Clinical Pharmacology of Anti-cancer Agents ESMO

226 Pages·2016·5.57 MB·English

by  Cristiana Sessa

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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

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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 [phone]). 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: [phone]
www.esmo.org
Email: [email protected]
Printed through s|s|media limited, Rickmansworth, Hertfordshire, UK
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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
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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
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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
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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
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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
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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, Unit of New Drugs and
Innovative Therapies, Department of Medical Oncology, Milan, Italy
Locatelli S.L. Medical Oncology, University of Milan, Milan;
Department of Oncology and Hematology, Humanitas Cancer Center,
IRCCS Istituto Clinico Humanitas, Rozzano (Milan), Italy
x Contributors
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