Potential of Dihydropyrimidine Dehydrogenase Genotypes in Personalizing 5-Fluorouracil Therapy Among Colorectal Cancer Patients

作者：Teh Lay Kek^*; Hamzah Sharina; Hashim Hazwanie; Bannur Zakaria; Zakaria Zainul Amiruddin; Ha**ullani Zakaria; Shia John Kwong Siew; Fijeraid Henry; Nor Azmid Md; Zailani Mohd; Ramasamy Prabu; Ngow Harris; Sood Suneet; Salleh Mohd Zaki

来源：Therapeutic Drug Monitoring, 2013, 35(5): 624-630.

DOI：10.1097/FTD.0b013e318290acd2

• 5-fluorouracil
• dihydropyrimidine dehydrogenase
• pharmacogenotypes
• adverse effect
• neutropenia

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%26gt;C (rs17376848) for serum concentrations of 5-FU in the studied group was 36.6% (P = 0.04). Similarly, DPYD*5 and 1896 T%26gt;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%26gt;C (rs17376848) are potentially useful predictive markers of patients%26apos; responses to 5-FU chemotherapy. Pharmacogenotyping is therefore recommended to guide dosing of 5-FU and prevent neutropenia.

• 出版日期2013-10