Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity.

Wei, Xiaoxiong; McLeod, Howard L.; McMURROUGH, J.; Gonzalez, Frank J.; Fernández-Salguero, Pedro M.

doi:10.1172/jci118830

Cited by 325 publications

(196 citation statements)

References 24 publications

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“…As a result, 5-FU degradation generally occurs in all tissues, including tumour tissues, but it reaches its highest level in the liver (Ho et al, 1986). In fact, a congenital deficiency of DPD can result in severe life-threatening toxicity when 5-FU is administered (Wei et al, 1996). In contrast, many experimental studies have demonstrated the intratumoural DPD activity to affect the resistance to 5-FU (Beck et al, 1994;Ishikawa et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT

et al. 2006

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The sensitivity to 5-fluorouracil (5-FU) has been reported to be associated with target molecule thymidylate synthase (TS), fluoropyrimidine-metabolising enzymes such as orotate phosphoribosyltransferase (OPRT), and dihydropyrimidine dehydrogenase (DPD). We performed an immunohistochemical study on the clinical significance of TS, OPRT, and DPD expression using 151 resected non-small-cell lung cancer (NSCLC) patients postoperatively treated with a combination of tegafur and uracil (UFT). Eightytwo carcinomas were TS-positive, 105 carcinomas were OPRT-positive, 68 carcinomas were DPD-positive. No correlation was observed in the HSCORE between the TS and OPRT expression (r ¼ 0.203), between the TS and DPD expression (r ¼ 0.098), or between the OPRT and DPD expression (r ¼ 0.074). Regarding the survival of NSCLC patients treated with UFT, the 5-year survival rate of patients with TS-negative tumours was significantly higher than that with TS-positive tumours (P ¼ 0.0133). The 5-year survival rate of patients with OPRT-positive stage II to III tumours was significantly higher than that with OPRT-negative stage II to III tumours (P ¼ 0.0145). In addition, the 5-year survival rate of patients with DPD-negative tumours was also significantly higher than that with DPD-positive tumours (P ¼ 0.0004). A Cox multivariate regression analysis revealed the TS status (hazard ratio 2.663; P ¼ 0.0003), OPRT status (hazard ratio 2.543; P ¼ 0.0005), and DPD status (hazard ratio 2.840; Po0.0001) to all be significant prognostic factors for the survival of resected NSCLC patients postoperatively treated with UFT.

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Section: Discussionmentioning

confidence: 99%

Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT

et al. 2006

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“…A set of studies [26][27][28][29][30] highlighted the pivotal role of DPYD gene polymorphisms in the insurgence of severe toxicity and led to the definition of pharmacogenetic guidelines for the diagnostic use of some DPYD SNPs testing (i.e., DPYDrs3918290, DPYD-rs67376798, and DPYD-rs55886062). 1 These results were further validated in successive studies which assessed the role of these SNPs in prospective clinical trials, 3,8,9 in retrospective patients collections 7,10,11 and in meta-analysis studies.…”

Section: Cancer Therapymentioning

confidence: 99%

Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

Toffoli

Giodini

Buonadonna

et al. 2015

Intl Journal of Cancer

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Pre-therapeutic DPYD pharmacogenetic test to prevent fluoropyrimidines (FL)-related toxicities is not yet common practice in medical oncology. We aimed at investigating the clinical validity of DPYD genetic analysis in a large series of oncological patients. Six hundred three cancer patients, treated with FL, have been retrospectively tested for eight DPYD polymorphisms (DPYD-rs3918290, DPYD-rs55886062, DPYD-rs67376798, DPYD-rs2297595, DPYD-rs1801160, DPYD-rs1801158, DPYDrs1801159, DPYD-rs17376848) for association with Grade 3 toxicity, developed within the first three cycles of therapy. DPYD-rs3918290 and DPYD-rs67376798 were associated to Grade 3 toxicity after bootstrap validation and Bonferroni correction (p 5 0.003, p 5 0.048). DPYD-rs55886062 was not significant likely due to its low allelic frequency, nonetheless one out of two heterozygous patients (compound heterozygous with DPYD-rs3918290) died from toxicity after one cycle. Test specificity for the analysis of DPYD-rs3918290, DPYD-rs55886062 and DPYD-rs67376798 was assessed to 99%. Among the seven patients carrying one variant DPYD-rs3918290, DPYD-rs55886062 or DPYD-rs67376798 allele, not developing Grade 3 toxicity, 57% needed a FL dose or schedule modification for moderate chronic toxicity. No other DPYD polymorphism was associated with Grade 3 toxicity. Our data demonstrate the clinical validity and specificity of the DPYD-rs3918290, DPYDrs55886062, DPYD-rs67376798 genotyping test to prevent FL-related Grade 3 toxicity and to preserve treatment compliance, and support its introduction in the clinical practice.The identification of the genetic bases of inter-individual variability in terms of response or toxicity to pharmacological treatments is a key point in the field of personalized therapy. Specifically, in the oncological setting the high variability observed in the tumor response to treatment and in the severity of toxicity emphasizes the importance of improving the knowledge on the clinical validity of the pharmacogenetic tests.Fluoropyrimidines (FL) are listed among the drugs with pharmacogenetic warnings. 1 Despite the acknowledged efficacy of these drugs in the treatment of different solid tumors, 2 the FL treatment remains challenging as a result of a considerable inter-patient variability in terms of efficacy and toxicity. 3,4 The pharmacogenetic research, aimed at defining predictive markers of FL response, mainly focused on the dihydropyrimidine dehydrogenase (DPD), which is the first and rate-limiting enzyme of FL catabolic pathway. Up to date, 160 single nucleotide polymorphisms (SNPs) that alter the DPD aminoacids sequence have been identified within the gene (DPYD) codifying for this enzyme 5,6 and many clinical studies have been trying to investigate their association with FL-related severe toxicities. 3,[7][8][9][10][11] Recently the discussion in the scientific community about the clinical effectiveness of pharmacogenetics has given rise to the publication of drug dosing guidelines with indications and recommendations about drug...

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“…The most common DPD mutation is located in the splice site of intron 14 (IVS14+1G>A), resulting in the deletion of exon 14 and thereby creating a nonfunctional enzyme [5,6]. It has been suggested that this mutation accounts for about 25 percent of 5-FU-associated toxicity [7].…”

Section: Introductionmentioning

confidence: 99%

Two cases of 5-fluorouracil toxicity linked with gene variants in the DPYD gene

Öfverholm¹,

Arkblad²,

Skrtic³

et al. 2010

Clinical Biochemistry

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Objectives: Dihydropyrimidine dehydrogenase (DPD) is the initial rate-limiting enzyme in endogenous pyrimidine catabolism and is responsible for the reduction of the pyrmidine analog 5-fluorouracil (5-FU). DPD deficiency is known to cause potentially lethal toxicity in patients receiving 5-FU. Design and Methods:Restriction fragment length polymorphism (RFLP) and DNA sequence analysis were performed on genomic DNA and mRNA.Results: In 400 patients that were diagnosed with cancer and were eligible for 5-FU treatment, 14 patients were found to be heterozygous for the splice-site mutation DPYD IVS14+1G>A, which corresponds to a population frequency of 3.5%. Two novel variants in the DPYD gene were identified. The first case was heterozygous for DPYD c.1796T>C (p.M599T). In the second case, we observed heterozygosity for the splice-site mutation DPYD IVS14+17A>G. Conclusions:We report two new DPYD gene variants, of which DPYD c.1796T>C is potentially pathogenic, whereas DPYD IVS14+17A>G is suggested as a variant without clinical significance.

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Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity.

Cited by 325 publications

References 24 publications

Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT

Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT

Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

Two cases of 5-fluorouracil toxicity linked with gene variants in the DPYD gene

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