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Clinical Pharmacology of Antiмcancer Agents A CLINI CLINICAL PHARMACOLOGY OF NTI- C ANTI-CANCER AGENTS C AL PHARMA AN Cristiana Sessa, Luca Gianni, Marina Garassino, Henk van Halteren www.esmo.org C ER A This is a user-friendly handbook, designed for young GENTS medical oncologists, where they can access the essential C information they need for providing the treatment which could OLOGY OF have the highest chance of being effective and tolerable. By finding out more about pharmacology from this handbook, young medical oncologists will be better able to assess the different options available and become more knowledgeable in the evaluation of new treatments. ESMO ESMO Handbook Series European Society for Medical Oncology CLINICAL PHARMACOLOGY OF Via Luigi Taddei 4, 6962 Viganello-Lugano, Switzerland Handbook Series ANTI-CANCER AGENTS Cristiana Sessa, Luca Gianni, Marina Garassino, Henk van Halteren ESMO Press · ISBN 978-88-906359-1-5 ISBN 978-88-906359-1-5 www.esmo.org 9 788890 635915 ESMO Handbook Series handbook_print_NEW.indd 1 30/08/12 16:32 ESMO HANDBOOK OF CLINICAL PHARMACOLOGY OF ANTI-CANCER AGENTS CM15 ESMO Handbook 2012 V14.indd1 1 2/9/12 17:17:35 ESMO HANDBOOK OF CLINICAL PHARMACOLOGY OF ANTI-CANCER AGENTS Edited by Cristiana Sessa Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Ospedale San Raffaele, IRCCS, Unit of New Drugs and Innovative Therapies, Department of Medical Oncology, Milan, Italy Luca Gianni Ospedale San Raffaele, IRCCS, Unit of New Drugs and Innovative Therapies, Department of Medical Oncology, Milan, Italy Marina Garassino Oncology Department, Istituto Nazionale dei Tumori, Milan, Italy Henk van Halteren Department of Internal Medicine, Gelderse Vallei Hospital, Ede, The Netherlands ESMO Press CM15 ESMO Handbook 2012 V14.indd3 3 2/9/12 17:17:35 First published in 2012 by ESMO Press © 2012 European Society for Medical Oncology All rights reserved. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission of the publisher or in accordance with the provisions of the Copyright, Designs, and Patents Act 1988 or under the terms of any license permitting limited copying issued by the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA (www.copyright.com/ or telephone 978-750-8400). Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the authors and publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. Although every effort has been made to ensure that drug doses, treatments, and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publisher nor the authors can be held responsible for errors or for any consequences arising from the use of information contained herein. For detailed prescribing information on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer. A CIP record for this book is available from the British Library. ISBN: 978-88-906359-1-5 For orders, corporate sales, foreign rights, and reprint permissions, please contact: ESMO Head Office Guidelines and Publishing Department Via Luigi Taddei 4 6962 Viganello-Lugano Switzerland Tel: +41 (0)91 973 19 00 www.esmo.org Email: [email protected] Printed through s|s|media limited, Rickmansworth, Hertfordshire, UK iv CM15 ESMO Handbook 2012 V14.indd4 4 2/9/12 17:17:35 Contents Contributors ix Reviewers xii Acknowledgments xiii Introduction xiv Abbreviations xvi 1 Preclinical Drug Development: Translating Basic Research into Clinical Work 1 Introduction 1 In-vitro Evaluation of New Anti-cancer Agents 2 Studies in Animal Models 4 Companion Diagnostics Development 6 Summary 7 Further Reading 8 2 Pharmacokinetics and Pharmacodynamics: Main Concepts and Clinical Applications 9 Introduction 9 Pharmacokinetics 11 Pharmacodynamics 24 Summary and Conclusions 29 Further Reading 29 v CM15 ESMO Handbook 2012 V14.indd5 5 2/9/12 17:17:35 3 Alkylating Agents 31 Introduction 31 Clinical Pharmacokinetics 34 Therapeutic Uses 34 Toxicities 35 Drug Resistance 41 Further Reading 43 4 Platinum Agents 44 Introduction 44 Clinical Pharmacology 45 Therapeutic Uses 47 Toxicities 50 Drug Resistance 51 Further Reading 52 5 Antimetabolites 53 Antifolates 53 Pyrimidine Analogs 58 Purine Analogs 63 Further Reading 68 6 Topoisomerase-I and -II Inhibitors 69 Topo-I Inhibitors 69 Topo-II Inhibitors 75 Further Reading 90 7 Tubulin-active Agents 92 Introduction 92 Vinca Alkaloids 92 Taxanes and New Taxane Formulations 93 Epothilones 99 Further Reading 102 vi Contents CM15 ESMO Handbook 2012 V14.indd6 6 2/9/12 17:17:36 8 Miscellaneous 103 Bleomycin, Mitomycin C, and Actinomycin 103 L-Asparaginase, Anagrelide, and Arsenic Trioxide 106 Hydroxyurea, Procarbazine, and Trabectedin 110 Tretinoin and Bexarotene 111 Further Reading 116 9 Hormonal Pathways Modulators of the Reproductive System 117 Antiestrogens 117 Aromatase Inhibitors (AIs) 119 Gonadotropin-Releasing Hormone (GnRH) Analogs 121 Gonadotropin-Releasing Hormone Antagonists 123 Progestins 124 Antiandrogens 124 Further Reading 128 10 Growth Factor Receptor Targeting: Anti-HER and Anti-IGF-1R 129 Introduction 129 Anti-HER Agents 129 Anti-IGF-1R Agents 138 Further Reading 140 11 Tumor Vessel Targeting 141 Angiogenesis 141 Antiangiogenic Agents 142 Vascular-targeting Agents (VTAs) 148 Lenalidomide and Thalidomide 149 Further Reading 152 12 Downstream Receptor Targeting: PI3K, mTOR, KRAS, BRAF, MEK 153 PI3K-AKT-mTOR Signaling Pathway 153 RAS-RAF-MEK-ERK Pathway 158 Further Reading 160 Contents vii CM15 ESMO Handbook 2012 V14.indd7 7 2/9/12 17:17:36 13 Cancer-related Receptor Targeting: Bcr-Abl, KIT, MET 161 Bcr-Abl 161 KIT 165 MET 166 Further Reading 169 14 Epigenetic Therapy: DNA Methyltransferase Inhibitors and Histone Deacetylase Inhibitors 170 Introduction 170 DNA Methyltransferase Inhibitors 171 Histone Deacetylase Inhibitors 171 Further Reading 175 15 Proteasome Inhibitors 176 The Ubiquitin Proteasome Pathway 176 The Proteasome 176 Perspectives 179 Further Reading 180 16 Monoclonal Antibodies for Targeted Treatment of Lymphoproliferative Neoplasias 181 Monoclonal Antibodies for Cancer Therapy 181 Anti-CD20 Antibodies 182 Anti-CD52 Antibodies 187 Anti-TNF Receptor Superfamily Antibodies 189 Further Reading 192 17 Immunomodulatory Drugs and Cytokines 193 Interleukin-2 (IL-2) 193 Interferon-alpha-2b/2a 195 Ipilimumab 198 Further Reading 199 Index 201 viii Contents CM15 ESMO Handbook 2012 V14.indd8 8 2/9/12 17:17:36 Contributors Barrière J. Centre Antoine Lacassagne, Nice, France Blank C. Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands Broggini M. Laboratory of Molecular Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy Calvert A.H. UCL Cancer Institute, University College London, London, UK Carlo-Stella C. Medical Oncology, University of Milan, Milan; Department of Oncology and Hematology, Humanitas Cancer Center, IRCCS Istituto Clinico Humanitas, Rozzano (Milan), Italy Catapano C. Institute of Oncology Research, Bellinzona, Switzerland Cervantes A. Department of Hematology and Medical Oncology; Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain Christinat A. Oncology Institute of Southern Switzerland, Bellinzona, Switzerland Damia G. Laboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy De Dosso S. Oncology Institute of Southern Switzerland, Bellinzona, Switzerland Del Conte G. Ospedale San Raffaele, IRCCS, Unit of New Drugs and Innovative Therapies, Department of Medical Oncology, Milan, Italy ix CM15 ESMO Handbook 2012 V14.indd9 9 2/9/12 17:17:36 Dienstmann R. Vall d’Hebron Institute of Oncology, Barcelona, Spain Diéras V. Department of Medical Oncology, Clinical Trial Unit, Institut Curie, Paris, France Driessen C. Interdisziplinäre Medizinische Dienste, Kantonsspital St Gallen, St Gallen, Switzerland Durigova A. Medical Oncology Department, CRLC Val d’Aurelle- Paul Lamarque, Montpellier, France Fasolo A. Ospedale San Raffaele, IRCCS, Unit of New Drugs and Innovative Therapies, Department of Medical Oncology, Milan, Italy Garassino M. Oncology Department, Istituto Nazionale dei Tumori, Milan, Italy Giacomini A. Medical Oncology, University of Milan, Milan; Department of Oncology and Hematology, Humanitas Cancer Center, IRCCS Istituto Clinico Humanitas, Rozzano (Milan), Italy Guidetti A. Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan; Medical Oncology, University of Milan, Milan, Italy Haanen J. Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands Le Tourneau C. Department of Medical Oncology, Clinical Trial Unit, Institut Curie, Paris, France Lobetti-Bodoni C. Oncology Institute of Southern Switzerland, Bellinzona, Switzerland Locatelli A. Ospedale San Raffaele, IRCCS,
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