Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients.
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.
*Pharmacogenomics Centre, Faculty of Pharmacy, Universiti Teknologi MARA; †Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra Malaysia, Selangor, Malaysia; ‡Department of Surgery, Kulliyah of Medicine, International Islamic University Malaysia, Kuantan, Malaysia; and §Department of Surgery, Faculty of Medicine, Universiti Teknologi MARA, Selangor, Malaysia.
Lay Kek
LK
Teh
Sharina
S
Hamzah
Hazwanie
H
Hashim
Zakaria
Z
Bannur
Zainul Amiruddin
ZA
Zakaria
Zakaria
Z
Hasbullani
John Kwong Siew
JK
Shia
Henry
H
Fijeraid
Azmid
A
Md Nor
Mohd
M
Zailani
Prabu
P
Ramasamy
Harris
H
Ngow
Suneet
S
Sood
Mohd Zaki
MZ
Salleh
D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions; D005472:Fluorouracil / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D011110:Polymorphism, Genetic / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil