Genetic Polymorphism of CYP2D6 and MDR1 in breast cancer patients treated with tamoxifen

Introduction: Tamoxifen is the drug of choice for the treatment of breast cancer patients who are positive for estrogen receptor. It is metabolized by Cytochrome P450 2D6 (CYP2D6) and the variations in CYP2D6 activity has been reported to have important therapeutic consequences which include develop...

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Main Authors:	Mohamad, NI, Ismail, S, Hamzah , S, Harun, R, Ngow , Harris Abdullah
Format:	Conference or Workshop Item
Language:	English
Published:	2010
Subjects:	RC Internal medicine RM Therapeutics. Pharmacology
Online Access:	http://irep.iium.edu.my/5238/ http://irep.iium.edu.my/5238/1/Abstract_CYP2D6_NNCC.pdf

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spelling	iium-52382011-11-10T03:03:21Z http://irep.iium.edu.my/5238/ Genetic Polymorphism of CYP2D6 and MDR1 in breast cancer patients treated with tamoxifen Mohamad, NI Ismail, S Hamzah , S Harun, R Ngow , Harris Abdullah RC Internal medicine RM Therapeutics. Pharmacology Introduction: Tamoxifen is the drug of choice for the treatment of breast cancer patients who are positive for estrogen receptor. It is metabolized by Cytochrome P450 2D6 (CYP2D6) and the variations in CYP2D6 activity has been reported to have important therapeutic consequences which include development of adverse events or therapeutic failure in susceptible individuals. Tamoxifen is known to inhibit P-glycoprotein while active metabolite of this drug activates the expression of MDR1 in MCF-7 cells (ref). This affects the intracellular concentrations tamoxifen and its active metabolites inside the tumour cells. Understanding the impact of this variability is useful to determine the choice and monitor response to therapy. Materials and methods: The study protocol is approved by the Medical Research Ethics Committee and local institutions. Genotyping methods for CYP2D6 and MDR1 were developed using multiplex allele specific PCR (ASPCR) approach. Selected samples were randomly sent for direct sequencing for validation of the ASPCR results. Twenty (20) breast cancer patients were screened for CYP2D6 (CYP2D64, CYP2D610, CYP2D614) and MDR1 ( G2677A/T, C3435T and C1236T). Result: CYP2D64 and CYP2D614 was absent in patients. The most common variants detected is CYP2D610 with 25% of homozygous CYP2D610/10 and 45% heterozygous CYP2D61/10 in breast cancer patients. Heterozygous C3435T was present at the highest frequency at 60%. G2677A/T and C1236T was found in 44.4% and 50% of the 18 samples successfully amplified. Discussion & conclusion: More than half the patients carry CYP2D6*10 and MDR1 variants which reduce the metabolic activity and expression of the efflux transporter. However, the clinical implications of the variation in dose adjustment and therapeutic effect require further confirmation from the ongoing study with a larger sample size. Keyword : CYP2D6, MDR1, Breast cancer 2010 Conference or Workshop Item NonPeerReviewed application/pdf en http://irep.iium.edu.my/5238/1/Abstract_CYP2D6_NNCC.pdf Mohamad, NI and Ismail, S and Hamzah , S and Harun, R and Ngow , Harris Abdullah (2010) Genetic Polymorphism of CYP2D6 and MDR1 in breast cancer patients treated with tamoxifen. In: National Committee For Clinical Research(NCCR) 2010- 13th NIH Scientific Meeting, 2th-4th June 2010, Royale Chulan, Kuala Lumpur.
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 RM Therapeutics. Pharmacology
spellingShingle	RC Internal medicine RM Therapeutics. Pharmacology Mohamad, NI Ismail, S Hamzah , S Harun, R Ngow , Harris Abdullah Genetic Polymorphism of CYP2D6 and MDR1 in breast cancer patients treated with tamoxifen
description	Introduction: Tamoxifen is the drug of choice for the treatment of breast cancer patients who are positive for estrogen receptor. It is metabolized by Cytochrome P450 2D6 (CYP2D6) and the variations in CYP2D6 activity has been reported to have important therapeutic consequences which include development of adverse events or therapeutic failure in susceptible individuals. Tamoxifen is known to inhibit P-glycoprotein while active metabolite of this drug activates the expression of MDR1 in MCF-7 cells (ref). This affects the intracellular concentrations tamoxifen and its active metabolites inside the tumour cells. Understanding the impact of this variability is useful to determine the choice and monitor response to therapy. Materials and methods: The study protocol is approved by the Medical Research Ethics Committee and local institutions. Genotyping methods for CYP2D6 and MDR1 were developed using multiplex allele specific PCR (ASPCR) approach. Selected samples were randomly sent for direct sequencing for validation of the ASPCR results. Twenty (20) breast cancer patients were screened for CYP2D6 (CYP2D64, CYP2D610, CYP2D614) and MDR1 ( G2677A/T, C3435T and C1236T). Result: CYP2D64 and CYP2D614 was absent in patients. The most common variants detected is CYP2D610 with 25% of homozygous CYP2D610/10 and 45% heterozygous CYP2D61/10 in breast cancer patients. Heterozygous C3435T was present at the highest frequency at 60%. G2677A/T and C1236T was found in 44.4% and 50% of the 18 samples successfully amplified. Discussion & conclusion: More than half the patients carry CYP2D6*10 and MDR1 variants which reduce the metabolic activity and expression of the efflux transporter. However, the clinical implications of the variation in dose adjustment and therapeutic effect require further confirmation from the ongoing study with a larger sample size. Keyword : CYP2D6, MDR1, Breast cancer
format	Conference or Workshop Item
author	Mohamad, NI Ismail, S Hamzah , S Harun, R Ngow , Harris Abdullah
author_facet	Mohamad, NI Ismail, S Hamzah , S Harun, R Ngow , Harris Abdullah
author_sort	Mohamad, NI
title	Genetic Polymorphism of CYP2D6 and MDR1 in breast cancer patients treated with tamoxifen
title_short	Genetic Polymorphism of CYP2D6 and MDR1 in breast cancer patients treated with tamoxifen
title_full	Genetic Polymorphism of CYP2D6 and MDR1 in breast cancer patients treated with tamoxifen
title_fullStr	Genetic Polymorphism of CYP2D6 and MDR1 in breast cancer patients treated with tamoxifen
title_full_unstemmed	Genetic Polymorphism of CYP2D6 and MDR1 in breast cancer patients treated with tamoxifen
title_sort	genetic polymorphism of cyp2d6 and mdr1 in breast cancer patients treated with tamoxifen
publishDate	2010
url	http://irep.iium.edu.my/5238/ http://irep.iium.edu.my/5238/1/Abstract_CYP2D6_NNCC.pdf
first_indexed	2023-09-18T20:13:43Z
last_indexed	2023-09-18T20:13:43Z
_version_	1777407648141934592

Genetic Polymorphism of CYP2D6 and MDR1 in breast cancer patients treated with tamoxifen

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