingested and taken up in the intestine, overcoming the problem of 5-FU degradation by dihydropyrimidine dehydrogenase. Once inside a cell, carmofur prodrug is converted into 5-FU. The mechanism of action of carmofur prodrug is traditionally thought to be the generation of 5-FU. However, carmofur is a highly potent acid ceramidase (AC) inhibitor. Ceramide influences cancer cell survival, growth and death. Inhibition of AC activity sensitizes tumor cells to the effects of antineoplastic agents and radiation. Product marketing for carmofur started in 1981. Carmofur has also been used as adjuvant chemotherapy for curatively resected colorectal cancer patients in China, Japan, and Finland for many years. Trials and meta-analyses have confirmed that the drug is ...
アルデヒド脱水素酵素欠損,フラッシュパターンおよびアルコール依存症の発症率:民族間での比 ...
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SWISS-MODEL Template Library (SMTL) entry for 1rak.1. Bacterial cytosine deaminase D314S mutant bound to 5-fluoro-4-(S)-hydroxyl-3,4-dihydropyrimidine.
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The results of the GEST study by Ueno and colleagues add to the intriguing potential role of the oral fluoropyrimidine S-1 in the treatment of pancreas adenocarcinoma. S-1 is a three-component drug consisting of tegafur (a prodrug of fluorouracil), gimeracil (5-chloro-2,4 dihydropyridine, or CDHP, a dihydropyrimidine dehydrogenase enzyme activity inhibitor), and oteracil (potassium oxonate). The drug has been extensively studied in Asia in gastrointestinal and other malignancies, and notable differences regarding pharmacogenomic and pharmacodynamic considerations have been inferred for Asian vs Western populations.. The results of the GEST study demonstrate noninferiority of S-1 to gemcitabine in advanced pancreatic cancer. However, overall survival superiority of a gemcitabine and S-1 combination over gemcitabine alone was not demonstrated. These results will lead to the use of S-1 as a single-agent instead of gemcitabine for front-line therapy for advanced pancreas adenocarcinoma in Asia for ...
Glucosephosphate Dehydrogenase Deficiency: A disease-producing enzyme deficiency subject to many variants, some of which cause a deficiency of GLUCOSE-6-PHOSPHATE DEHYDROGENASE activity in erythrocytes, leading to hemolytic anemia.
OBJECTIVE The aim of this study was to explore the genetic features of a family with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (MHBDD) which may provide the basis for the diagnosis and genetic counseling. METHOD Clinical data of the proband was collected, total RNA and genomic DNA were extracted from the peripheral blood. The whole coding region of the ACAT1 gene was amplified by RT-PCR. 5 noncoding region of the ACAT1 gene and all 6 exons and flanking intron regions of the HADH2 gene were amplified by PCR. All amplification products were directly sequenced and compared with the reference sequence. RESULT (1) The patient was a one-year-old boy who presented with psychomotor retardation and astasia when he was admitted to the hospital. Biochemical test revealed slight hyperlactatemia (3.19 mmol/L) and magnetic resonance imaging showed delayed myelination. 2-Methylacetoacetyl-CoA thiolase deficiency was suggested by gas chromatography-mass spectrometry. (2) There was no mutation in the
6.. Fanin M, Anichini A, Cassandrini D, Fiorillo C, Scapolan S, Minetti C, Cassanello M, Donati MA, Siciliano G, DAmico A, Lilliu F, Bruno C, Angelini C (2012) Allelic and phenotypic heterogeneity in 49 Italian patients with the muscle form of CPT-II deficiency. Clin Genet 82:232-239. https://doi.org/10.1111/j.1399-0004.2011.01786.x ...
Free, official coding info for 2018 ICD-10-CM E71.311 - includes detailed rules, notes, synonyms, ICD-9-CM conversion, index and annotation crosswalks, DRG grouping and more.
Treatment for Glucose 6-Phosphate Dehydrogenase Deficiency. Find Doctors Near You, Book Appointment, Consult Online, View Doctor Fees, Address, Phone Numbers and Reviews. Doctors for Glucose 6-Phosphate Dehydrogenase Deficiency | Lybrate
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