Pharmacogenetics of doxorubicin in asian breast cancer patients

PHARMACOGENETICS OF DOXORUBICIN IN ASIAN BREAST CANCER PATIENTS SUMAN LAL CHIRAMMAL SUGUNAN (MBBS, MSc) A THESIS SUBMITTED FOR THE DEGREE OF PHILOSOPHY DEPARTMENT OF PHARMACOLOGY NATIONAL UNIVERSITY OF SINGAPORE 2008 ACKNOWLEDGEMENTS The research done towards this thesis was carried out under the direct supervision and guidance of Assoc Prof Balram Chowbay at the National Cancer Centre, Singapore I wish to deeply thank him for lending me his support and guidance through each stage of the research and preparation of this thesis This would not have been possible without his persistence and attention to detail I am greatly indebted to my principal supervisor Prof Edmund Lee at the National University of Singapore, whose generous encouragement, guidance and support has been vital throughout the period of my post-graduate study Much gratitude is due to my laboratory colleagues Xiaoxiang and Edwin, who have made significant experimental and analytical contributions to this thesis I am particularly thankful to Dr Zee Wan Wong and other members of the breast cancer team from the Department of Medical Oncology at the National Cancer Centre, who actively collaborated with the Clinical Pharmacology Laboratory and provided vital clinical support for this study Last but not least, I would like to extend my sincere thanks and gratitude to all the patients who have been involved in the study leading to this thesis This study was supported by research grants from the Singapore Cancer Syndicate (Singapore Cancer Syndicate grant SCS-PS0023) and SingHealth (SingHealth Research Fund SRF-SU110/2004) CONTENTS ACKNOWLEDGEMENTS I SUMMARY IX PUBLICATIONS AND ABSTRACTS XII LIST OF TABLES XV LIST OF FIGURES XVIII CHAPTER 1: INTRODUCTION 1.1 BREAST CANCER CHEMOTHERAPY 1.1.1 Incidence and Trends 1.1.2 Neo-adjuvant and Adjuvant Chemotherapy 1.1.3 Breast Cancer Chemotherapy Regimens 1.1.4 Anthracycline Based Chemotherapy 1.2 CLINICAL PHARMACOLOGY OF DOXORUBICIN 11 1.2.1 Introduction 11 1.2.2 Chemistry 11 1.2.3 Mechanism of Action 12 1.2.4 Pharmacokinetics 14 1.2.4.1 Administration and Distribution 14 1.2.4.2 Metabolism 15 1.2.4.3 Excretion 17 1.2.5 Pharmacodynamics 18 1.3 PHARMACOGENETICS OF DOXORUBICIN 1.3.1 Overview 23 23 1.3.2 Pharmacogenetics of Nuclear Receptors, Drug Transporters and Drug Metabolizing Enzymes 1.3.2.1 Regulatory Nuclear Receptors 1.3.2.1.1 Pregnane X receptor (PXR) 1.3.2.2 Doxorubicin Efflux Transporters 25 25 26 29 1.3.2.2.1 ATP binding cassette, sub family B1 (ABCB1) 31 1.3.2.2.2 ATP binding cassette, sub family G2 (ABCG2) 34 1.3.2.2.3 ATP binding cassette, sub family B5 (ABCB5) 38 1.3.2.2.4 ATP binding cassette, sub family C5 (ABCC5) 40 1.3.2.2.5 Ral-Binding Protein 1; RALBP1 (RLIP76) 43 1.3.2.3 Doxorubicin Influx Transporters 1.3.2.3.1 Solute carrier family, member 16 (SLC22A16) 1.3.2.4 Doxorubicin Metabolizing Enzymes 47 48 50 1.3.2.4.1 Carbonyl Reductase (CBR1) 51 1.3.2.4.2 Carbonyl Reductase (CBR3) 52 1.4 STUDY HYPOTHESIS 54 1.5 OBJECTIVES 54 III CHAPTER 2: MATERIALS AND METHODS 56 2.1 STUDY DESIGN 56 2.2 STUDY POPULATION 57 2.2.1 Healthy Subjects 57 2.2.2 Breast Cancer Patients 57 2.2.2.1 Patient Definition 58 2.2.2.2 Inclusion Criteria 58 2.2.2.3 Exclusion Criteria 59 2.2.2.4 Screening Evaluations 59 2.2.2.5 Doxorubicin Administration and Dosing Schedule 60 2.2.2.6 Concomitant Therapy 61 2.2.3 Liver Tissues 61 2.3 CHEMICALS AND REAGENTS 63 2.4 PHARMACOGENETIC ANALYSIS 65 2.4.1 DNA Extraction 65 2.4.1.1 Whole Blood 65 2.4.1.2 Liver Tissues 66 2.4.2 Polymerase Chain Reactions (PCR) 67 2.4.3 Purification of PCR Fragments 70 2.4.4 DNA Sequencing 70 2.4.5 Pharmacogenetics of Nuclear Receptors 73 2.4.5.1 Pregnane X Receptor (PXR) 2.4.6 Pharmacogenetics of Doxorubicin Transporters 73 74 2.4.6.1 ATP binding cassette, sub family B1 (ABCB1) 74 2.4.6.2 ATP binding cassette, sub family G2 (ABCG2) 75 2.4.6.3 ATP binding cassette, sub family C5 (ABCC5) 76 2.4.6.4 ATP binding cassette, sub family B5 (ABCB5) 78 2.4.6.5 Ral-Binding Protein 1; RALBP1 (RLIP76) 80 IV 2.4.6.6 Solute carrier family, member 16 (SLC22A16) 2.4.7 Pharmacogenetics of Doxorubicin Metabolizing Enzymes 81 82 2.4.7.1 Carbonyl Reductase (CBR1) 82 2.4.7.2 Carbonyl Reductase (CBR3) 83 2.5 HEPATIC EXPRESSION 84 2.5.1 RNA Extraction from Liver Tissues 84 2.5.2 Real Time Reverse-Transcription PCR (RT-PCR) 85 2.6 PHARMACOKINETICS OF DOXORUBICIN AND DOXORUBICINOL 87 2.6.1 High performance Liquid Chromatography (HPLC) Assay 2.6.1.1 Instrumentation and Chromatographic Conditions 87 87 2.6.1.2 Standard Stock Solution, Calibration and Quality Control Samples 2.6.2 HPLC determination of Doxorubicin and Doxorubicinol 88 88 2.6.2.1 Sample Preparation and Analysis 88 2.6.2.2 Estimation of Pharmacokinetic Parameters 89 2.7 STATISTICAL ANALYSIS 92 2.7.1 Pharmacogenetic Analysis 92 2.7.2 Analysis of Hepatic Expression 92 2.7.3 Pharmacokinetic-Pharmacogenetic Correlations 93 V CHAPTER 3: RESULTS AND DISCUSSION 94 3.1 DEMOGRAPHICS OF ASIAN BREAST CANCER PATIENTS 94 3.2 PHARMACOKINETICS OF DOXORUBICIN 95 3.3 PHARMACOKINETICS OF DOXORUBICINOL 100 3.4 PHARMACOKINETIC-PHARMACOGENETIC CORRELATES OF NUCLEAR RECEPTORS 3.4.1 Pregnane X Receptor (PXR) 3.4.1.1 PXR Pharmacogenetics 105 105 105 3.4.1.1.1 Linkage Disequilibrium and LD Blocks 110 3.4.1.1.2 PXR Haplotypes and Network Analysis 115 3.4.1.2 PXR Haplotypes and ABCB1 Hepatic Expression 120 3.4.1.3 Pharmacokinetic-Pharmacogenetic Associations 124 3.4.1.4 Discussion 126 3.5 PHARMACOKINETIC-PHARMACOGENETIC CORRELATES OF DRUG TRANSPORTERS 3.5.1 ATP binding cassette, subfamily B1 (ABCB1) 133 133 3.5.1.1 ABCB1 Pharmacogenetics 133 3.5.1.2 Pharmacokinetic-Pharmacogenetic Associations 135 3.5.1.3 ABCB1 Hepatic Expression 141 3.5.1.4 Discussion 143 3.5.2 ATP binding cassette, subfamily G2 (ABCG2) 148 3.5.2.1 ABCG2 Pharmacogenetics 148 3.5.2.2 Pharmacokinetic-Pharmacogenetic Associations 148 3.5.2.3 ABCG2 Hepatic Expression 150 3.5.2.4 Discussion 151 3.5.3 ATP binding cassette, subfamily C5 (ABCC5) 154 VI 3.5.3.1 ABCC5 Pharmacogenetics 154 3.5.3.2 Pharmacokinetic-Pharmacogenetic Associations 156 3.5.3.3 ABCC5 Hepatic Expression 163 3.5.3.4 Discussion 166 3.5.4 ATP binding cassette, subfamily B5 (ABCB5) 169 3.5.4.1 ABCB5 Pharmacogenetics 169 3.5.4.2 Pharmacokinetic-Pharmacogenetic Associations 171 3.5.4.3 Discussion 172 3.5.5 Ral-Binding Protein 1; RALBP1 (RLIP76) 174 3.5.5.1 RLIP76 Pharmacogenetics 174 3.5.5.2 RLIP76 Hepatic Expression 174 3.5.5.3 Discussion 175 3.5.6 Solute carrier family, member 16 (SLC22A16) 177 3.5.6.1 SLC22A16 Pharmacogenetics 177 3.5.6.2 Pharmacokinetic-Pharmacogenetic Associations 179 3.5.6.3 SLC22A16 Hepatic Expression 182 3.5.6.4 Discussion 184 3.6 PHARMACOKINETIC-PHARMACOGENETIC CORRELATES OF DRUG METABOLIZING ENZYMES 188 3.6.1 Carbonyl Reductase (CBR1) 3.6.1.1 CBR1 Pharmacogenetics 188 188 3.6.1.1.1 Linkage Disequilibrium, Haplotypes and Diplotypes 190 3.6.1.2 Pharmacokinetic-Pharmacogenetic Associations 193 3.6.1.3 CBR1 Hepatic Expression 199 3.6.2 Carbonyl Reductase (CBR3) 3.6.2.1 CBR3 Pharmacogenetics 201 201 3.6.2.1.1 Linkage Disequilibrium, Haplotypes and Diplotypes 3.6.2.2 Pharmacokinetic-Pharmacogenetic Associations 3.6.3 Discussion 204 207 207 VII CHAPTER 4: CONCLUSION AND FUTURE RESEARCH DIRECTIONS 214 A: APPENDIX 216 B: APPENDIX 218 BIBLIOGRAPHY 219 VIII SUMMARY This thesis aimed to comprehensively evaluate the pharmacogenetics of the regulatory nuclear receptor Pregnane-X Receptor (PXR), influx (SLC22A16) and efflux drug transporters (ABCB1, ABCG2, ABCC5, ABCB5 and RLIP76) and drug metabolizing enzymes (CBR1, CBR3) across the biochemical pathway of doxorubicin in Asian breast cancer patients receiving doxorubicin based adjuvant chemotherapy The moderately linked ABCB1 1236CC-2677GG-3435CC genotypes were associated with significantly increased exposure levels, peak plasma concentrations and reduced clearance of doxorubicin in patients who were homozygous for the variant alleles at the three ABCB1 loci Breast cancer 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