Potential of dihydropyrimidine dehydrogenase genotypes in personalising 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...

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Main Authors:	Ngow, Harris Abdullah, Lay , Kek Teh, Hamzah, Sharina, Hashim, Hazwanie, Bannur, Zakaria, Zakaria, Zainul Amiruddin, Hasbullani, Zakaria, John Kwong, Siew Shia, Henry, Fijeraid, Md Nor, Azmid, Zailani, Mohd, Prabu, Ramasamy, Suneet, S, Salleh, Mohd Zaki
Format:	Article
Language:	English
Published:	International Association of Therapeutic Drug Monitoring and Clinical Toxicology 2011
Subjects:	RC Internal medicine
Online Access:	http://irep.iium.edu.my/43026/ http://irep.iium.edu.my/43026/ http://irep.iium.edu.my/43026/1/potential.pdf

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spelling	iium-430262015-06-01T06:39:56Z http://irep.iium.edu.my/43026/ Potential of dihydropyrimidine dehydrogenase genotypes in personalising 5-fluorouracil therapy among colorectal cancer patients Ngow, Harris Abdullah Lay , Kek Teh Hamzah, Sharina Hashim, Hazwanie Bannur, Zakaria Zakaria, Zainul Amiruddin Hasbullani, Zakaria John Kwong, Siew Shia Henry, Fijeraid Md Nor, Azmid Zailani, Mohd Prabu, Ramasamy Suneet, S Salleh, Mohd Zaki RC Internal medicine 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 DPYD5 (rs1801159) and 1896 T>C (rs17376848) for serum concentrations of 5-FU in the studied group was 36.6% (P = 0.04). Similarly, DPYD5 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. International Association of Therapeutic Drug Monitoring and Clinical Toxicology 2011 Article PeerReviewed application/pdf en http://irep.iium.edu.my/43026/1/potential.pdf 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 http://journals.lww.com/drug-monitoring/pages/default.aspx
repository_type	Digital Repository
institution_category	Local University
institution	International Islamic University Malaysia
building	IIUM Repository
collection	Online Access
language	English
topic	RC Internal medicine
spellingShingle	RC Internal medicine Ngow, Harris Abdullah Lay , Kek Teh Hamzah, Sharina Hashim, Hazwanie Bannur, Zakaria Zakaria, Zainul Amiruddin Hasbullani, Zakaria John Kwong, Siew Shia Henry, Fijeraid Md Nor, Azmid Zailani, Mohd Prabu, Ramasamy Suneet, S Salleh, Mohd Zaki Potential of dihydropyrimidine dehydrogenase genotypes in personalising 5-fluorouracil therapy among colorectal cancer patients
description	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 DPYD5 (rs1801159) and 1896 T>C (rs17376848) for serum concentrations of 5-FU in the studied group was 36.6% (P = 0.04). Similarly, DPYD5 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.
format	Article
author	Ngow, Harris Abdullah Lay , Kek Teh Hamzah, Sharina Hashim, Hazwanie Bannur, Zakaria Zakaria, Zainul Amiruddin Hasbullani, Zakaria John Kwong, Siew Shia Henry, Fijeraid Md Nor, Azmid Zailani, Mohd Prabu, Ramasamy Suneet, S Salleh, Mohd Zaki
author_facet	Ngow, Harris Abdullah Lay , Kek Teh Hamzah, Sharina Hashim, Hazwanie Bannur, Zakaria Zakaria, Zainul Amiruddin Hasbullani, Zakaria John Kwong, Siew Shia Henry, Fijeraid Md Nor, Azmid Zailani, Mohd Prabu, Ramasamy Suneet, S Salleh, Mohd Zaki
author_sort	Ngow, Harris Abdullah
title	Potential of dihydropyrimidine dehydrogenase genotypes in personalising 5-fluorouracil therapy among colorectal cancer patients
title_short	Potential of dihydropyrimidine dehydrogenase genotypes in personalising 5-fluorouracil therapy among colorectal cancer patients
title_full	Potential of dihydropyrimidine dehydrogenase genotypes in personalising 5-fluorouracil therapy among colorectal cancer patients
title_fullStr	Potential of dihydropyrimidine dehydrogenase genotypes in personalising 5-fluorouracil therapy among colorectal cancer patients
title_full_unstemmed	Potential of dihydropyrimidine dehydrogenase genotypes in personalising 5-fluorouracil therapy among colorectal cancer patients
title_sort	potential of dihydropyrimidine dehydrogenase genotypes in personalising 5-fluorouracil therapy among colorectal cancer patients
publisher	International Association of Therapeutic Drug Monitoring and Clinical Toxicology
publishDate	2011
url	http://irep.iium.edu.my/43026/ http://irep.iium.edu.my/43026/ http://irep.iium.edu.my/43026/1/potential.pdf
first_indexed	2023-09-18T21:01:17Z
last_indexed	2023-09-18T21:01:17Z
_version_	1777410640418177024

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

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