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

Ngow, Harris Abdullah and Lay , Kek Teh and Hamzah, Sharina and Hashim, Hazwanie and Bannur, Zakaria and Zakaria, Zainul Amiruddin and Hasbullani, Zakaria and John Kwong, Siew Shia and Henry, Fijeraid and Md Nor, Azmid and Zailani, Mohd and Prabu, Ramasamy and Suneet, S and Salleh, Mohd Zaki (2011) Potential of dihydropyrimidine dehydrogenase genotypes in personalising 5-fluorouracil therapy among colorectal cancer patients. Therapeutic Drug Monitoring, 35 (5). pp. 624-630. ISSN 0163-4356

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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.

Item Type:	Article (Journal)
Additional Information:	4393/43026
Uncontrolled Keywords:	5-fluorouracil; dihydropyrimidine dehydrogenase; pharmacogenotypes; adverse effect; neutropenia
Subjects:	R Medicine > RC Internal medicine
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Medicine > Department of Internal Medicine
Depositing User:	Mrs Noor Azlin Asnam
Date Deposited:	01 Jun 2015 14:39
Last Modified:	01 Jun 2015 14:39
URI:	http://irep.iium.edu.my/id/eprint/43026

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