Table Of ContentChemistry 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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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
