Chemistry and pharmacology of anticancer drugs

619 Pages·2021·189.473 MB·English

by  Ilona Pysz, David E. Thurston

Chemistry and Pharmacology of
Anticancer Drugs

Chemistry and Pharmacology of
Anticancer Drugs
Second Edition
David E. Thurston and Ilona Pysz
Second edition published 2021
by CRC Press
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and by CRC Press
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First edition published by CRC Press 2007
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Library of Congress Cataloging-in-Publication Data
Names: Thurston, David E., author. | Pysz, Ilona, author.
Title: Chemistry and pharmacology of anticancer drugs / David E. Thurston,
Ilona Pysz.
Description: Second edition. | Boca Raton : CRC Press, 2021. | Includes
bibliographical references and index.
Identifiers: LCCN 2020045896 (print) | LCCN 2020045897 (ebook) | ISBN
9781439853269 (paperback) | ISBN 9781138323582 (hardback) | ISBN
9781315374727 (ebook)
Subjects: LCSH: Antineoplastic agents.
Classification: LCC RS431.A64 T48 2021 (print) | LCC RS431.A64 (ebook) |
DDC 615.7/98--dc23
LC record available at https://lccn .loc .gov /2020045896
LC ebook record available at https://lccn .loc .gov /2020045897
ISBN: 9781138323582(hbk)
ISBN: 9781439853269(pbk)
ISBN: 9781315374727(ebk)
Access the companion website: www .h ttps: / /rou tledg etext books .com/ textb ooks/ 97814 39853 269
Dedication
This book is dedicated to cancer patients worldwide who participate in clinical trials.
Their valuable contribution furthers our knowledge of the treatment of cancer.

Contents
Preface.................................................................................................................................................................................xix
Acknowledgments ...............................................................................................................................................................xxi
The Authors .....................................................................................................................................................................xxiii
From the Authors and Publisher ........................................................................................................................................xxv
Chapter 1 Introduction to Cancer......................................................................................................................................1
1.1 Incidence and Mortality ........................................................................................................................1
1.2 Terminology ..........................................................................................................................................3
1.3 Metastases .............................................................................................................................................5
1.4 Diagnosis and Screening .......................................................................................................................5
1.5 Tumorigenesis: The Formation of Cancer Cells ....................................................................................6
1.6 The Causes of Cancer ............................................................................................................................9
1.6.1 Internal Factors.........................................................................................................................9
1.6.1.1 Mutations ..................................................................................................................9
1.6.1.2 Epigenetic Changes .................................................................................................10
1.6.1.3 Modified Gene Expression .....................................................................................10
1.6.1.4 Cancer Stem Cells ..................................................................................................11
1.6.2 External Factors .....................................................................................................................11
1.6.2.1 Viruses ....................................................................................................................11
1.6.2.2 Bacterial Infections .................................................................................................11
1.6.2.3 Worm Infections .....................................................................................................11
1.6.2.4 Direct Transmission of Cancer ...............................................................................12
1.6.2.5 Chemicals ...............................................................................................................12
1.6.2.6 Radioactivity ...........................................................................................................13
1.6.2.7 Electromagnetic Radiation .....................................................................................14
1.6.2.8 Effects of Cancer Treatments .................................................................................15
1.6.3 Hereditary Factors ..................................................................................................................16
1.7 Treatments ...........................................................................................................................................16
1.7.1 Surgery ...................................................................................................................................16
1.7.2 Chemotherapy ........................................................................................................................16
1.7.3 Radiotherapy ..........................................................................................................................17
1.7.4 Chemoradiotherapy ................................................................................................................17
1.7.5 Photodynamic Therapy (PDT) ...............................................................................................18
1.7.6 Biological Agents ...................................................................................................................18
1.8 Accessibility of Therapeutic Agents to Tumor Cells ...........................................................................18
1.9 Limiting the Toxicity of Chemotherapeutic Agents ............................................................................18
1.9.1 Dose Scheduling and Cell Cycle ............................................................................................19
1.9.2 Co-Administration of Other Agents .......................................................................................20
1.9.3 Novel Formulations and Prodrugs ..........................................................................................20
1.9.4 Limiting Toxicity to Hair and Nails .......................................................................................20
1.9.5 Pharmacogenomic Markers of Toxicity .................................................................................21
1.9.6 Infertility Following Cancer Treatment .................................................................................21
1.10 Overview of Mechanisms of Action of Chemotherapeutic Agents .....................................................21
1.11 Drug Resistance ...................................................................................................................................22
1.12 Combination Chemotherapy ................................................................................................................24
1.13 Use of Additional Therapeutic Agents ................................................................................................25
1.14 Cost of Cancer Care ............................................................................................................................26
1.15 Conclusions ..........................................................................................................................................26
Chapter 2 The Evolution of Anticancer Therapies .........................................................................................................27
2.1 Introduction .........................................................................................................................................27
2.2 The Discovery of New Anticancer Agents ..........................................................................................28
vii
viii Contents
2.2.1 Sources of Novel “Lead” Molecules ......................................................................................29
2.3 Research Tools and Methodologies for Drug Discovery .....................................................................30
2.3.1 Genomic-Based Methodologies .............................................................................................31
2.3.1.1 Gene Mutations as Potential Drug Targets .............................................................33
2.3.1.2 Gene Hunting and DNA Sequencing ......................................................................34
2.3.1.3 Genomics and Proteomics ......................................................................................34
2.3.1.4 Protein Structural Studies .......................................................................................35
2.3.2 Chemical Technologies ..........................................................................................................36
2.3.3 Screening Methodologies .......................................................................................................36
2.3.4 In Vivo Models .......................................................................................................................37
2.3.5 Drug Resistance and Personalized Chronotherapy ................................................................39
2.3.6 Natural Products as a Source of New Lead Molecules ..........................................................40
2.3.7 Cancer Stem Cells ..................................................................................................................41
2.3.8 Drug Repurposing (or Drug Repositioning) ...........................................................................42
2.3.9 Fragment-Based Drug Discovery ...........................................................................................43
2.3.10 AI in Drug Discovery .............................................................................................................44
2.4 Funding the Discovery of New Anticancer Agents .............................................................................46
2.5 Conclusions and the Future of Drug Discovery ..................................................................................46
Chapter 3 Antimetabolites ..............................................................................................................................................49
3.1 Introduction .........................................................................................................................................49
3.2 Dihydrofolate Reductase (DHFR) Inhibitors ......................................................................................49
3.2.1 Methotrexate (MTX) ..............................................................................................................49
3.2.2 Pralatrexate (FolotynTM) .........................................................................................................52
3.3 Thymidylate Synthase Inhibitors ........................................................................................................52
3.3.1 Raltitrexed (Tomudex™) ........................................................................................................53
3.3.2 Pemetrexed (AlimtaTM) ...........................................................................................................54
3.3.3 Nolatrexed (ThymitaqTM) .......................................................................................................55
3.4 Purine Antimetabolites ........................................................................................................................55
3.4.1 Mercaptopurine (Puri-NetholTM; 6MP) ..................................................................................56
3.4.2 Tioguanine (LanvisTM) ...........................................................................................................58
3.4.3 Fludarabine Phosphate (FludaraTM) .......................................................................................58
3.4.4 Cladribine (LeustatTM and LitakTM) .......................................................................................58
3.4.5 Clofarabine (EvoltraTM) ..........................................................................................................59
3.4.6 Nelarabine (AtrianceTM) .........................................................................................................59
3.5 Pyrimidine Antimetabolites ................................................................................................................59
3.5.1 5-Fluorouracil (5-FU).............................................................................................................59
3.5.2 Tegafur (UftoralTM) ................................................................................................................61
3.5.3 Gemcitabine (GemzarTM) .......................................................................................................62
3.5.4 Capecitabine (XelodaTM) ........................................................................................................62
3.5.5 Cytarabine (CytosarTM, AlexanTM, ARA-C) ..........................................................................62
3.5.6 Azacitidine (VidazaTM)...........................................................................................................63
3.5.7 Decitabine (DacogenTM) .........................................................................................................63
3.5.8 Trifluridine & Tipiracil (LonsurfTM) ......................................................................................63
3.6 Adenosine Deaminase Inhibitors ........................................................................................................64
3.6.1 Pentostatin (NipentTM) ............................................................................................................64
3.7 Ribonucleotide Reductase Inhibitors ...................................................................................................64
3.7.1 Hydroxycarbamide (HydreaTM) ..............................................................................................64
3.7.2 Triapine ..................................................................................................................................65
3.7.3 Tezacitabine ............................................................................................................................65
3.8 Conclusions ..........................................................................................................................................65
Chapter 4 Antitubulin Agents .........................................................................................................................................67
4.1 Introduction .........................................................................................................................................67
4.1.1 Structure of Microtubules ......................................................................................................67
Contents ix
4.1.2 Microtubule Dynamics ...........................................................................................................67
4.1.3 Tubulin Inhibitors ...................................................................................................................69
4.2 Vinca Alkaloids ...................................................................................................................................71
4.2.1 Vinblastine (VelbeTM) .............................................................................................................73
4.2.2 Vincristine (OncovinTM) .........................................................................................................74
4.2.3 Vindesine (EldisineTM) ...........................................................................................................74
4.2.4 Vinorelbine (NavelbineTM)......................................................................................................74
4.2.5 Vinflunine (JavlorTM) ..............................................................................................................74
4.3 Halichondrin B Analogues ..................................................................................................................75
4.3.1 Eribulin mesylate (HalavenTM) ...............................................................................................75
4.4 The Taxanes .........................................................................................................................................76
4.4.1 Paclitaxel (TaxolTM, AbraxaneTM)...........................................................................................79
4.4.2 Docetaxel (TaxotereTM, DocecadTM) ......................................................................................81
4.4.3 Cabazitaxel (JevtanaTM) ..........................................................................................................81
4.4.4 Larotaxel ................................................................................................................................82
4.4.5 TPI 287 ...................................................................................................................................82
4.4.6 MAC-321 ................................................................................................................................83
4.5 The Epothilones ...................................................................................................................................84
4.5.1 Ixabepilone (IxempraTM) ........................................................................................................86
4.5.2 Epothilones in Clinical Development ....................................................................................87
4.5.2.1 Utidelone (Depoxythilone or UTD1) ......................................................................88
4.6 New Approaches to Targeting Microtubule-Related Mechanisms .....................................................88
4.6.1 Novel Targets of Mitotic Mediators .......................................................................................88
4.6.2 Aurora Kinase Inhibitors ........................................................................................................89
4.6.3 Polo-Like Kinases (PLKs) .....................................................................................................90
4.6.4 Novel Tubulin-Interacting Agents ..........................................................................................91
4.6.4.1 Cevipabulin (TTI-237) ............................................................................................92
4.7 Conclusions ..........................................................................................................................................93
Chapter 5 Nucleic Acids as Therapeutic Targets and Agents .........................................................................................95
5.1 Introduction .........................................................................................................................................95
5.2 Alkylating Agents ................................................................................................................................95
5.2.1 Methylating Agents ................................................................................................................96
5.2.1.1 Dacarbazine (DTIC-DomeTM) ................................................................................96
5.2.1.2 Temozolomide (TemodalTM) ...................................................................................97
5.2.1.3 Procarbazine .........................................................................................................100
5.2.2 Alkylating Agents ................................................................................................................101
5.2.2.1 Trabectedin (YondelisTM) ......................................................................................101
5.2.2.2 Experimental Alkylating Agents ..........................................................................102
5.3 Cross-Linking Agents........................................................................................................................104
5.3.1 Nitrogen Mustards ................................................................................................................105
5.3.1.1 Aliphatic Nitrogen Mustards ................................................................................105
5.3.1.2 Aromatic Nitrogen Mustards ................................................................................107
5.3.1.3 Conjugated Nitrogen Mustards .............................................................................112
5.3.2 Aziridines .............................................................................................................................114
5.3.2.1 Thiotepa (TepadinaTM) ..........................................................................................114
5.3.2.2 Benzoquinone Analogues .....................................................................................114
5.3.3 Epoxides (Treosulfan, OvastatTM) ........................................................................................115
5.3.4 Methanesulfonates (MyleranTM, BusilvexTM) .......................................................................115
5.3.5 Nitrosoureas .........................................................................................................................116
5.3.5.1 Lomustine (CCNU) ..............................................................................................117
5.3.5.2 Carmustine (BiCNUTM) ........................................................................................117
5.3.5.3 Streptozotocin (ZanosarTM) ...................................................................................118
5.3.6 Platinum Complexes .............................................................................................................119
5.3.6.1 Cisplatin ................................................................................................................120
5.3.6.2 Carboplatin ...........................................................................................................123