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Eur J Cancer 2019 Jan 11;107:60-67. Epub 2018 Dec 11.

Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands.

Background: Fluoropyrimidine therapy including capecitabine or 5-fluorouracil can result in severe treatment-related toxicity in up to 30% of patients. Toxicity is often related to reduced activity of dihydropyrimidine dehydrogenase, the main metabolic fluoropyrimidine enzyme, primarily caused by genetic DPYD polymorphisms. In a large prospective study, it was concluded that upfront DPYD-guided dose individualisation is able to improve safety of fluoropyrimidine-based therapy. Read More

Front Pharmacol 2018 15;9:1309. Epub 2018 Nov 15.

Department of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, United States.

Pharmacogenomic testing may have clinical value in the treatment of patients with gastrointestinal malignancies such as colorectal and pancreatic cancer. These types of cancer are often treated with combination chemotherapy regimens. These regimens can lead to severe adverse effects in patients with diminished drug tolerability potentially due to certain genetic variants in the enzymes involved in the metabolism of the chemotherapies. Read More

Int J Cancer 2018 Nov 28. Epub 2018 Nov 28.

Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.

Carriers of the genetic DPYD*2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine-associated toxicity. Upfront DPYD*2A genotype-based dose reductions improve patient safety, but uncertainty exists whether this has a negative impact on treatment effectiveness. Therefore, our study investigated effectiveness and safety of DPYD*2A genotype-guided dosing. Read More

Eur J Cancer 2018 Nov 23;104:210-218. Epub 2018 Oct 23.

Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands. Electronic address:

Background: Prospective DPYD genotyping prevents severe fluoropyrimidine (FP)-induced toxicity by decreasing dosages in DPYD variant allele carriers. FP dosages in chemoradiation therapy (CRT) are lower than those in other FP-containing regimens. Pharmacogenetic guidelines do not distinguish between regimens, leaving physicians in doubt to apply dose reductions. Read More

Lancet Oncol 2018 Nov 19;19(11):1459-1467. Epub 2018 Oct 19.

Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands. Electronic address:

Background: Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A [rs3918290, c.1905+1G>A, IVS14+1G>A], c. Read More

Front Oncol 2018 24;8:279. Epub 2018 Jul 24.

Department of Clinical Oncology, Queen Mary Hospital, Hong Kong, Hong Kong.

The fluoropyrimidine anticancer drug, especially 5- fluorouracil (5-FU) and its prodrug capecitabine are still being the backbone of chemotherapeutic regimens for colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) is the crucial enzyme in the catabolism of 5-FU. Over the past 30 years, there is substantial clinical evidence showing that DPD deficiency is strongly associated with severe and fatal fluoropyrimidine-induced toxicity. Read More

J Gastrointest Oncol 2018 Jun;9(3):416-424

Medical Oncology, The University of South Alabama, Mitchell Cancer Institute, Mobile, Alabama, USA.

Background: The correlation between DPYD*9A (c.85T>C) genotype and dihydropyrimidine dehydrogenase (DPD) deficiency clinical phenotype is controversial. Reference laboratories either did not perform DPYD*9A genotyping or have stopped DPYD*9A genotyping and limited genotyping to high-risk variants (DPYD*2A, DPYD*13 and DPYD*9B) only. Read More

Ther Drug Monit 2018 08;40(4):495-502

School of Pharmacy, Pharmacy Australia Center of Excellence, The University of Queensland.

Background: Chemotherapy for colorectal, head and neck, and breast cancer continues to rely heavily on 5-fluorouracil and its oral prodrug capecitabine. Associations of serious fluoropyrimidine adverse effects have focused on inherited deficiency of the catabolic enzyme, dihydropyrimidine dehydrogenase. However, abnormal dihydropyrimidine dehydrogenase activity accounts for only about one-third of observed toxicity cases. Read More

Drug Metab Dispos 2018 08 16;46(8):1083-1090. Epub 2018 May 16.

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (E.H., Yo.N., F.A., Yu.N., N.H., M.H.), and Tohoku Medical Megabank Organization (S.S., J.Y., M.N., M.Y., M.H.), and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., H.Y., N.M., M.H.)

Dihydropyrimidine dehydrogenase (DPD, EC 1.3.1. Read More

JAMA Oncol 2018 Jun;4(6):806-813

Department of Laboratory Medicine, University of Washington, Seattle.

Importance: Universal tumor screening for Lynch syndrome (LS) in colorectal cancer (CRC) is recommended and involves up to 6 sequential tests. Somatic gene testing is performed on stage IV CRCs for treatment determination. The diagnostic workup for patients with CRC could be simplified and improved using a single up-front tumor next-generation sequencing test if it has higher sensitivity and specificity than the current screening protocol. Read More

Oncotarget 2018 Feb 10;9(10):9114-9136. Epub 2018 Jan 10.

Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland.

The differences in patients' response to the same medication, toxicity included, are one of the major problems in breast cancer treatment. Chemotherapy toxicity makes a significant clinical problem due to decreased quality of life, prolongation of treatment and reinforcement of negative emotions associated with therapy. In this study we evaluated the genetic and clinical risk factors of FAC chemotherapy-related toxicities in the group of 324 breast cancer patients. Read More

Oncotarget 2018 Jan 21;9(8):7859-7866. Epub 2017 Dec 21.

Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Our study addresses the issue of the clinical reliability of three candidate DPYD and one UGT single nucleotide polymorphisms in predicting 5-fluorouracil- and irinotecan-related adverse events. To this purpose, we took advantage of a large cohort of metastatic colorectal cancer patients treated with first-line 5-fluorouracil- and irinotecan-based chemotherapy regimens (i.e. Read More

Bull Cancer 2018 Apr 24;105(4):397-407. Epub 2018 Feb 24.

Laboratoire d'oncopharmacologie, centre Antoine-Lacassagne, 33, avenue de Valombrose, 06189 Nice cedex 2, France. Electronic address:

Fluoropyrimidines (FU) are still the most prescribed anticancer drugs for the treatment of solid cancers. However, fluoropyrimidines cause severe toxicities in 10 to 40% of patients and toxic deaths in 0.2 to 0. Read More

Clin Pharmacol Ther 2018 Oct 2;104(4):709-718. Epub 2018 Feb 2.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.

Deleterious variants in dihydropyrimidine dehydrogenase (DPD, DPYD gene) can be highly predictive of clinical toxicity to the widely prescribed chemotherapeutic 5-fluorouracil (5-FU). However, there are very limited data pertaining to the functional consequences of the >450 reported no-synonymous DPYD variants. We developed a DPYD-specific variant classifier (DPYD-Varifier) using machine learning and in vitro functional data for 156 missense DPYD variants. Read More

Pharmacogenomics 2018 02 14;19(3):227-241. Epub 2017 Dec 14.

GN Ramachandran Knowledge Center for Genome Informatics, CSIR Institute of Genomics & Integrative Biology, Mathura Road, Delhi 110025, India.

Aim: Adverse drug reactions to 5-Fluorouracil(5-FU) is frequent and largely attributable to genetic variations in the DPYD gene, a rate limiting enzyme that clears 5-FU. The study aims at understanding the pharmacogenetic landscape of DPYD variants in south Asian populations.

Materials & Methods: Systematic analysis of population scale genome wide datasets of over 3000 south Asians was performed. Read More

Cancer Chemother Pharmacol 2018 01 13;81(1):119-129. Epub 2017 Nov 13.

Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh.

Background: Significant inter-individual variation in the sensitivity to 5-fluorouracil (5-FU) represents a major therapeutic hindrance either by impairing drug response or inducing adverse drug reactions (ADRs). This study aimed at exploring the cause behind this inter-individual alterations in consequences of 5-fluorouracil-based chemotherapy by investigating the effects of DPYD*2A and MTHFR C677T polymorphisms on toxicity and response of 5-FU in Bangladeshi colorectal cancer patients.

Methods: Colorectal cancer patients (n = 161) receiving 5-FU-based chemotherapy were prospectively enrolled. Read More

Ann Oncol 2017 Dec;28(12):2915-2922

Division of Pharmacology.

The fluoropyrimidine anticancer drugs, especially 5-fluorouracil (5-FU) and capecitabine, are frequently prescribed for several types of cancer, including breast, colorectal, head and neck and gastric cancer. In the current drug labels of 5-FU and capecitabine in the European Union and the United States, no adaptive dosing strategies are incorporated for polymorphic metabolism of 5-FU. Although treatment with fluoropyrimidines is generally well tolerated, a major clinical limitation is that a proportion of the treated population experiences severe, sometimes life-threatening, fluoropyrimidine-related toxicity. Read More

Int J Cancer 2018 01 30;142(2):424-430. Epub 2017 Sep 30.

Laboratory Genetic Metabolic Diseases, Departments of Clinical Chemistry and Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Fluoropyrimidines are frequently used anti-cancer drugs. It is known that patients with reduced activity of dihydropyrimidine dehydrogenase (DPD), the key metabolic enzyme in fluoropyrimidine inactivation, are at increased risk of developing severe fluoropyrimidine-related toxicity. Upfront screening for DPD deficiency and dose reduction in patients with partial DPD deficiency is recommended and improves patient safety. Read More

Sci Rep 2017 Aug 29;7(1):9711. Epub 2017 Aug 29.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Hematology/Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.

Nucleotide metabolism in cancer cells can influence malignant behavior and intrinsic resistance to therapy. Here we describe p53-dependent control of the rate-limiting enzyme in the pyrimidine catabolic pathway, dihydropyrimidine dehydrogenase (DPYD) and its effect on pharmacokinetics of and response to 5-fluorouracil (5-FU). Using in silico/chromatin-immunoprecipitation (ChIP) analysis we identify a conserved p53 DNA-binding site (p53BS) downstream of the DPYD gene with increased p53 occupancy following 5-FU treatment of cells. Read More

Pharmacogenomics 2017 Aug 26;18(13):1215-1223. Epub 2017 Jul 26.

Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Aim: To identify genetic variants associated with capecitabine toxicity in fluoropyrimidine pathway genes using exome sequencing.

Patients & Methods: Exomes from eight capecitabine-treated patients with severe adverse reactions (grade >2), among a population of 319, were sequenced (Ion Proton). SNPs in genes classified as potentially damaging (Sorting Intolerant from Tolerant and Polymorphism Phenotyping v2) were tested for association with toxicity in a validation cohort of 319 capecitabine-treated patients. Read More

Asian Pac J Cancer Prev 2017 06 25;18(6):1651-1654. Epub 2017 Jun 25.

Thrombosis Haemostasis Laboratory, University of Jordan, Amman, Jordan.

Background: Dihydropyrimidine dehydrogenase (DPD) is a crucial enzyme in the catabolism of 5-fluorouracil (5-FU), a drug that is frequently used in cancer therapy. Patients with deficient DPD activity are at risk of developing severe 5-FU–associated toxicity. One possible cause of deficiency is genetic polymorphisms in the DPD gene, such as IVS14+1G>A. Read More

Tumour Biol 2017 06;39(6):1010428317701629

6 Dutch Medicines Evaluation Board (CBG-MEB), Utrecht, The Netherlands.

Zhao et al. investigated the association between germline genetic polymorphisms in DPYD, the gene encoding dihydropyrimidine dehydrogenase, and (1) the risk of developing pediatric acute lymphoblastic leukemia and (2) outcome of acute lymphoblastic leukemia following the treatment with 5-fluorouracil plus oxaliplatin (FOLFOX). The authors found that the common DPYD variant c. Read More

Chemotherapy 2017 15;62(5):323-326. Epub 2017 Jun 15.

Unit of Clinical Pharmacology, Department of Laboratory Medicine, ASST Fatebenefratelli-Sacco, Milan, Italy.

While the majority of patients can be treated safely with fluoropyrimidine, some experience severe fluoropyrimidine-associated toxicity. The frequency and severity of these adverse events vary from patient to patient and are partially explained by genetic polymorphism into the dihydropyrimidine dehydrogenase (DPYD) gene. Carriers of the rare allelic variants DPYD*2A, DPYD*13, and DPYD D949V are more likely to experience severe adverse reactions during fluoropyrimidine-based therapy. Read More

PLoS One 2017 8;12(5):e0175998. Epub 2017 May 8.

Centre Antoine Lacassagne, Nice, France.

Background: Deficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency screening, including DPYD genotyping and phenotyping. The goal of this prospective observational study was to perform exhaustive exome DPYD sequencing and to examine relationships between DPYD variants and toxicity in advanced breast cancer patients receiving capecitabine. Read More

Br J Cancer 2017 May 20;116(11):1415-1424. Epub 2017 Apr 20.

Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam 1066CX, The Netherlands.

Background: We investigated the predictive value of dihydropyrimidine dehydrogenase (DPD) phenotype, measured as pretreatment serum uracil and dihydrouracil concentrations, for severe as well as fatal fluoropyrimidine-associated toxicity in 550 patients treated previously with fluoropyrimidines during a prospective multicenter study.

Methods: Pretreatment serum concentrations of uracil and dihydrouracil were measured using a validated LC-MS/MS method. The primary endpoint of this analysis was global (any) severe fluoropyrimidine-associated toxicity, that is, grade ⩾3 toxicity according to the NCI CTC-AE v3. Read More

Pharmacol Res 2017 Jun 27;120:133-137. Epub 2017 Mar 27.

Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. Electronic address:

Predicting individual risk of chemotherapy-induced severe adverse reaction is a critical issue when selecting the best treatment for cancer patients. SNPs have been identified in genes involved in the pharmacodynamics of fluoropyrimidines, and guidelines even recommend genotyping some DPYD variants in order to estimate the risk of toxicity. However, the predictive value of this approach remains insufficient, thus limiting its clinical implementation. Read More

Anticancer Drugs 2017 06;28(5):551-556

Departments of aClinical and Molecular Medicine bRadiological Oncological and Pathological Sciences cNeurosciences, Mental Health and Sensory Organs (NESMOS), 'Sapienza' University of Rome dDepartment of Medical Oncology, Sant'Andrea Hospital eLaboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute fIstituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.

Fluoropyrimidines combined with other agents are commonly used for gastrointestinal cancer treatment. Considering that severe toxicities occur in 30% of patients, we aimed to structure a nomogram to predict toxicity, based on metabolic parameter and patients' characteristics. We retrospectively enrolled patients affected by gastrointestinal tract cancers. Read More

Clin Pharmacol Ther 2017 Oct 26;102(4):662-670. Epub 2017 May 26.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.

Dihydropyrimidine dehydrogenase (DPD; DPYD gene) variants have emerged as reliable predictors of adverse toxicity to the chemotherapy agent 5-fluorouracil (5-FU). The intronic DPYD variant rs75017182 has been recently suggested to promote alternative splicing of DPYD. However, both the extent of alternative splicing and the true contribution of rs75017182 to DPD function remain unclear. Read More

Curr Pharm Des 2017 ;23(14):2028-2034

Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Background: Fluoropyrimidines are widely used in the treatment of solid tumors and remain the backbone of many combination chemotherapy regimens. Despite their clinical benefit, they are associated with frequent gastrointestinal and hematological toxicities, which often lead to treatment discontinuation. Fluoropyrimidines undergo complex anabolic and catabolic biotransformation. Read More

Biochim Biophys Acta Mol Basis Dis 2017 03 24;1863(3):721-730. Epub 2016 Dec 24.

Academic Medical Center, University of Amsterdam, Emma Children's Hospital, Departments of Clinical Chemistry, Pediatrics and Clinical Genetics, Laboratory Genetic Metabolic Diseases, Amsterdam, The Netherlands.

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Genetic variations in DPD have emerged as predictive risk factors for severe fluoropyrimidine toxicity. Here, we report novel and rare genetic variants underlying DPD deficiency in 9 cancer patients presenting with severe fluoropyrimidine-associated toxicity. Read More

Pharmacogenomics J 2017 10 20;17(5):441-451. Epub 2016 Dec 20.

Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

The main treatment for advanced gastric cancer is fluoropyrimidine and platinum-based chemotherapy. We investigated the clinical validitiy of 19 candidate pharmacogenetic variants in ENOSF1 (enolase superfamily member 1), TYMS, CDA, MTHFR, TYMP, DPYD, ERCC1, ERCC2, GSTP1, GSTT1, GSTM1, CYP3A4 and CYP3A5 in relation to overall survival (OS), progression-free survival, objective response rate (ORR) and toxicity in 185 patients receiving triplet chemotherapy. The formal significance threshold was P<0. Read More

Eur J Clin Pharmacol 2017 Feb 18;73(2):157-164. Epub 2016 Nov 18.

Clinical and Molecular Medicine Department, Sapienza University of Rome - Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.

Background: On account of the lack of predictive biomarkers of toxicity, we investigated whether polymorphisms of genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with outcomes of adjuvant capecitabine in patients with early stage gastrointestinal cancers.

Methods: Genotyping of DPYD GIVS14A, MTHFR C677T and A1298C SNPs were performed by pyro-sequencing technology. PCR analysis was used for genotyping TYMS-TSER. Read More

Anticancer Drugs 2017 03;28(3):322-326

Departments of aClinical and Molecular Medicine bNeurosciences, Mental Health and Sensory Organs (NESMOS), 'Sapienza' University of Rome Departments of cMedical Oncology dGeneral Surgery, Sant'Andrea Hospital eIstituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.

5-Fluorouracil is commonly used for gastrointestinal cancer treatment in an adjuvant setting; however, the toxicity can lead to a reduction, delay, or discontinuation of treatment. We retrospectively investigated the association between the 5-fluorouracil degradation rate (5-FUDR) and genetic polymorphisms of TSER, DPYD, and MHTFR with toxicity in colorectal cancer patients treated with adjuvant FOLFOX. Pretreatment 5-FUDR and MTHFR A1298T or C677T, TSER, and DPYD gene polymorphisms were characterized in stages II-III colorectal cancer patients. Read More

Cancer Res 2016 11 30;76(21):6362-6373. Epub 2016 Aug 30.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota.

The antimetabolite 5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs. Dihydropyrimidine dehydrogenase (DPD) is a major determinant of 5-FU response and toxicity. Although DPYD variants may affect 5-FU metabolism, they do not completely explain the reported variability in DPD function or the resultant differences in treatment response. Read More

Cureus 2016 Sep 14;8(9):e783. Epub 2016 Sep 14.

Oncology, Tufts Medical Center, Tufts University School of Medicine.

5-Fluorouracil (5-FU) is the backbone of the chemotherapy regimens approved for treatment of many malignancies, especially colorectal cancer (CRC). The incidence of cardiotoxicity associated with 5-FU ranges between 1.5% to 18% and is most commonly manifested as anginal symptoms. Read More

Oncotarget 2017 Feb;8(8):14050-14057

Advanced Molecular Diagnostic, IDI-IRCCS, Rome, Italy.

Background: 5-fluorouracil (5-FU) based chemotherapy is the most common first line regimen used in gastric and gastroesophageal junction cancer, but development of severe toxicity is a main concern in the treatment. The present study is aimed to evaluate a novel pre-treatment assay, known as the 5-FU degradation rate (5-FUDR), as a predictive factor for 5-FU toxicity.

Methods: Pre-treatment 5-FUDR and gene polymorphisms related to 5-FU metabolism (DPYDIVS14+1G>A, MTHFRA1298T or C677T, TMYS TSER) were characterized in gastro-esophageal cancer patients. Read More

Clin Pharmacol Ther 2017 03 26;101(3):382-390. Epub 2016 Nov 26.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.

Clinical studies have identified specific genetic variants in dihydropyrimidine dehydrogenase (DPD; DPYD gene) as predictors of severe adverse toxicity to the commonly used chemotherapeutic 5-fluorouracil (5-FU); however, these studies have focused on European and European-American populations. Our laboratory recently demonstrated that additional variants in non-European haplotypes are predictive of 5-FU toxicity. The objective of this study was to identify potential risk variants in an understudied East African population relevant to our institution's catchment area. Read More

PLoS One 2016;11(9):e0163105. Epub 2016 Sep 22.

Department of Clinical and Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.

Background: 5-FU based chemotherapy is the most common first line regimen used for metastatic colorectal cancer (mCRC). Identification of predictive markers of response to chemotherapy is a challenging approach for drug selection. The present study analyzes the predictive role of 5-FU degradation rate (5-FUDR) and genetic polymorphisms (MTHFR, TSER, DPYD) on survival. Read More

Clin Pharmacokinet 2017 04;56(4):317-337

Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Emma Children's Hospital, F0-220, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Cancer treatment is becoming more and more individually based as a result of the large inter-individual differences that exist in treatment outcome and toxicity when patients are treated using population-based drug doses. Polymorphisms in genes encoding drug-metabolizing enzymes and transporters can significantly influence uptake, metabolism, and elimination of anticancer drugs. As a result, the altered pharmacokinetics can greatly influence drug efficacy and toxicity. Read More

Cancer Treat Rev 2016 Nov 13;50:23-34. Epub 2016 Aug 13.

Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Faculty of Science, Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.

Fluoropyrimidines remain the cornerstone of treatment for different types of cancer, and are used by an estimated two million patients annually. The toxicity associated with fluoropyrimidine therapy is substantial, however, and affects around 30% of the patients, with 0.5-1% suffering fatal toxicity. Read More

Cancer Treat Rev 2016 Nov 10;50:9-22. Epub 2016 Aug 10.

Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address:

Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) and approved for treatment of various malignancies. Hereditary genetic variants may affect a drug's pharmacokinetics or pharmacodynamics and account for differences in treatment response and adverse events among patients. In this review we present the current knowledge on genetic variants, commonly single-nucleotide polymorphisms (SNPs), tested in cohorts of cancer patients and possibly useful for prediction of capecitabine efficacy or toxicity. Read More

Anticancer Drugs 2016 11;27(10):1044-9

aClinical and Molecular Medicine Department bAdvanced Molecular Diagnostics Unit cDepartment of Neurosciences, Mental Health and Sensory Organs, Sant'Andrea Hospital, Sapienza University dGenetic Epidemiology Unit, National Centre for Epidemiology, Surveillance and Health Promotion, National Institute of Health, Rome, Italy.

Low doses of drugs delivered at close, regular intervals are increasingly being used to manage patients with different neoplasms. Despite the good tolerability, treatment-related adverse events still occur following metronomic protocols. The aim of this study was to retrospectively investigate whether polymorphisms of different genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with the outcome of a low-dose capecitabine schedule. Read More

Cancer Chemother Pharmacol 2016 10 20;78(4):875-80. Epub 2016 Aug 20.

Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Purpose: Dihydropyrimidine dehydrogenase (DPD) is a critical determinant of 5-fluorouracil pharmacology, and reduced activity of DPD as a result of deleterious polymorphisms in the gene encoding DPD (DPYD) can result in severe treatment-related toxicity. Dosing recommendations to individualize treatment have been provided for three DPYD variants (DPYD*2A, c.2846A>T, and c. Read More

J Cancer Res Ther 2016 Apr-Jun;12(2):782-6

Molecular Testing Laboratory, Hanzhong 3201 Hospital, School of Medicine, Xi'An Jiaotong University' Shaanxi, China.

Aim Of Study: Fluorouracil drugs and irinotecan are commonly used in the treatment of colorectal cancer (CRC), but some patients have severe toxic side effects in the conventional dose. DPYD*2A/*5A/*9A and UGT1A1 * 6/*28 polymorphisms are related to the toxicity of fluorouracil drugs and irinotecan, respectively. Herein, we investigated the frequencies of DPYD*2A/*5A/*9A and UGT1A1 * 6/*28 genotypes in Chinese CRC patients. Read More

Scand J Clin Lab Invest Suppl 2016 25;245:S30-3. Epub 2016 Jul 25.

a Centre Antoine-Lacassagne , Nice Cedex , France.

Background: Sequencing of DPYD exome was conducted in a prospective cohort of advanced breast cancer patients receiving capecitabine.

Methods: A total of 243 patients were analyzed. Digestive, neurologic and hematotoxicity over cycles 1-2 showed 10. Read More

Cancer Chemother Pharmacol 2016 Jul 8;78(1):151-6. Epub 2016 Jun 8.

Mayo Clinic, Rochester, MN, USA.

Background: 5-Fluorouracil (5-FU), an analog of uracil, is one of the most commonly used chemotherapeutic agents and like other agents has a narrow therapeutic index limited by toxicity. Compared to previous attempts, uridine triacetate (Vistogard) has shown to increase the potential efficacy of 5-FU by allowing administering a higher dose and decreasing the toxicity. Recently, Vistogard received orphan drug designation from the FDA as an antidote in the treatment of 5-FU poisoning and from the European Medicines Agency as a treatment for 5-FU overdose. Read More

Pharmacogenomics 2016 05 16;17(7):721-9. Epub 2016 May 16.

Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands.

Aim: Fluoropyrimidines are commonly used anti-cancer drugs, but lead to severe toxicity in 10-30% of patients. Prospective DPYD screening identifies patients at risk for toxicity and leads to a safer treatment with fluoropyrimidines. This study evaluated the routinely application of prospective DPYD screening at the Leiden University Medical Center. Read More

J Oncol Pharm Pract 2017 Jul 27;23(5):396-398. Epub 2016 Apr 27.

1 University Hospital of the Canary Islands (HUC), CTRA OFRA S/N La Cuesta, SAN Cristobal De La Laguna, Spain.

Colorectal cancer is the second most common cancer in Europe. Most antineoplastic regimens in first-line treatment involve 5-fluorouracil or oral prodrug capecitabine, combined with other antineoplastic agents such as oxaliplatin or irinotecan. It is well known that 5-fluorouracil and capecitabine are agents that can be toxic in cases of decreased dihydropyrimidine dehydrogenase activity because this enzyme is the main limiting factor in the metabolism of both agents. Read More