Abstract
5-Fluorouracil (5-FU) is rapidly degraded by dihyropyrimidine dehydrogenase (DPD). Therefore, DPD deficiency can lead to severe toxicity or even death following treatment with 5-FU or capecitabine. Different tests based on assessing DPD enzyme activity, genetic variants in DPYD and mRNA variants have been studied for screening for DPD deficiency, but none of these are implemented broadly into clinical practice. We give an overview of the tests that can be used to detect DPD deficiency and discuss the advantages and disadvantages of these tests.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Diasio RB, Harris BE . Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 1989; 16: 215–237.
Fleming RA, Milano G, Thyss A, Etienne MC, Renee N, Schneider M et al. Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. Cancer Res 1992; 52: 2899–2902.
Harris BE, Song R, Soong SJ, Diasio RB . Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res 1990; 50: 197–201.
Etienne MC, Lagrange JL, Dassonville O, Fleming R, Thyss A, Renee N et al. Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol 1994; 12: 2248–2253.
van Kuilenburg AB, Meinsma R, Zoetekouw L, Van Gennip AH . Increased risk of grade IV neutropenia after administration of 5-fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: high prevalence of the IVS14+1g>a mutation. Int J Cancer 2002; 101: 253–258.
Ciccolini J, Mercier C, Dahan L, Evrard A, Boyer JC, Richard K et al. Toxic death-case after capecitabine+oxaliplatin (XELOX) administration: probable implication of dihydropyrimidine deshydrogenase deficiency. Cancer Chemother Pharmacol 2006; 58: 272–275.
Maring JG, van Kuilenburg AB, Haasjes J, Piersma H, Groen HJ, Uges DR et al. Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene. Br J Cancer 2002; 86: 1028–1033.
van Kuilenburg AB, Hausler P, Schalhorn A, Tanck MW, Proost JH, Terborg C et al. Evaluation of 5-fluorouracil pharmacokinetics in cancer patients with a c.1905+1G>A mutation in DPYD by means of a Bayesian limited sampling strategy. Clin Pharmacokinet 2012; 51: 163–174.
Mercier C, Ciccolini J . Severe or lethal toxicities upon capecitabine intake: is DPYD genetic polymorphism the ideal culprit? Trends Pharmacol Sci 2007; 28: 597–598.
Yang CG, Ciccolini J, Blesius A, Dahan L, Bagarry-Liegey D, Brunet C et al. DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity. Cancer Chemother Pharmacol 2011; 67: 49–56.
van Kuilenburg AB, Muller EW, Haasjes J, Meinsma R, Zoetekouw L, Waterham HR et al. Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency. Clin Cancer Res 2001; 7: 1149–1153.
Lu Z, Zhang R, Carpenter JT, Diasio RB . Decreased dihydropyrimidine dehydrogenase activity in a population of patients with breast cancer: implication for 5-fluorouracil-based chemotherapy. Clin Cancer Res 1998; 4: 325–329.
Boisdron-Celle M, Remaud G, Traore S, Poirier AL, Gamelin L, Morel A et al. 5-Fluorouracil-related severe toxicity: a comparison of different methods for the pretherapeutic detection of dihydropyrimidine dehydrogenase deficiency. Cancer Lett 2007; 249: 271–282.
van Kuilenburg AB, van Lenthe H, Van Gennip AH . Activity of pyrimidine degradation enzymes in normal tissues. Nucleosides Nucleotides Nucleic Acids 2006; 25: 1211–1214.
Naguib FN, el Kouni MH, Cha S . Enzymes of uracil catabolism in normal and neoplastic human tissues. Cancer Res 1985; 45: 5405–5412.
Lu Z, Zhang R, Diasio RB . Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res 1993; 53: 5433–5438.
van Kuilenburg AB, van LH, Zoetekouw L, Kulik W . HPLC-electrospray tandem mass spectrometry for rapid determination of dihydropyrimidine dehydrogenase activity. Clin Chem 2007; 53: 528–530.
van Kuilenburg AB, van LH, Tromp A, Veltman PC, Van Gennip AH . Pitfalls in the diagnosis of patients with a partial dihydropyrimidine dehydrogenase deficiency. Clin Chem 2000; 46: 9–17.
Johnson MR, Yan J, Shao L, Albin N, Diasio RB . Semi-automated radioassay for determination of dihydropyrimidine dehydrogenase (DPD) activity. Screening cancer patients for DPD deficiency, a condition associated with 5-fluorouracil toxicity. J Chromatogr B Biomed Sci Appl 1997; 696: 183–191.
Dobashi K, Ohe E, Yamaguchi K, Takeshita S, Ayabe T, Miyazaki M et al. Severe 5-fluorouracil-induced toxicity due to increased dihydropyrimidine dehydrogenase activity: report of a patient survival and urinary pyrimidine and dihydropyrimidine levels. Int J Clin Oncol 1999; 4: 241–243.
Lostia AM, Lionetto L, Ialongo C, Gentile G, Viterbo A, Malaguti P et al. A liquid chromatography-tandem mass spectrometry method for the determination of 5-Fluorouracil degradation rate by intact peripheral blood mononuclear cells. Ther Drug Monit 2009; 31: 482–488.
Liem LK, Choong LH, Woo KT . Porous graphitic carbon shows promise for the rapid screening partial DPD deficiency in lymphocyte dihydropyrimidine dehydrogenase in Chinese, Indian and Malay in Singapore by using semi-automated HPLC-radioassay. Clin Biochem 2002; 35: 181–187.
Di PA, Danesi R, Falcone A, Cionini L, Vannozzi F, Masi G et al. Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients. Ann Oncol 2001; 12: 1301–1306.
Mattison LK, Ezzeldin H, Carpenter M, Modak A, Johnson MR, Diasio RB . Rapid identification of dihydropyrimidine dehydrogenase deficiency by using a novel 2-13C-uracil breath test. Clin Cancer Res 2004; 10: 2652–2658.
Mattison LK, Fourie J, Hirao Y, Koga T, Desmond RA, King JR et al. The uracil breath test in the assessment of dihydropyrimidine dehydrogenase activity: pharmacokinetic relationship between expired 13CO2 and plasma [2-13C]dihydrouracil. Clin Cancer Res 2006; 12: 549–555.
Mattison LK, Fourie J, Desmond RA, Modak A, Saif MW, Diasio RB . Increased prevalence of dihydropyrimidine dehydrogenase deficiency in African-Americans compared with Caucasians. Clin Cancer Res 2006; 12: 5491–5495.
van Staveren MC, Theeuwes-Oonk B, Guchelaar HJ, van Kuilenburg AB, Maring JG . Pharmacokinetics of orally administered uracil in healthy volunteers and in DPD-deficient patients, a possible tool for screening of DPD deficiency. Cancer Chemother Pharmacol 2011; 68: 1611–1617.
Ciccolini J, Mercier C, Evrard A, Dahan L, Boyer JC, Duffaud F et al. A rapid and inexpensive method for anticipating severe toxicity to fluorouracil and fluorouracil-based chemotherapy. Ther Drug Monit 2006; 28: 678–685.
Bi D, Anderson LW, Shapiro J, Shapiro A, Grem JL, Takimoto CH . Measurement of plasma uracil using gas chromatography-mass spectrometry in normal individuals and in patients receiving inhibitors of dihydropyrimidine dehydrogenase. J Chromatogr B Biomed Sci Appl 2000; 738: 249–258.
Ben FR, Gross E, Ben AS, Hassine H, Saguem S . The dihydrouracil/uracil ratio in plasma, clinical and genetic analysis for screening of dihydropyrimidine dehydrogenase deficiency in colorectal cancer patients treated with 5-fluorouracil. Pathol Biol (Paris) 2009; 57: 470–476.
Ciccolini J, Mercier C, Blachon MF, Favre R, Durand A, Lacarelle B . A simple and rapid high-performance liquid chromatographic (HPLC) method for 5-fluorouracil (5-FU) assay in plasma and possible detection of patients with impaired dihydropyrimidine dehydrogenase (DPD) activity. J Clin Pharm Ther 2004; 29: 307–315.
Zhou ZW, Wang GQ, Wan dS, Lu ZH, Chen YB, Li S et al. The dihydrouracil/uracil ratios in plasma and toxicities of 5-fluorouracil-based adjuvant chemotherapy in colorectal cancer patients. Chemotherapy 2007; 53: 127–131.
Gamelin E, Boisdron-Celle M, Guerin-Meyer V, Delva R, Lortholary A, Genevieve F et al. Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer: a potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage. J Clin Oncol 1999; 17: 1105.
Garg MB, Sevester JC, Sakoff JA, Ackland SP . Simple liquid chromatographic method for the determination of uracil and dihydrouracil plasma levels: a potential pretreatment predictor of 5-fluorouracil toxicity. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 774: 223–230.
Sumi S, Kidouchi K, Ohba S, Wada Y . Automated screening system for purine and pyrimidine metabolism disorders using high-performance liquid chromatography. J Chromatogr B Biomed Appl 1995; 672: 233–239.
Remaud G, Boisdron-Celle M, Hameline C, Morel A, Gamelin E . An accurate dihydrouracil/uracil determination using improved high performance liquid chromatography method for preventing fluoropyrimidines-related toxicity in clinical practice. J Chromatogr B Analyt Technol Biomed Life Sci 2005; 823: 98–107.
Kristensen MH, Pedersen P, Mejer J . The value of dihydrouracil/uracil plasma ratios in predicting 5-fluorouracil-related toxicity in colorectal cancer patients. J Int Med Res 2010; 38: 1313–1323.
Jiang H, Lu J, Ji J . Circadian rhythm of dihydrouracil/uracil ratios in biological fluids: a potential biomarker for dihydropyrimidine dehydrogenase levels. Br J Pharmacol 2004; 141: 616–623.
Di PA, Danesi R, Ciofi L, Vannozzi F, Bocci G, Lastella M et al. Improved analysis of 5-Fluorouracil and 5,6-dihydro-5-Fluorouracil by HPLC with diode array detection for determination of cellular dihydropyrimidine dehydrogenase activity and pharmacokinetic profiling. Ther Drug Monit 2005; 27: 362–368.
Deporte-Fety R, Picot M, Amiand M, Moreau A, Campion L, Lanoe D et al. High-performance liquid chromatographic assay with ultraviolet detection for quantification of dihydrofluorouracil in human lymphocytes: application to measurement of dihydropyrimidine dehydrogenase activity. J Chromatogr B Biomed Sci Appl 2001; 762: 203–209.
Remaud G, Boisdron-Celle M, Morel A, Gamelin A . Sensitive MS/MS-liquid chromatography assay for simultaneous determination of tegafur, 5-fluorouracil and 5-fluorodihydrouracil in plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2005; 824: 153–160.
Beumer JH, Boisdron-Celle M, Clarke W, Courtney JB, Egorin MJ, Gamelin E et al. Multicenter evaluation of a novel nanoparticle immunoassay for 5-fluorouracil on the Olympus AU400 analyzer. Ther Drug Monit 2009; 31: 688–694.
Bocci G, Barbara C, Vannozzi F, Di PA, Melosi A, Barsanti G et al. A pharmacokinetic-based test to prevent severe 5-fluorouracil toxicity. Clin Pharmacol Ther 2006; 80: 384–395.
Bocci G, Danesi R, Di Paolo AD, Innocenti F, Allegrini G, Falcone A et al. Comparative pharmacokinetic analysis of 5-fluorouracil and its major metabolite 5-fluoro-5,6-dihydrouracil after conventional and reduced test dose in cancer patients. Clin Cancer Res 2000; 6: 3032–3037.
Di PA, Danesi R, Vannozzi F, Falcone A, Mini E, Cionini L et al. Limited sampling model for the analysis of 5-fluorouracil pharmacokinetics in adjuvant chemotherapy for colorectal cancer. Clin Pharmacol Ther 2002; 72: 627–637.
van Kuilenburg AB, Maring JG, Schalhorn A, Terborg C, Schmalenberg H, Behnke D et al. Pharmacokinetics of 5-fluorouracil in patients heterozygous for the IVS14+1 G>A mutation in the dihydropyrimidine dehydrogenase gene. Nucleosides Nucleotides Nucleic Acids 2008; 27: 692–698.
Ezzeldin H, Okamoto Y, Johnson MR, Diasio RB . A high-throughput denaturing high-performance liquid chromatography method for the identification of variant alleles associated with dihydropyrimidine dehydrogenase deficiency. Anal Biochem 2002; 306: 63–73.
Fischer J, Schwab M, Eichelbaum M, Zanger UM . Mutational analysis of the human dihydropyrimidine dehydrogenase gene by denaturing high-performance liquid chromatography. Genet Test 2003; 7: 97–105.
Gross E, Ullrich T, Seck K, Mueller V, de Wit WM, von Schilling SC et al. Detailed analysis of five mutations in dihydropyrimidine dehydrogenase detected in cancer patients with 5-fluorouracil-related side effects. Hum Mutat 2003; 22: 498.
van Kuilenburg AB, Dobritzsch D, Meinsma R, Haasjes J, Waterham HR, Nowaczyk MJ et al. Novel disease-causing mutations in the dihydropyrimidine dehydrogenase gene interpreted by analysis of the three-dimensional protein structure. Biochem J 2002; 364: 157–163.
Weidensee S, Goettig P, Bertone M, Haas D, Magdolen V, Kiechle M et al. A mild phenotype of dihydropyrimidine dehydrogenase deficiency and developmental retardation associated with a missense mutation affecting cofactor binding. Clin Biochem 2011; 44: 722–724.
Ahluwalia R, Freimuth R, McLeod HL, Marsh S . Use of pyrosequencing to detect clinically relevant polymorphisms in dihydropyrimidine dehydrogenase. Clin Chem 2003; 49: 1661–1664.
Amstutz U, Farese S, Aebi S, Largiader CR . Dihydropyrimidine dehydrogenase gene variation and severe 5-fluorouracil toxicity: a haplotype assessment. Pharmacogenomics 2009; 10: 931–944.
Morel A, Boisdron-Celle M, Fey L, Soulie P, Craipeau MC, Traore S et al. Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther 2006; 5: 2895–2904.
Nauck M, Gierens H, Marz W, Wieland H . Rapid detection of a common dihydropyrimidine dehydrogenase mutation associated with 5-fluorouracil toxicity and congenital thymine uraciluria using fluorogenic hybridization probes. Clin Biochem 2001; 34: 103–105.
Salgueiro N, Veiga I, Fragoso M, Sousa O, Costa N, Pellon ML et al. Mutations in exon 14 of dihydropyrimidine dehydrogenase and 5-fluorouracil toxicity in Portuguese colorectal cancer patients. Genet Med 2004; 6: 102–107.
van Kuilenburg AB, Haasjes J, Richel DJ, Zoetekouw L, van LH, De Abreu RA et al. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res 2000; 6: 4705–4712.
Deenen MJ, Tol J, Burylo AM, Doodeman VD, de Boer A, Vincent A et al. Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Clin Cancer Res 2011; 17: 3455–3468.
van Kuilenburg AB, Meijer J, Mul AN, Meinsma R, Schmid V, Dobritzsch D et al. Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity. Hum Genet 2010; 128: 529–538.
van Kuilenburg AB, Vreken P, Abeling NG, Bakker HD, Meinsma R, van LH et al. Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Hum Genet 1999; 104: 1–9.
Giorgio E, Caroti C, Mattioli F, Uliana V, Parodi MI, D'Amico M et al. Severe fluoropyrimidine-related toxicity: clinical implications of DPYD analysis and UH2/U ratio evaluation. Cancer Chemother Pharmacol 2011; 68: 1355–1361.
Magne N, Etienne-Grimaldi MC, Cals L, Renee N, Formento JL, Francoual M et al. Dihydropyrimidine dehydrogenase activity and the IVS14+1G>A mutation in patients developing 5FU-related toxicity. Br J Clin Pharmacol 2007; 64: 237–240.
Okamoto Y, Ueta A, Sumi S, Ito T, Okubo Y, Jose Y et al. SSCP screening of the dihydropyrimidine dehydrogenase gene polymorphisms of the Japanese population using a semi-automated electrophoresis unit. Biochem Genet 2007; 45: 713–724.
Ezzeldin HH, Lee AM, Mattison LK, Diasio RB . Methylation of the DPYD promoter: an alternative mechanism for dihydropyrimidine dehydrogenase deficiency in cancer patients. Clin Cancer Res 2005; 11: 8699–8705.
Noguchi T, Tanimoto K, Shimokuni T, Ukon K, Tsujimoto H, Fukushima M et al. Aberrant methylation of DPYD promoter, DPYD expression, and cellular sensitivity to 5-fluorouracil in cancer cells. Clin Cancer Res 2004; 10: 7100–7107.
Amstutz U, Farese S, Aebi S, Largiader CR . Hypermethylation of the DPYD promoter region is not a major predictor of severe toxicity in 5-fluorouracil based chemotherapy. J Exp Clin Cancer Res 2008; 27: 54.
Savva-Bordalo J, Ramalho-Carvalho J, Pinheiro M, Costa VL, Rodrigues A, Dias PC et al. Promoter methylation and large intragenic rearrangements of DPYD are not implicated in severe toxicity to 5-fluorouracil-based chemotherapy in gastrointestinal cancer patients. BMC Cancer 2010; 10: 470.
Raida M, Schwabe W, Hausler P, van Kuilenburg AB, Van Gennip AH, Behnke D et al. Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5′-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)- related toxicity compared with controls. Clin Cancer Res 2001; 7: 2832–2839.
Seck K, Riemer S, Kates R, Ullrich T, Lutz V, Harbeck N et al. Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in a cohort of Caucasian individuals. Clin Cancer Res 2005; 11: 5886–5892.
Johnson MR, Wang K, Smith JB, Heslin MJ, Diasio RB . Quantitation of dihydropyrimidine dehydrogenase expression by real-time reverse transcription polymerase chain reaction. Anal Biochem 2000; 278: 175–184.
van Kuilenburg AB, Meinsma R, Zoetekouw L, Van Gennip AH . High prevalence of the IVS14+1G>A mutation in the dihydropyrimidine dehydrogenase gene of patients with severe 5-fluorouracil-associated toxicity. Pharmacogenetics 2002; 12: 555–558.
Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J et al. Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 2008; 26: 2131–2138.
Gamelin EC, Danquechin-Dorval EM, Dumesnil YF, Maillart PJ, Goudier MJ, Burtin PC et al. Relationship between 5-fluorouracil (5-FU) dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing 5-FU. Cancer 1996; 77: 441–451.
van Kuilenburg AB, van LH, Blom MJ, Mul EP, Van Gennip AH . Profound variation in dihydropyrimidine dehydrogenase activity in human blood cells: major implications for the detection of partly deficient patients. Br J Cancer 1999; 79: 620–626.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
van Staveren, M., Jan Guchelaar, H., van Kuilenburg, A. et al. Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency. Pharmacogenomics J 13, 389–395 (2013). https://doi.org/10.1038/tpj.2013.25
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/tpj.2013.25
Keywords
This article is cited by
-
Preemptive screening of DPYD as part of clinical practice: high prevalence of a novel exon 4 deletion in the Finnish population
Cancer Chemotherapy and Pharmacology (2021)
-
Comparison of a thymine challenge test and endogenous uracil–dihydrouracil levels for assessment of fluoropyrimidine toxicity risk
Cancer Chemotherapy and Pharmacology (2021)
-
Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene–drug interaction of DPYD and fluoropyrimidines
European Journal of Human Genetics (2020)
-
Clinical implementation of pre-treatment DPYD genotyping in capecitabine-treated metastatic breast cancer patients
Breast Cancer Research and Treatment (2019)
-
Prevalence of the DPYD variant (Y186C) in Brazilian individuals of African ancestry
Cancer Chemotherapy and Pharmacology (2019)