5-Fluorouracil and dihydropyrimidine dehydrogenase

Kubota, Tetsuro

doi:10.1007/s10147-003-0319-7

Cited by 39 publications

(25 citation statements)

References 23 publications

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“…(DPYS; OMIM 222748; EC 3.5.2.2) and finally β-ureidopropionase (UPB1; OMIM 606673; EC 3.5.1.6) converting fluoro-β-ureidopropionate to fluoro-β-alanine excreted in urine [3,4]. Dihydropyrimidine dehydrogenase is ubiquitously expressed cytosolic enzyme with a high activity in the liver and mononuclear lymphocytes [5].…”

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confidence: 99%

“…Both homozygotes and heterozygotes carrying mutations in DPYD altering structure of the enzyme were shown to have decreased 5-FU catabolism [10]. Over 50 different sequence variants of DPYD were described in patients with severe toxicity following 5-FU treatment so far, and several of them are referred to as disease-causing gene alterations [10][11][12]. Despite the widely accepted disease-causing mutations (e.g.…”

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Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy

Kleibl

Fidlerová²,

Kleiblová³

et al. 2009

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Alterations in dihydropyrimidine dehydrogenase gene (DPYD) coding for the key enzyme (DPD) of fluoropyrimidines (FPs) catabolism contribute to the development of serious FPs-related toxicity. We performed mutation analysis of DPYD based on cDNA sequencing in 76 predominantly colorectal cancer patients treated by FPs with early development of high (grade 3-4) hematological and/or gastrointestinal toxicity. Six previously described [85T>C (C29R), 496A>G (M166V), 775A>G (K259E), 1601G>A (S534N), 1627A>G (I543V), IVS14+1G>A, 2194G>A (V732I)] and two novel [187A>G (K63E) and 1050 G>A (R357H)] non-synonymous DPYD variants were found in 56/76 (73.7%) high-toxicity patients. Subsequently, these alterations were analyzed in 48 patients with excellent long-term tolerance of FPs and in 243 controls and were detected in 37/48 (77.1%) and 166/243 (68.3%) cases, respectively. Analysis of these alterations as risk factors for development of toxicity in pooled FPs-treated population demonstrated that C29R negatively correlated with overall gastrointestinal toxicity (OR = 0.48; 95%CI 0.23-1.0) and M166V in women protected against overall hematological toxicity and neutropenia (both OR = 0.26; 95%CI 0.07-0.89), whereas IVS14+1G>A (found in five high-toxicity patients only) increased risk of mucositis in overall population (OR = 7.0; 95%CI 1.1-44.53), and thrombocytopenia in women (OR = 10.8; 95%CI 1.24-93.98). Moreover, we identified a strong association of V732I with leucopenia (OR = 8.17; 95%CI 2.44 -27.31) and neutropenia (OR=2.78; 95% CI 1.03-7.51). Our data enabled characterization of "high risk" haplotypes (carriers of IVS14+1G>A or V732 lacking M166V) representing small (22% female and 11% male patients), population in high risk of serious hematological toxicity development, and in patients with "lower risk" that unlikely develop serious hematological toxicity [carriers of M166V without IVS14+1G>A and V732I in females (32% women), and non-carriers of C29R, M166V, IVS14+1G>A, and V732I in males (46% men)]. Our results indicate that genotyping of several DPYD variants may lead to stratification of patients with respect to the risk of serious hematological toxicity development during FPs treatment. Key words: dihydropyrimidine dehydrogenase gene [DPYD], fluoropyrimidines, 5-fluorouracil toxicity, mutation analysis, haplotypes, association study* Corresponding author † These authors contributed equally to this work.Fluoropyrimidines -5-fluorouracil (5-FU) and its derivates (e.g. capecitabine) -belong to the most frequently used anticancer drugs in treatment of solid cancers. Mechanism of action of 5-FU involves its anabolic conversions to 5-fluoropyrimidine nucleotides that exert profound inhibitory effect on thymidylate synthetase activity and interfere with RNA and DNA metabolism [1]. The development of severe toxicity is the critical complication of 5-FU-based therapy. It occurs in nearly one third of cases with progression to life-threatening complications in approximately 0.5% patients [2].About 80% of 5-FU is quickly ina...

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confidence: 99%

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confidence: 99%

Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy

Kleibl

Fidlerová²,

Kleiblová³

et al. 2009

neo

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“…The need to understand the catabolic and biosynthetic roles of this pathway is demonstrated by recent discoveries of human pathologies that appear to be associated with these enzymes. DPD deficiency among patients is associated with toxic reactions to 5-fluorouracil (5-FU), one of the most commonly prescribed chemotherapeutic agents used to treat cancer (van Kuilenburg et al 2000;Gross et al 2003;Kubota 2003;van Kuilenburg 2004). Furthermore, deficiencies for DPD, DHP, or bAS have been reported among individuals exhibiting a variety of clinical presentations, including convulsive and other neurological disorders (Hamajima et al 1998;van Kuilenburg et al 1999van Kuilenburg et al , 2002van Kuilenburg et al , 2003van Kuilenburg et al , 2005.…”

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Analysis of Pyrimidine Catabolism inDrosophila melanogasterUsing Epistatic Interactions With Mutations of Pyrimidine Biosynthesis and β-Alanine Metabolism

Rawls

2006

Genetics

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The biochemical pathway for pyrimidine catabolism links the pathways for pyrimidine biosynthesis and salvage with b-alanine metabolism, providing an array of epistatic interactions with which to analyze mutations of these pathways. Loss-of-function mutations have been identified and characterized for each of the enzymes for pyrimidine catabolism: dihydropyrimidine dehydrogenase (DPD), su(r) mutants; dihydropyrimidinase (DHP), CRMP mutants; b-alanine synthase (bAS), pyd3 mutants. For all three genes, mutants are viable and fertile and manifest no obvious phenotypes, aside from a variety of epistatic interactions. Mutations of all three genes disrupt suppression by the rudimentary gain-of-function mutation (r Su(b) ) of the dark cuticle phenotype of black mutants in which b-alanine pools are diminished; these results confirm that pyrimidines are the major source of b-alanine in cuticle pigmentation. The truncated wing phenotype of rudimentary mutants is suppressed completely by su(r) mutations and partially by CRMP mutations; however, no suppression is exhibited by pyd3 mutations. Similarly, su(r) mutants are hypersensitive to dietary 5-fluorouracil, CRMP mutants are less sensitive, and pyd3 mutants exhibit wild-type sensitivity. These results are discussed in the context of similar consequences of 5-fluoropyrimidine toxicity and pyrimidine catabolism mutations in humans.

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“…5-FU is thought to act through its active metabolite 5-fluorodeoxyuridine diphosphate, which, together with the coenzyme 5,10-methylenetetrahydrofolate, forms a covalent ternary complex with the DNA de novo synthesizing enzyme thymidine synthetase (TS), blocking the conversion of deoxyuridine monophosphate to thymidine monophosphate and thus inhibiting DNA synthesis. Although the cytotoxic effects of 5-FU are directly mediated via the anabolic pathway, 80% of the 5-FU administered is catabolized by the degrading enzyme dihydropyrimidine dehydrogenase (DPD) [6, 7]. Pharmacogenetic variability of these enzymes might be a major determinant of variations in the outcome of cancer patients treated with 5-FU [8,9,10,11,12,13].…”

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confidence: 99%

Overexpression of the Orotate Phosphoribosyl-Transferase Gene Enhances the Effect of 5-Fluorouracil on Gastric Cancer Cell Lines

Taomoto

Yoshida²,

Wada³

et al. 2006

Oncology

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Objective: Orotate phosphoribosyl-transferase (OPRT) is the initial enzyme of the 5-fluorouracil (5-FU) metabolic pathway, converting 5-FU into 5-fluorouridinemonophosphate, which is the most important mechanism of 5-FU activation. We therefore investigated whether overexpression of the OPRT gene enhances sensitivity to 5-FU. Methods: An expression vector of the OPRT gene (pTARGET-OPRT) was transfected into two gastric cancer cell lines, TMK-1 and MKN-45, with low baseline expression levels of OPRT. The sensitivity to and anti-tumor activity of 5-FU were then investigated in vitro and in vivo in these two transfected clones (TMK-OPRT and MKN-OPRT). Results: Although cell growth was unaltered compared to parent cells, overexpression of the OPRT gene was confirmed by Western blotting in both the TMK-OPRT and MKN-OPRT cells. OPRT enzyme activity increased 38-fold in TMK-OPRT cells and 8.0 fold in MKN-OPRT cells compared to their parent cells. Interestingly, although the sensitivity to Adriamycin, cis-platinum, mitomycin C and paclitaxel was unaltered in the transfected clones, the sensitivity to 5-FU was increased 14.2- and 6.0-fold in TMK-OPRT and MKN-OPRT cells, respectively, compared to their parent cells. Moreover, enhanced sensitivity was also confirmed in the in vivo study. Conclusion: The results indicate that overexpression of the OPRT gene plays an important role in the antiproliferative effect of 5-FU and might therefore be a predictive factor of response to 5-FU in gastric cancer patients.

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5-Fluorouracil and dihydropyrimidine dehydrogenase

Cited by 39 publications

References 23 publications

Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy

Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy

Analysis of Pyrimidine Catabolism inDrosophila melanogasterUsing Epistatic Interactions With Mutations of Pyrimidine Biosynthesis and β-Alanine Metabolism

Overexpression of the Orotate Phosphoribosyl-Transferase Gene Enhances the Effect of 5-Fluorouracil on Gastric Cancer Cell Lines

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