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Clin Colorectal Cancer 2021 Apr 6. Epub 2021 Apr 6.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI. Electronic address:

Cancers (Basel) 2021 Mar 24;13(7). Epub 2021 Mar 24.

Oxford Cancer Biomarkers, The Magdalen Centre, Oxford Science Park, Robert Robinson Avenue, Oxford OX4 4GA, UK.

Efficacy of 5-Fluorouracil (5-FU)-based chemotherapy is limited by significant toxicity. Tests based upon variants in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines with high level evidence of a link to dihydropyrimidine dehydrogenase (DPD) phenotype and 5-FU toxicity are available to identify patients at high risk of severe adverse events (AEs). We previously reported associations between rs1213215, rs2612091, and NM_000110. Read More

Front Genet 2021 9;12:626954. Epub 2021 Mar 9.

Faculty of Health Sciences, Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa.

Cancer is a critical health burden in Africa, and mortality rates are rising rapidly. Treatments are expensive and often cause adverse drug reactions (ADRs). Fluoropyrimidine treatments can lead to severe toxicity events which have been linked to variants within the dihydropyrimidine dehydrogenase () gene. Read More

Curr Oncol 2020 12 18;28(1):94-97. Epub 2020 Dec 18.

London Health Sciences Centre and Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5W9, Canada.

5-fluorouracil (5-FU) and its pro-drug capecitabine are widely used anticancer agents. Most 5-FU catabolism is dependent on dihydropyrimidine dehydrogenase (DPD) encoded by the gene, and variants that reduce DPD function increase 5-FU toxicity. Most DPD deficient patients are heterozygous and can be treated with reduced 5-FU dosing. Read More

Cancer Chemother Pharmacol 2021 May 9;87(5):711-716. Epub 2021 Mar 9.

Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Purpose: Standard dosages of fluoropyrimidine chemotherapy result in severe toxicity in a substantial proportion of patients, however, routine pre-therapeutic toxicity prediction remains uncommon. A thymine (THY) challenge test can discriminate risk of severe gastrointestinal toxicity in patients receiving fluoropyrimidine monotherapy. We aimed to measure endogenous plasma uracil (U) and its ratio to dihydrouracil (DHU), and assess the performance of these parameters compared with the THY challenge test to evaluate risk of severe toxicity. Read More

Br J Clin Pharmacol 2021 Jan 24. Epub 2021 Jan 24.

Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, INO-F, Bern, Switzerland.

Aims: The aim of this study was to identify risk variants and haplotypes that impair dihydropyrimidine dehydrogenase (DPD) activity and are, therefore, candidate risk variants for severe toxicity to 5-fluorouracil (5-FU) chemotherapy.

Methods: Plasma dihydrouracil/uracil (UH /U) ratios were measured as a population marker for DPD activity in a total of 1382 subjects from 4 independent studies. Genotype and haplotype correlations with UH /U ratios were assessed. Read More

Acta Clin Belg 2021 Jan 11:1-7. Epub 2021 Jan 11.

Department of Gastroenterology, UZ Gent, Gent.

Fluoropyrimidines such as 5-Fluorouracil (5-FU), capecitabine and tegafur are drugs that are often used in the treatment of maliginancies. The enzyme dihydropyrimidine dehydrogenase (DPD) is the first and rate limiting enzyme of 5-FU catabolism. Genetic variations within the DPYD gene (encoding for DPD protein) can lead to reduced or absent DPD activity. Read More

Ann Gastroenterol 2021 12;34(1):68-72. Epub 2020 Oct 12.

Department of Oncology, University Hospital Antwerp, Edegem, Belgium (Hans Prenen).

Background: 5-Fluorouracil (5-FU) is an agent frequently used in the treatment of solid cancers. A deficiency in the enzyme that catabolizes 5-FU leads to severe toxicity. The gene responsible for this enzyme is , located on chromosome 1q22. Read More

Int J Mol Sci 2020 Dec 17;21(24). Epub 2020 Dec 17.

IRSET (Institut de Recherche en Santé, Environnement et Travail), University of Rennes, CHU Rennes, EHESP, UMR_S 1085, 35000 Rennes, France.

Regarding several cytotoxic agents, it was evidenced that genetic polymorphisms in genes encoding enzymes involved in their metabolism are associated with higher risk of toxicity. Genotyping these genes before treatment is a valuable strategy to prevent side effects and to predict individual response to drug therapy. This pharmacogenetic approach is recommended for chemotherapies such as thiopurines (azathioprine, 6-mercaptopurine, thioguanine), irinotecan, and fluoropyrimidines (capecitabine and 5-fluorouracil). Read More

Pharmacogenomics 2021 01 11;22(2):81-85. Epub 2020 Dec 11.

Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Cancers of the colon are commonly treated with fluoropyrimidines, which often cause severe toxicities in patients with certain variants in . Y186C (rs115232898) and a variant in the 3' untranslated region (rs12132152) are uncommon alleles previously observed in African-Americans. An African-American female underwent 5-fluorouracil-based therapy (400 mg/m bolus, 1200 mg/m/day over 46 h). Read More

Arch Pharmacol Ther 2020 ;2(1):6-8

Mayo Clinic, Rochester, MN, Rochester, MN, USA.

World J Surg Oncol 2020 Dec 6;18(1):321. Epub 2020 Dec 6.

Department of Research Experimental Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-Sen University, No. 63 Huangtang Road, Meijiang District, Meizhou, 514031, People's Republic of China.

Background: Fluoropyrimidines and platinum are still widely used for colorectal cancer (CRC) management. Several studies have reported that mutations of dihydropyrimidine dehydrogenase (DPYD) and glutathione S-transferase pi-1 (GSTP1) polymorphisms are related to chemotherapy-related adverse events. In the present study, we purposed to assess the impact of DPYD and GSTP1 variants on the toxicity of adjuvant chemotherapy risk among the Hakka population, minimize adverse events, and to maximize therapy outcome for individualized treatment. Read More

Oncologist 2021 04 23;26(4):e597-e602. Epub 2020 Dec 23.

Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec, Canada.

Background: Fluoropyrimidines are used in chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. DPYD*2A polymorphism is one of the most studied variants. Read More

Pharmaceuticals (Basel) 2020 Nov 23;13(11). Epub 2020 Nov 23.

Centre Georges-François Leclerc, 21000 Dijon, France.

In order to limit 5-fluorouracil (5-FU) toxicity, some health agencies recommend evaluating dihydropyrimidine dehydrogenase (DPD) deficiency before any 5-FU treatment introduction. In our study, we investigated relationships between 5-FU clearance and markers of DPD activity such as uracilemia (U), dihydrouracilemia (UH)/U ratio, or genotype of the gene encoding DPD (). All patients with gastrointestinal cancers who received 5-FU-based regimens form March 2018 to June 2020 were included in our study. Read More

Swiss Med Wkly 2020 Nov 24;150:w20375. Epub 2020 Nov 24.

Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Switzerland / Swiss Group of Pharmacogenomics and Personalised Therapy.

Fluoropyrimidines (FPs), mainly 5-fluorouracil (5-FU) and its oral prodrug capecitabine (Cap), remain the backbone of the treatment of many different solid tumors. Despite their broad use in clinical routine, 10–40% of patients experience severe, and in rare cases (0.2–0. Read More

JCO Oncol Pract 2020 12 16;16(12):793-798. Epub 2020 Nov 16.

Centre Antoine-Lacassagne, Nice, France.

Fluoropyrimidines (fluorouracil, capecitabine, and other analogs) are highly used anticancer drugs worldwide. However, patients with cancer treated with these drugs might experience severe, life-threatening toxicity because of germline genetic variation in the gene. This is a genetic predisposition with an established mechanistic basis that links genetic variation in the gene to an increase in systemic drug exposure, resulting in an increased risk of toxicity. Read More

J Gene Med 2021 Jan 20;23(1):e3289. Epub 2020 Nov 20.

Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad, India.

Background: The present study aimed to delineate the pharmacologically relevant dihydropyrimidine dehydrogenase (DPYD) variants in the Indian population.

Methods: We screened 2000 Indian subjects for DPYD variants using the Infinium Global Screening Array (GSA) (Illumina Inc., San Diego, CA, USA). Read More

Oncol Res Treat 2020 23;43(11):628-636. Epub 2020 Oct 23.

Klinik für Innere Medizin I, Universitätsklinikum Ulm, Ulm, Germany.

Background: 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2-1. Read More

Surg Oncol 2020 Dec 19;35:388-398. Epub 2020 Sep 19.

Epidemiology and Public Health Research Group Centre for Public Health, Queen's University of Belfast, Belfast, Northern Ireland, United Kingdom. Electronic address:

ABCB1, DPYD, MHTFR, XRCC1, ERCC1, GSTP1 and UGT1A1 genetic variants affect proteins related to CRC chemotherapy toxicity. A retrospective cohort study was conducted in 194 CRC patients. In first line treatment, DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 4. Read More

Clin Pharmacol Ther 2021 Mar 12;109(3):591-604. Epub 2020 Nov 12.

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.

Fluoropyrimidines are widely used in the treatment of several types of solid tumors. Although most often well tolerated, severe toxicity is encountered in ~ 20-30% of the patients. Individualized dosing for these patients can reduce the incidence of severe fluoropyrimidine-related toxicity. Read More

Pharmacotherapy 2020 11 19;40(11):1108-1129. Epub 2020 Oct 19.

Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Gastrointestinal (GI) malignancies are among the most commonly diagnosed cancers worldwide. Despite the introduction of targeted and immunotherapy agents in the treatment landscape, cytotoxic agents, such as fluoropyrimidines and irinotecan, remain as the cornerstone of chemotherapy for many of these tumors. Pharmacogenetics (PGx) is a rapidly evolving field that accounts for interpatient variability in drug metabolism to predict therapeutic response and toxicity. Read More

Drug Metab Pers Ther 2020 Sep 23. Epub 2020 Sep 23.

Department of Pharmacology, JIPMER, Puducherry, India.

Objectives High interindividual variability was reported with capecitabine toxicities among colorectal cancer (CRC) patients. DPYD*9A polymorphism was reported responsible for grade 3 or 4 toxicities. Finding the phenotypic association between DPYD*9A polymorphism and 5-fluorouracil (5-FU) plasma levels will give a better prediction for toxicity susceptibility. Read More

J Pers Med 2020 Sep 3;10(3). Epub 2020 Sep 3.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy.

Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the gene. FP pharmacogenetics, including four polymorphisms (-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the -PGx should be performed prior to starting FP. Read More

Front Oncol 2020 4;10:1155. Epub 2020 Aug 4.

Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy.

Intensive oncological treatment integrated with resection of metastases raised the clinical outcome of metastatic colorectal cancer (MCRC). In clinical practice, complex evaluation of clinical (age, performance status, comorbidities), and biological (tumoral genotype, pharmacogenomic) parameters addresses tailored, personalized multidisciplinary treatment strategies. Patients with MCRC unsuitable for first-line intensive medical treatments are prevalent and showed worse clinical outcome. Read More

Avicenna J Med Biotechnol 2020 Jul-Sep;12(3):157-164

Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.

Background: The fluoropyrimidine drug 5-Fluorouracil (5-FU) and the prodrug capecitabine have been extensively used for treatment of many types of cancer including colorectal, gastric, head and neck. Approximately, 10 to 25% of patients suffer from severe fluoropyrimidine-induced toxicity. This may lead to dose reduction and treatment discontinuation. Read More

Cancer Sci 2020 Sep 20;111(9):3359-3366. Epub 2020 Jul 20.

Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan.

Cancer treatment with a fluoropyrimidine (FP) is often accompanied by severe toxicity that may be dependent on the activity of catalytic enzymes encoded by the DPYD, DPYS, and UPB1 genes. Genotype-guided dose individualization of FP therapy has been proposed in western countries, but our knowledge of the relevant genetic variants in East Asian populations is presently limited. To investigate the association between these genetic variations and FP-related high toxicity in a Japanese population, we obtained blood samples from 301 patients who received this chemotherapy and sequenced the coding exons and flanking intron regions of their DPYD, DPYS, and UPB1 genes. Read More

BMC Cancer 2020 Jun 16;20(1):560. Epub 2020 Jun 16.

Department of Pathology, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, Iran.

Background: 5-Fluorouracil (5-FU) and capecitabine are fluoropyrimidine derivatives that mainly metabolized with dihydropyrimidine dehydrogenase enzyme (DPD). The genetic polymorphism in the genes encoding this enzyme may result in a decrease or loss of enzyme activity which may lead to the accumulation of medicines, their metabolites and potential toxicity.

Method: This cross-sectional study was conducted on 88 participants with colorectal cancer (CRC). Read More

Cancer Chemother Pharmacol 2020 07 11;86(1):45-54. Epub 2020 Jun 11.

Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Doctor Esquerdo 46, 28007, Madrid, Spain.

Purpose: Several clinical guidelines recommend genetic screening of DPYD, including coverage of the variants c.1905 + 1G>A(DPYD*2A), c.1679T>G(DPYD*13), c. Read More