Potential of Dihydropyrimidine Dehydrogenase Genotypes in Personalizing 5-Fluorouracil Therapy Among Colorectal Cancer Patients
- 1 October 2013
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Therapeutic Drug Monitoring
- Vol. 35 (5), 624-630
- https://doi.org/10.1097/ftd.0b013e318290acd2
Abstract
Background: Dihydropyrimidine dehydrogenase (DPD) is a pyrimidine catabolic enzyme involved in the initial and rate-limiting step of the catabolic pathway of toxic metabolites of 5-fluorouracil (5-FU). Several studies have reported that deficiency of DPD and polymorphisms of its gene are related to 5-FU toxicities and death. Association between serum concentration of 5-FU and its related toxicity has also been previously demonstrated. Hence, this study aims to understand the role of DPYD variants in serum level of 5-FU and the risk of developing toxicity to prevent adverse reactions and maximize therapy outcome for personalized medicine. Methods: A total of 26 patients comprising 3 different ethnic groups (Malay, Chinese, and Indian) diagnosed with colorectal cancer and treated with 5-FU chemotherapy regimen from local hospital were recruited. Polymerase chain reaction and denaturing high-performance liquid chromatography methods were developed to screen polymorphisms of DPYD gene. High-performance liquid chromatography–based quantification assay was developed to measure the serum concentration of 5-FU among these patients. Results: Patients with DPYD genotypes of deficient enzyme activity had higher median serum levels of 5-FU compared with normal DPD group (median, 11.51 mcg/mL; 95% confidence interval, 10.18–16.11 versus median, 0.83 mcg/mL; 95% confidence interval, 0.55–5.90, Mann–Whitney U test; P = 0.010). Patients with neutropenia (n = 11) had significantly higher serum concentrations of 5-FU as compared with those with normal white blood cell count (n = 15) (Mann–Whitney U test, P = 0.031). Combined regression analysis showed that the predictive power of DPYD*5 (rs1801159) and 1896 T>C (rs17376848) for serum concentrations of 5-FU in the studied group was 36.6% (P = 0.04). Similarly, DPYD*5 and 1896 T>C accounted for 29.9% of the occurrences of neutropenia (analysis of variance, P = 0.017). Conclusions: This study revealed that DPYD*5 (rs1801159) and 1896 T>C (rs17376848) are potentially useful predictive markers of patients’ responses to 5-FU chemotherapy. Pharmacogenotyping is therefore recommended to guide dosing of 5-FU and prevent neutropenia.Keywords
This publication has 18 references indexed in Scilit:
- A Personalized Approach to Cancer Treatment: How Biomarkers Can HelpClinical Chemistry, 2008
- Body Composition as an Independent Determinant of 5-Fluorouracil–Based Chemotherapy ToxicityClinical Cancer Research, 2007
- Increased dihydropyrimidine dehydrogenase activity associated with mild toxicity in patients treated with 5-fluorouracil and leucovorinEuropean Journal of Cancer, 2007
- Identification of a novel mutation in the dihydropyrimidine dehydrogenase gene in a patient with a lethal outcome following 5-fluorouracil administration and the determination of its frequency in a population of 500 patients with colorectal carcinomaClinical Biochemistry, 2007
- A Rapid and Inexpensive Method for Anticipating Severe Toxicity to Fluorouracil and Fluorouracil-based ChemotherapyTherapeutic Drug Monitoring, 2006
- The Uracil Breath Test in the Assessment of Dihydropyrimidine Dehydrogenase Activity: Pharmacokinetic Relationship between Expired 13CO2 and Plasma [2-13C]DihydrouracilClinical Cancer Research, 2006
- Analysis of the DPYD Gene Implicated in 5-Fluorouracil Catabolism in a Cohort of Caucasian IndividualsClinical Cancer Research, 2005
- Characterization of the Human Dihydropyrimidine Dehydrogenase GeneGenomics, 1998
- Measurement of plasma 5-fluorouracil by high-performance liquid chromatography with comparison of results to tissue drug levels observed using in vivo 19F magnetic resonance spectroscopy in patients on a protracted venous infusion with or without interferon-αAnnals of Oncology, 1996
- Human Polymorphism in Drug Metabolism: Mutation in the Dihydropyrimidine Dehydrogenase Gene Results in Exon Skipping and Thymine UracilureaDNA and Cell Biology, 1995