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

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...

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Main Authors:	Teh, Lay Kek, Hamzah, Sharina, Hashim, Hazwanie, Bannur, Zakaria, Zakaria, Zainul Amiruddin, Hasbullani, Zakaria, Kwong, John Siew Shia, Fijeraid, Henry, Md Nor, Azmid, Mohd Zailani,, Ramasamy, Prabu, Ngow, Harris, Sood, Suneet, Salleh, Mohd Zaki
Format:	Article
Language:	English
Published:	Lippincott Williams & Wilkins 2013
Online Access:	http://psasir.upm.edu.my/id/eprint/29679/1/Potential%20of%20dihydropyrimidine%20dehydrogenase%20genotypes%20in%20personalizing%205.pdf http://psasir.upm.edu.my/id/eprint/29679/
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spelling	my.upm.eprints.296792015-12-08T01:51:34Z http://psasir.upm.edu.my/id/eprint/29679/ Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients Teh, Lay Kek Hamzah, Sharina Hashim, Hazwanie Bannur, Zakaria Zakaria, Zainul Amiruddin Hasbullani, Zakaria Kwong, John Siew Shia Fijeraid, Henry Md Nor, Azmid Mohd Zailani, Ramasamy, Prabu Ngow, Harris Sood, Suneet Salleh, Mohd Zaki 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. Lippincott Williams & Wilkins 2013-10 Article PeerReviewed application/pdf en http://psasir.upm.edu.my/id/eprint/29679/1/Potential%20of%20dihydropyrimidine%20dehydrogenase%20genotypes%20in%20personalizing%205.pdf Teh, Lay Kek and Hamzah, Sharina and Hashim, Hazwanie and Bannur, Zakaria and Zakaria, Zainul Amiruddin and Hasbullani, Zakaria and Kwong, John Siew Shia and Fijeraid, Henry and Md Nor, Azmid and Mohd Zailani, and Ramasamy, Prabu and Ngow, Harris and Sood, Suneet and Salleh, Mohd Zaki (2013) Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients. Therapeutic Drug Monitoring, 35 (5). pp. 624-630. ISSN 0163-4356; ESSN: 1536-3694 10.1097/FTD.0b013e318290acd2
institution	Universiti Putra Malaysia
building	UPM Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	Universiti Putra Malaysia
content_source	UPM Institutional Repository
url_provider	http://psasir.upm.edu.my/
language	English
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	Teh, Lay Kek Hamzah, Sharina Hashim, Hazwanie Bannur, Zakaria Zakaria, Zainul Amiruddin Hasbullani, Zakaria Kwong, John Siew Shia Fijeraid, Henry Md Nor, Azmid Mohd Zailani, Ramasamy, Prabu Ngow, Harris Sood, Suneet Salleh, Mohd Zaki
spellingShingle	Teh, Lay Kek Hamzah, Sharina Hashim, Hazwanie Bannur, Zakaria Zakaria, Zainul Amiruddin Hasbullani, Zakaria Kwong, John Siew Shia Fijeraid, Henry Md Nor, Azmid Mohd Zailani, Ramasamy, Prabu Ngow, Harris Sood, Suneet Salleh, Mohd Zaki Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients
author_facet	Teh, Lay Kek Hamzah, Sharina Hashim, Hazwanie Bannur, Zakaria Zakaria, Zainul Amiruddin Hasbullani, Zakaria Kwong, John Siew Shia Fijeraid, Henry Md Nor, Azmid Mohd Zailani, Ramasamy, Prabu Ngow, Harris Sood, Suneet Salleh, Mohd Zaki
author_sort	Teh, Lay Kek
title	Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients
title_short	Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients
title_full	Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients
title_fullStr	Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients
title_full_unstemmed	Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients
title_sort	potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients
publisher	Lippincott Williams & Wilkins
publishDate	2013
url	http://psasir.upm.edu.my/id/eprint/29679/1/Potential%20of%20dihydropyrimidine%20dehydrogenase%20genotypes%20in%20personalizing%205.pdf http://psasir.upm.edu.my/id/eprint/29679/
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score	13.211869

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

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