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Interaction of Mesna with Platinum Chemotherapy Agents Cisplatin and Carboplatin: Chemistry, in Vitro, in Vivo, and Clinical Pharmacokinetics

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Interaction of Mesna with Platinum Chemotherapy Agents Cisplatin and Carboplatin: Chemistry, in Vitro, in Vivo, and Clinical Pharmacokinetics University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies Legacy Theses 2001 Interaction of Mesna with platinum chemotherapy agents Cisplatin and Carboplatin: chemistry, in vitro, in vivo, and clinical pharmacokinetics Kangarloo, Shahbal B. Kangarloo, S. B. (2001). Interaction of Mesna with platinum chemotherapy agents Cisplatin and Carboplatin: chemistry, in vitro, in vivo, and clinical pharmacokinetics (Unpublished master's thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/16467 http://hdl.handle.net/1880/41240 master thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca The author of this thesis has granted the University of Calgary a non-exclusive license to reproduce and distribute copies of this thesis to users of the University of Calgary Archives. Copyright remains with the author. Theses and dissertations available in the University of Calgary Institutional Repository are solely for the purpose of private study and research. They may not be copied or reproduced, except as permitted by copyright laws, without written authority of the copyright owner. Any commercial use or publication is strictly prohibited. The original Partial Copyright License attesting to these terms and signed by the author of this thesis may be found in the original print version of the thesis, held by the University of Calgary Archives. The thesis approval page signed by the examining committee may also be found in the original print version of the thesis held in the University of Calgary Archives. Please contact the University of Calgary Archives for further information, E-mail: [email protected] Telephone: (403) 220-7271 Website: http://www.ucalgary.ca/archives/ UNIVERSITY OF CALGARY Interaction of Mesna with Platinum Chemotherapy Agents Cisplatin and Carboplatin: Chemistry, in vitro, in vivo and Clinical Pharmacokinetics by Shahbal B. Kangarloo A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE DEPARTMENT OF MEDICAL SCIENCE CALGARY, ALBERTA OCTOBER, 2001 © Shahbal B. Kangarloo 2001 ABSTRACT Sodium 2-mercapethanesulfonate (mesna) often comes into contact with platinum drugs (Pt-drugs) cisplatin and carboplatin in combination protocols involving oxazaphosphorines and Pt-drugs. This co-administration might be unfavorable based on the inactivation of Pt-drugs by thiol groups in vitro. To elucidate whether mesna reduces effectiveness of Pt-drugs, the chemical reaction, in vitro and in vivo interactions, and clinical pharmacokinetics of Pt- drugs in combination with mesna were investigated. Mesna reacted with cisplatin in a fast 2 to 1 reaction as opposed to a slow 1 to 1 reaction with carboplatin. In glioma cells, mesna significantly reduced platinum accumulation and DNA binding of cisplatin but not that of carboplatin. Tumors and various tissues in SCID mice did not show a reduction in platinum levels and platinum-DNA adducts in presence of mesna. Pharmacokinetics of cisplatin and carboplatin were not affected by the co-administration of mesna in pediatric patients. Thus this thesis led to the reassurance that it is safe to combine mesna with Pt-drugs in combination chemotherapy protocols, provided that the agents are not mixed in solution prior to infusion into the patients. iii ACKNOWLEDGMENTS I wish to express my deepest gratitude to my supervisors: Dr. Johannes Wolff, and Dr. Stefan Gluck. To Dr. Wolff, who introduced me to the field of pharmacokinetics, for his patience and encouragement throughout this thesis, and for obtaining the funding and giving me the opportunity to perform this study in his laboratory. I owe my sincere thanks to my co-supervisor Dr. Gluck, for his guidance and constant interest in this project and in particular his support in providing me with the environment to finish this thesis in addition to his careful reading of this manuscript during its preparation. I am most grateful to Dr. Suman Gangopadhyay for her valuable advice and unlimited help with the scientific rationale and design of my experiments from day one to the end of this thesis. My warmest thanks goes to Shadi Fattahi, for her encouragement, enthusiasm, her genuine interest in my research, and her patience throughout this project. I specifically like to thank Shadi for her skillful help in formatting this thesis. I would like to thank the members of my supervisory committee, Dr. R. N. Johnston, and Dr. M. Hollenberg for their advice on several aspects of this project. I would like to thank Dr. G.G. Miller for his contribution as an external examiner. I also would like to thank my co-workers Sandra Bitner and Sharon Clark for their support and unforgettable moments spent during completion of this thesis. In particular I thank Sandra for her assistance with the animal work involved in this thesis. Finally, I would like to thank my family, my parents, and my brothers who have been the pillar of support throughout this degree. I wish to thank them all for their invaluable support and encouragement. This project was supported financially by the Alberta Cancer Board, the Alberta Children's Hospital Foundation, and the Steve Fonyo Foundation, all of which are gratefully acknowledged. iv DEDICATION I dedicate this thesis to Mr. N. Shafiee, my lifelong teacher, who always believed in me. v TABLE OF CONTENTS ABSTRACT HI ACKNOWLEDGMENTS IV DEDICATION V TABLE OF CONTENTS VI LIST OF FIGURES IX LIST OF TABLES i XI LIST OF ABBREVIATIONS XII CHAPTER ONE: BACKGROUND 1 INTRODUCTION 1 CISPLATIN 1 History 1 Chemistry 3 Mechanism of action 7 DNA as the critical target for Pt-drugs 8 Cellular proteins that bind to Pt-DNA adducts 10 Resistance 12 Drug uptake/efflux 12 Inactivation of cisplatin by cellular thiols 15 Post DNA-binding mechanisms 15 Clinical Pharmacology 16 Activity 16 Toxicity 17 Clinical Administration 18 Pharmacokinetics 19 CARBOPLATIN 20 Clinical Pharmacology 22 Activity 22 Toxicity 22 Clinical Administration 23 Pharmacokinetics 23 MESNA 24 CYCLOPHOSPHAMIDE 27 IFOSFAMIDE 27 COMBINATIONS OF PLATINUM-DRUGS WITH OXAZAPHOSPHORINES 28 INTERACTIONS OF PLATINUM-DRUGS WITH MESNA 29 RATIONAL AND HYPOTHESES 33 SPECIFIC AIMS 34 CHAPTER TWO: CHEMICAL REACTION BETWEEN MESNA AND THE PLATINUM DRUGS 35 vi METHODS 35 Reagents 35 Colorimetric determination ofmesna 35 Determination of Drug Kinetics 36 Analysis of reaction kinetics 36 Stoichiometry ofmesna binding Pt-drugs 38 Statistical Analysis 39 RESULTS 39 Reaction kinetics ofmesna and cisplatin 39 Reaction kinetics ofmesna and carboplatin 42 Stoichiometry ofmesna binding cisplatin 42 Stoichiometry ofmesna binding carboplatin 45 DISCUSSION 48 CHAPTER THREE: INFLUENCE OF MESNA ON PLATINUM CELLULAR ACCUMULATION, AND PLATINUM DNA BINDING OF CISPLATIN AND CARBOPLATIN IN MALIGNANT GLIOMA CELLS 53 METHODS 53 Reagents 53 Brain tumor cell lines 53 Cytotoxicity testing 54 Platinum DNA binding and cellular accumulation 55 Isolation of genomic DNA from glioma cell pellets 55 Isolation of total cellular lysates from glioma cell pellets 56 In vitro protein binding of cisplatin 57 Platinum measurements 57 Sample preparation 57 Instrumentation 58 Calibration 60 Statistical Analysis 60 RESULTS 61 Cytotoxicity testing 61 Kinetics of Platinum DNA binding and extracellular protein binding 64 Influence ofmesna on DNA binding and cellular accumulation of Pt-agents in glioma cells 66 DISCUSSION 72 Influence of mesna on cisplatin's Pt-DNA binding and cellular Pt accumulation 72 Mesna entry into glioma cells 73 Influence ofmesna on Pt-DNA binding of carboplatin 75 Cytotoxicity testing, Pt-DNA, and Pt-protein binding kinetics 76 CHAPTER FOUR: INFLUENCE OF MESNA ON TISSUE, TUMOR, AND DNA PLATINUM LEVELS OF CISPLATIN IN TUMOR BEARING SCID/NOD MICE 79 METHODS 79 vii Animals 79 Tumor Implantation 79 Drug treatments 80 Tissue preparations 80 Isolation of genomic DNA from mouse tumor and tissue 80 Platinum measurements 81 Statistical analysis 81 RESULTS 82 Influence of Mesna on tumor and tissue platinum concentrations in tumor bearing SCID/NOD mice 82 Influence of Mesna on tissue DNA and tumor DNA platinum concentrations in tumor bearing SCID/NOD mice 85 Influence ofmesna on renal toxicity of cisplatin 85 DISCUSSION 91 CHAPTER FIVE: INFLUENCE OF MESNA ON PHARMACOKINETICS OF CISPLATIN AND CARBOPLATIN IN PEDIATRIC PATIENTS 94 METHODS 94 Patients 94 Sampling 94 Platinum analysis 97 Pharmacokinetic analysis 98 Statistical analysis 101 RESULTS 101 Pharmacokinetics of cisplatin in children 101 Influence ofmesna on pharmacokinetics of cisplatin in children 108 Pharmacokinetics of carboplatin in children 108 Influence ofmesna on pharmacokinetics of carboplatin in children 114 DISCUSSION 119 CONCLUSIONS 123 FUTURE DIRECTIONS 124 REFERENCES 126 viii LIST OF FIGURES Figure 1.1: Interaction of Pt-drugs with mesna in combination chemotherapy involving oxazaphosphorines 2 Figure 1.2: Chemical structures 4 Figure 1.3: Ligand substitution pathways for cisplatin 6 Figure 1.4: Major adducts formed in the interaction of cisplatin with DNA 9 Figure 1.5: Possible mechanisms of resistance to cisplatin 13 Figure 1.6: Mesna distribution and inactivation of ifosfamide toxic metabolite in the bladder 26 Figure
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