Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients

Ther Drug Monit. 2013 Oct;35(5):624-30. doi: 10.1097/FTD.0b013e318290acd2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / adverse effects
  • Antimetabolites, Antineoplastic / blood
  • Antimetabolites, Antineoplastic / pharmacokinetics*
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Colorectal Neoplasms / blood
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Dihydrouracil Dehydrogenase (NADP) / genetics*
  • Drug-Related Side Effects and Adverse Reactions
  • Fluorouracil / adverse effects
  • Fluorouracil / blood
  • Fluorouracil / pharmacokinetics*
  • Fluorouracil / therapeutic use*
  • Genotype
  • Humans
  • Polymorphism, Genetic / genetics


  • Antimetabolites, Antineoplastic
  • Dihydrouracil Dehydrogenase (NADP)
  • Fluorouracil