Chemistry and pharmacology of anticancer drugs

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Cover Half Title Title Page Copyright Page Dedication Table of Contents Preface Acknowledgments The Authors From the Authors and Publisher Chapter 1 Introduction to Cancer 1.1 Incidence and Mortality 1.2 Terminology 1.3 Metastases 1.4 Diagnosis and Screening 1.5 Tumorigenesis: The Formation of Cancer Cells 1.6 The Causes of Cancer 1.6.1 Internal Factors 1.6.1.1 Mutations 1.6.1.2 Epigenetic Changes 1.6.1.3 Modified Gene Expression 1.6.1.4 Cancer Stem Cells 1.6.2 External Factors 1.6.2.1 Viruses 1.6.2.2 Bacterial Infections 1.6.2.3 Worm Infections 1.6.2.4 Direct Transmission of Cancer 1.6.2.5 Chemicals 1.6.2.6 Radioactivity 1.6.2.7 Electromagnetic Radiation 1.6.2.8 Effects of Cancer Treatments 1.6.3 Hereditary Factors 1.7 Treatments 1.7.1 Surgery 1.7.2 Chemotherapy 1.7.3 Radiotherapy 1.7.4 Chemoradiotherapy 1.7.5 Photodynamic Therapy (PDT) 1.7.6 Biological Agents 1.8 Accessibility of Therapeutic Agents to Tumor Cells 1.9 Limiting the Toxicity of Chemotherapeutic Agents 1.9.1 Dose Scheduling and Cell Cycle 1.9.2 Co-Administration of Other Agents 1.9.3 Novel Formulations and Prodrugs 1.9.4 Limiting Toxicity to Hair and Nails 1.9.5 Pharmacogenomic Markers of Toxicity 1.9.6 Infertility Following Cancer Treatment 1.10 Overview of Mechanisms of Action of Chemotherapeutic Agents 1.11 Drug Resistance 1.12 Combination Chemotherapy 1.13 Use of Additional Therapeutic Agents 1.14 Cost of Cancer Care 1.15 Conclusions Chapter 2 The Evolution of Anticancer Therapies 2.1 Introduction 2.2 The Discovery of New Anticancer Agents 2.2.1 Sources of Novel “Lead” Molecules 2.3 Research Tools and Methodologies for Drug Discovery 2.3.1 Genomic-Based Methodologies 2.3.1.1 Gene Mutations as Potential Drug Targets 2.3.1.2 Gene Hunting and DNA Sequencing 2.3.1.3 Genomics and Proteomics 2.3.1.4 Protein Structural Studies 2.3.2 Chemical Technologies 2.3.3 Screening Methodologies 2.3.4 In Vivo Models 2.3.5 Drug Resistance and Personalized Chronotherapy 2.3.6 Natural Products as a Source of New Lead Molecules 2.3.7 Cancer Stem Cells 2.3.8 Drug Repurposing (or Drug Repositioning) 2.3.9 Fragment-Based Drug Discovery 2.3.10 AI in Drug Discovery 2.4 Funding the Discovery of New Anticancer Agents 2.5 Conclusions and the Future of Drug Discovery Chapter 3 Antimetabolites 3.1 Introduction 3.2 Dihydrofolate Reductase (DHFR) Inhibitors 3.2.1 Methotrexate (MTX) 3.2.2 Pralatrexate (FolotynTM) 3.3 Thymidylate Synthase Inhibitors 3.3.1 Raltitrexed (Tomudex™) 3.3.2 Pemetrexed (AlimtaTM) 3.3.3 Nolatrexed (ThymitaqTM) 3.4 Purine Antimetabolites 3.4.1 Mercaptopurine (Puri-NetholTM; 6MP) 3.4.2 Tioguanine (LanvisTM) 3.4.3 Fludarabine Phosphate (FludaraTM) 3.4.4 Cladribine (LeustatTM and LitakTM) 3.4.5 Clofarabine (EvoltraTM) 3.4.6 Nelarabine (AtrianceTM) 3.5 Pyrimidine Antimetabolites 3.5.1 5-Fluorouracil (5-FU) 3.5.2 Tegafur (UftoralTM) 3.5.3 Gemcitabine (GemzarTM) 3.5.4 Capecitabine (XelodaTM) 3.5.5 Cytarabine (CytosarTM, AlexanTM, ARA-C) 3.5.6 Azacitidine (VidazaTM) 3.5.7 Decitabine (DacogenTM) 3.5.8 Trifluridine & Tipiracil (LonsurfTM) 3.6 Adenosine Deaminase Inhibitors 3.6.1 Pentostatin (NipentTM) 3.7 Ribonucleotide Reductase Inhibitors 3.7.1 Hydroxycarbamide (HydreaTM) 3.7.2 Triapine 3.7.3 Tezacitabine 3.8 Conclusions Chapter 4 Antitubulin Agents 4.1 Introduction 4.1.1 Structure of Microtubules 4.1.2 Microtubule Dynamics 4.1.3 Tubulin Inhibitors 4.2 Vinca Alkaloids 4.2.1 Vinblastine (VelbeTM) 4.2.2 Vincristine (OncovinTM) 4.2.3 Vindesine (EldisineTM) 4.2.4 Vinorelbine (NavelbineTM) 4.2.5 Vinflunine (JavlorTM) 4.3 Halichondrin B Analogues 4.3.1 Eribulin mesylate (HalavenTM) 4.4 The Taxanes 4.4.1 Paclitaxel (TaxolTM, AbraxaneTM) 4.4.2 Docetaxel (TaxotereTM, DocecadTM) 4.4.3 Cabazitaxel (JevtanaTM) 4.4.4 Larotaxel 4.4.5 TPI 287 4.4.6 MAC-321 4.5 The Epothilones 4.5.1 Ixabepilone (IxempraTM) 4.5.2 Epothilones in Clinical Development 4.5.2.1 Utidelone (Depoxythilone or UTD1) 4.6 New Approaches to Targeting Microtubule-Related Mechanisms 4.6.1 Novel Targets of Mitotic Mediators 4.6.2 Aurora Kinase Inhibitors 4.6.3 Polo-Like Kinases (PLKs) 4.6.4 Novel Tubulin-Interacting Agents 4.6.4.1 Cevipabulin (TTI-237) 4.7 Conclusions Chapter 5 Nucleic Acids as Therapeutic Targets and Agents 5.1 Introduction 5.2 Alkylating Agents 5.2.1 Methylating Agents 5.2.1.1 Dacarbazine (DTIC-DomeTM) 5.2.1.2 Temozolomide (TemodalTM) 5.2.1.3 Procarbazine 5.2.2 Alkylating Agents 5.2.2.1 Trabectedin (YondelisTM) 5.2.2.2 Experimental Alkylating Agents 5.3 Cross-Linking Agents 5.3.1 Nitrogen Mustards 5.3.1.1 Aliphatic Nitrogen Mustards 5.3.1.2 Aromatic Nitrogen Mustards 5.3.1.3 Conjugated Nitrogen Mustards 5.3.2 Aziridines 5.3.2.1 Thiotepa (TepadinaTM) 5.3.2.2 Benzoquinone Analogues 5.3.3 Epoxides (Treosulfan, OvastatTM) 5.3.4 Methanesulfonates (MyleranTM, BusilvexTM) 5.3.5 Nitrosoureas 5.3.5.1 Lomustine (CCNU) 5.3.5.2 Carmustine (BiCNUTM) 5.3.5.3 Streptozotocin (ZanosarTM) 5.3.6 Platinum Complexes 5.3.6.1 Cisplatin 5.3.6.2 Carboplatin 5.3.6.3 Oxaliplatin 5.3.6.4 Other Cisplatin Analogs 5.3.7 Carbinolamines 5.3.8 Cyclopropanes 5.3.9 Mitomycin-C 5.3.10 Sequence-Selective DNA Cross-Linking Agents 5.3.10.1 PBD Dimers (SJG-136) 5.3.10.2 Cyclopropanepyrroloindole (CPl) Dimer (Bizelesin) 5.4 Intercalating Agents 5.4.1 Anthracyclines 5.4.1.1 Doxorubicin 5.4.1.2 Daunorubicin 5.4.1.3 Aclarubicin 5.4.1.4 Epirubicin 5.4.1.5 Idarubicin 5.4.1.6 Pirarubicin 5.4.2 Anthracenes 5.4.2.1 Mitoxantrone (OnkotroneTM, NovantroneTM) 5.4.2.2 Pixantrone (PixuvriTM) 5.4.3 Phenoxazines 5.4.3.1 Dactinomycin (Cosmegen LyovacTM) 5.5 Topoisomerase Inhibitors 5.5.1 Topoisomerase I Inhibitors 5.5.1.1 Topotecan (HycamtinTM) 5.5.1.2 Irinotecan 5.5.2 Topoisomerase II Inhibitors 5.5.2.1 Etoposide 5.5.2.2 Teniposide 5.5.2.3 Amsacrine 5.5.2.4 Ellipticine 5.6 DNA-Cleaving Agents 5.6.1 Bleomycins 5.6.2 Enediynes 5.6.2.1 Neocarzinostatin 5.6.2.2 Calicheamicins 5.6.2.3 Esperamicin 5.6.2.4 Dynemicin A 5.7 Nucleic Acid Targeting 5.7.1 Introduction 5.7.2 Duplex DNA Targeting 5.7.2.1 Small Molecules 5.7.3 Quadruplex DNA Targeting 5.7.3.1 Telomerase Targeting Agents 5.7.3.2 Promoter Quadruplex Targeting 5.7.3.3 Transcription Factor Inhibition 5.7.4 RNA-Targeting Approaches 5.7.4.1 Introduction 5.7.4.2 Antisense Oligonucleotides 5.7.4.3 RNA Interference (RNAi) 5.7.4.4 MicroRNA (miRNA) 5.7.4.5 Backbone-Modified Nucleic Acids 5.7.4.6 Ribozymes 5.7.4.7 Small Molecule RNA Targeting 5.8 DNA-Repair Inhibitors 5.8.1 Introduction 5.8.2 PARP Inhibitors 5.8.3 ATR Inhibitors 5.8.4 ATM Inhibitors 5.9 Epigenetic-Based Therapies 5.9.1 Introduction 5.9.2 DNA Methyltransferase Inhibitors 5.9.3 Histone Deacetylase Inhibitors 5.10 Radio- and Chemo-Sensitizing and Protecting Agents 5.11 Gene Therapy 5.12 Conclusions Chapter 6 Small-Molecule Targeted Therapies 6.1 Introduction 6.2 Protein Kinase Inhibitors 6.2.1 Classification of Protein Kinases 6.2.1.1 Functions of Protein Kinases 6.2.1.2 Mechanism of Signal Transfer 6.2.1.3 Regulation of Kinase Activity by Drugs 6.2.1.4 Role of Protein Kinases in Cancer 6.2.1.5 Development of Inhibitors of Protein and Receptor Kinases 6.2.1.6 Protein Kinase Inhibitors in Clinical Use or Development 6.3 Hedgehog Pathway Inhibitors 6.3.1 Vismodegib (ErivedgeTM) 6.3.2 Sonidegib (OdomzoTM) 6.3.3 Glasdegib (DaurismoTM) 6.3.4 TAK-441 6.3.5 BMS-833923 6.4 Cell-Cycle (CDK) Inhibitors 6.4.1 Palbociclib (IbranceTM) 6.4.2 Ribociclib (Kisqali™) 6.4.3 Abemaciclib (VerzeniosTM) 6.4.4 Trilaciclib (G1T-28) 6.4.5 Voruciclib (P1446A-05) 6.5 Proteasome Inhibitors 6.5.1 Bortezomib (VelcadeTM) 6.5.2 Carfilzomib (KyprolisTM) 6.5.3 Ixazomib (NinlaroTM) 6.5.4 Salinosporamide A 6.6 Phosphatidylinositol 3-Kinase (PI3K/AKT/mTOR) Pathway Inhibitors 6.6.1 PIK3 Inhibitors 6.6.1.1 Idelalisib (ZydeligTM) 6.6.1.2 Copanlisib (AliqopaTM) 6.6.1.3 Duvelisib (CopiktraTM) 6.6.1.4 Alpelisib (PiqrayTM) 6.6.1.5 Other PI3K Inhibitors 6.6.2 AKT (Protein Kinase B) Inhibitors 6.6.3 mTOR Inhibitors 6.6.3.1 Everolimus (AfinitorTM) 6.6.3.2 Temsirolimus (ToriselTM) 6.7 Apoptosis Inhibitors 6.7.1 Venetoclax (VenclyxtoTM) 6.8 HDM2-p53 Interaction Inhibitors 6.8.1 Idasanutlin (RG7388) 6.8.2 AMG-232 6.9 Retinoids 6.9.1 Tretinoin (VesanoidTM) 6.9.2 Bexarotene (TargtretinTM) 6.9.3 Alitretinoin (PanretinTM) 6.10 Antimetastatic Agents 6.11 Heat Shock Protein (HSP) Inhibitors 6.12 Conclusions Chapter 7 Antibody-Based Therapies 7.1 Introduction 7.1.1 Strategies for the Use of Antibodies in Anticancer Therapies 7.1.2 Anatomy of Antibodies 7.1.3 Types of Antibodies Used 7.1.3.1 Full-Size Antibodies 7.1.3.2 Other Antibody Formats 7.1.4 Nomenclature of Antibodies 7.1.5 Reasons for the Slow Emergence of Antibody-Based Therapies 7.1.6 Production of Antibodies 7.1.6.1 Introduction 7.1.6.2 Hybridoma Technology 7.1.6.3 Chimeric, Humanized, and Human Antibodies 7.1.7 Tumor-Associated Antigen Selection 7.1.8 Strategies to Improve the Properties of Antibodies 7.1.8.1 GlycoMAbTM Technology 7.1.8.2 Bispecific Antibodies 7.2 Antibodies as Single Agents (Naked mAbs) 7.2.1 Mechanism of Action of Naked mAbs 7.2.1.1 Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) 7.2.1.2 Complement-Dependent Cytotoxicity (CDC) 7.2.1.3 Cell Signaling 7.2.2 Examples of Approved Single (“Naked”) Antibodies 7.2.2.1 HER2 Receptor 7.2.2.2 VEGFR and VEGF 7.2.2.3 EGFR Receptor 7.2.2.4 CD Receptors 7.2.2.5 Immuno-oncological (IO) Inhibitors 7.2.2.6 RANK Receptor 7.2.2.7 Antibodies in Development 7.3 Antibody Conjugates (“Immunoconjugates”) 7.3.1 Antibody-Drug Conjugates (ADCs) 7.3.1.1 Antigen/Antibody Choice and Internalization 7.3.1.2 Payload Structure and Potency 7.3.1.3 Linker Structures and Properties 7.3.1.4 Conjugation and Loading of Payloads on Antibody 7.3.1.5 Chemistry Manufacturing Control (CMC) 7.3.1.6 Biodistribution of ADCs 7.3.1.7 Use of Biomarkers to Guide ADC Therapy 7.3.1.8 Approved ADCs and Immunotoxins 7.3.2 Antibody-Radionuclide Conjugates (Radioimmunoconjugates) 7.3.2.1 Introduction 7.3.2.2 Directly Linked Radioisotope 7.3.2.3 Chelate-Linked Radioisotope 7.3.2.4 Others Radioimmunoconjugates in Development 7.3.3 Antibody–Cytokine Conjugates (Immunocytokines) 7.3.3.1 Introduction 7.3.3.2 Cytokines 7.3.3.3 Mechanism of Action of Immunocytokines 7.3.3.4 Examples of Immunocytokines in Clinical Development 7.3.4 Antibody-Nanoparticle Conjugates (Immunoliposomes) 7.3.4.1 Introduction 7.3.4.2 Cytotoxic Agents 7.3.4.3 Radioisotopes 7.3.4.4 Antigenic Protein 7.3.4.5 Gene Therapy 7.3.5 Antibody-RNAi Conjugates (ARCs) 7.3.6 Antibody-Directed Enzyme Prodrug Therapy (ADEPT) 7.3.6.1 Introduction 7.3.6.2 Carboxypeptidase G2 (CPG2)-Based ADEPT 7.4 Bi-Specific Antibodies 7.4.1 Introduction 7.4.2 Manufacture of BsMABs 7.4.3 Types of Bispecific Antibodies 7.4.3.1 Tri-functional Antibodies (Triomabs) 7.4.3.2 Bispecific T-Cell Engagers (BiTEs) 7.4.3.3 Diabodies (Db) 7.4.4 Bispecifics Approved 7.4.4.1 Blinatumomab (Blincyto™) 7.4.5 BsMAbs in Development 7.4.6 Bispecific Antibodies Drug Conjugates (ADCs) 7.4.7 BsAb Radioimmunotherapies 7.5 Conclusion Chapter 8 Endocrine Therapies 8.1 Introduction 8.2 Breast Cancer 8.2.1 Role of Estrogen in Tumor Growth 8.2.1.1 Introduction 8.2.1.2 Estrogen Types and Activities 8.2.1.3 Structure of the Estrogen Receptor 8.2.1.4 Signal Transduction 8.2.1.5 Impact of Estrogen on Disease 8.2.2 Other Treatment Options 8.2.2.1 Early Breast Cancer 8.2.2.2 Advanced Breast Cancer 8.2.2.3 Metastatic Disease 8.2.3 Selective Estrogen Receptor Modulators and Degraders (SERMs and SERDs) 8.2.3.1 Introduction 8.2.3.2 Triphenylethylene Analogues 8.2.3.3 Benzothiophene Analogues 8.2.3.4 Steroidal Anti-Estrogen 8.2.3.5 Aromatase Inhibitors 8.3 Prostate Cancer 8.3.1 Introduction 8.3.2 Gonadotropin-Releasing Hormone (GnRH) Analogues 8.3.2.1 Gonadotropin-Releasing Hormone (GnRH) 8.3.2.2 GnRH Agonist Analogues 8.3.2.3 GnRH Antagonist Analogues 8.3.3 Anti-Androgens 8.3.3.1 Steroidal Antiandrogens (SAAs) 8.3.3.2 Non-Steroidal Anti-Androgens (NSAAs) 8.3.3.3 Experimental Anti-Androgen Agents 8.4 Neuroendocrine Tumors (NETS) 8.4.1 Somatostatin Analogues 8.4.1.1 Octreotide (SandostatinTM) 8.4.1.2 Lanreotide (SomatulineTM) 8.4.1.3 Pasireotide (SigniforTM) 8.5 Sex Hormones 8.5.1 Introduction 8.5.2 Estrogen Therapy 8.5.2.1 Diethylstilbestrol (DES) 8.5.2.2 Ethinylestradiol (EE) 8.5.3 Progestogen Therapy 8.5.3.1 Medroxyprogesterone Acetate (ProveraTM) 8.5.3.2 Megestrol Acetate (MegaceTM) 8.5.3.3 Norethisterone (Primolut NTM, UtovlanTM) 8.5.3.4 Gestonorone Caproate (DepostatTM, PrimostatTM) 8.6 Mitotane (LysodrenTM) 8.7 Sulfatase Inhibitors 8.8 Conclusions Chapter 9 Immunomodulatory Therapies 9.1 Introduction 9.2 Cytokines 9.2.1 Interferons 9.2.1.1 Interferon Alfa (IFN-α) 9.2.1.2 Interferon Gamma-1b (IFN-1b, ImmukinTM) 9.2.2 Interleukins 9.2.2.1 Interleukin-2 (IL-2, Aldesleukin, Proleukin™) 9.2.2.2 IL 12 9.2.2.3 IL 21 9.2.2.4 IL 15 9.2.3 Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) 9.2.3.1 Sargramostim (marketed as Leukine™) 9.3 Vaccines 9.3.1 Types of Cancer Vaccines 9.3.2 Approved Cancer Vaccines 9.3.2.1 Prophylactic Vaccines 9.3.2.2 Treatment Vaccines 9.3.3 Experimental Vaccines 9.3.3.1 Prophylactic Vaccines 9.3.3.2 Treatment Vaccines 9.4 Adoptive Cell-Based Therapies 9.4.1 Adoptive Cell-Based Anticancer Therapies Based on T Cells 9.4.1.1 Adoptive Cell-Based Anticancer Therapies Using Tumor Infiltrating Lymphocytes (TIL) 9.4.1.2 Adoptive Cell-Based Anticancer Therapies Using Genetically Modified Peripheral Blood T Cells 9.4.2 Adoptive Cell-Based Anticancer Therapies Using Other Immune Infiltrating Cells 9.4.2.1 Adoptive Cell-Based Anticancer Therapies Using Natural Killer (NK) Cells 9.4.2.2 Adoptive Cell-Based Anticancer Therapies Using Dendritic Cells 9.4.2.3 Adoptive Cell-Based Anticancer Therapies Using Macrophages 9.5 Small-Molecule Immunomodulatory Agents 9.5.1 Thalidomide-Based Agents 9.5.1.1 Thalidomide (ThalomidTM) 9.5.1.2 Lenalidomide (RevlimidTM) 9.5.1.3 Pomalidomide (PomalystTM, ImnovidTM) 9.5.2 Plerixafor (MozobilTM) 9.5.3 Mifamurtide (MepactTM) 9.5.4 Imiquimod (AldaraTM, ZyclaraTM) 9.6 Conclusions Chapter 10 Alternative Tumor-Targeting Strategies 10.1 Introduction 10.2 Vascular-Targeting Strategies 10.2.1 Antiangiogenic Agents 10.2.1.1 Monoclonal Antibodies 10.2.1.2 Tyrosine Kinase Inhibitors 10.2.1.3 Thalidomide and Related Analogues 10.2.2 Vascular Disruptive Agents (VDAs) 10.2.2.1 Combretastatins 10.2.2.2 Fosbretabulin 10.3 Hypoxia-Based Approaches 10.3.1 Mitomycin 10.3.2 AQ4N (Banoxantrone) 10.4 Enzyme-Based Approaches 10.4.1 Amino Acid Deprivation Therapy (AADT) 10.4.1.1 Asparaginase (SpectrilaTM, ErwinaseTM, OncasparTM, ElsparTM) 10.4.1.2 Pegargiminase (ADI-PEG 20) 10.4.1.3 Arginase 10.4.2 Antibody-Directed Enzyme Prodrug Therapy (ADEPT)-Based Approaches 10.4.2.1 Antibody-Directed Enzyme Prodrug Therapy (ADEPT) 10.4.2.2 GDEPT and VDEPT 10.4.3 Enzyme Prodrug Therapy 10.4.4 Cofactor-Mediated Prodrug Therapy 10.5 Nanoparticles and Conjugate Technologies 10.5.1 Enhanced Permeation and Retention (EPR) Effect 10.5.2 Approved Nanotechnology-Based Products 10.5.2.1 Liposomal Doxorubicin (CaelyxTM, DoxilTM, MyocetTM) 10.5.2.2 nabTM-paclitaxel (AbrexaneTM) 10.5.2.3 Liposomal Irinotecan (OnivydeTM) 10.5.2.4 Liposomal Daunorubicin/Cytarabine (VyxeosTM) 10.5.3 Novel Nanotechnology Approaches 10.5.3.1 Internal Triggers 10.5.3.2 External Triggers 10.5.3.3 Nanobot Technology 10.6 Photoactivated Therapies 10.6.1 Porfimer Sodium (PhotophrinTM) 10.6.2 Temoporfin (FoscanTM) 10.6.3 δ-Aminolevulinic Acid 10.6.4 Methyl Aminolevulinate (MetvixTM, MetvixiaTM) 10.6.5 Photoactivated Antibody-Drug Conjugates (ADCs) 10.7 Ultrasound Ablation Approaches 10.8 Electromagnetic Approaches 10.8.1 Near Infrared Activated Nanoshells 10.8.2 Microwave Ablation 10.9 Radioactive Nanoparticles 10.10 Intracranial Delivery 10.10.1 GliadelTM Wafer Implants 10.10.2 Nanotechnology Approaches 10.10.3 MRI-Guided Catheters 10.11 Boron Neutron Capture Therapy (BNCT) 10.12 Conclusions Chapter 11 The Precision Medicine Approach in Oncology 11.1 Introduction and Background 11.2 Uses of Genomic Information 11.3 Genetic Variability and SNPs 11.4 Components of the Precision Medicine Approach 11.4.1 Pharmacogenetics and Pharmacogenomics 11.4.2 Metabolism and Its Effect on Drug Efficacy and Toxicity 11.4.3 Metabonomics 11.4.4 Biomarkers 11.4.5 Epigenetics 11.5 Technologies in Personalized Medicine 11.5.1 Introduction 11.5.2 Technologies Available 11.5.2.1 Genome Sequencing 11.5.2.2 Gene Expression 11.5.2.3 Functional Genomics 11.5.2.4 Proteomics 11.5.2.5 Toxicogenomics 11.5.2.6 Metabonomics 11.5.3 Emerging Technologies 11.5.3.1 Peptidomics 11.5.3.2 Histomics 11.5.3.3 Circulating Cancer Cells (CTCs) 11.5.3.4 Circulating Tumor Nucleic Acids 11.5.3.5 Epigenetics 11.5.3.6 Microfluidics and Multiplexing Technologies 11.5.3.7 Bioinformatics Concepts and Tools 11.6 Applications of Precision Medicine in Oncology 11.6.1 Introduction 11.6.2 Screening for Risk of Disease Development 11.6.2.1 Prostate-Specific Antigen (PSA) 11.6.2.2 Colorectal Cancer (CRC) 11.6.2.3 Pancreatic Cancer 11.6.2.4 Ovarian Cancer 11.6.2.5 Brain Cancer 11.6.2.6 Breast Cancer 11.6.2.7 Oral Cancer (OC) 11.6.2.8 Bladder Cancer 11.6.2.9 Cervical Cancer 11.6.3 Predisposition Biomarker Assays (Predictive Genetic Tests for Cancer Risk) 11.6.4 Biomarker Screening to Select Optimal Treatments 11.6.4.1 Introduction 11.6.4.2 HER2 (Breast Cancer) 11.6.4.3 PD-LI (IO Responsive Tumors) 11.6.4.4 BRAF Mutations (Melanoma) 11.6.4.5 EML4-ALK Mutations (Lung Cancer) 11.6.4.6 EGFR Mutations (Lung Cancer) 11.6.4.7 Androgen Receptor Mutations (Prostate Cancer) 11.6.4.8 Hematological Cancers 11.6.5 Prognosis, Staging, and Risk of Disease Reoccurrence 11.6.5.1 Breast Cancer 11.6.5.2 Prostate Cancer 11.6.5.3 Colorectal Cancer 11.6.6 Biomarkers Used to Predict Toxicity of Chemotherapeutic Agents 11.6.6.1 Introduction 11.6.6.2 UGT1A1 (Irinotecan) 11.6.6.3 Dihydropyrimidine Dehydrogenase (DPD) (Capecitabine and 5-FU) 11.6.6.4 Thiopurine S-Methyltransferase [TPMT] for Purine Antimetabolites 11.6.6.5 AmpliChipTM CYP450 Test 11.6.7 Use of Biomarkers in Drug Discovery 11.6.8 Use of Biomarkers in Clinical Trials 11.6.9 Chemosensitivity Testing 11.6.10 Novel Technologies For Personalizing Drug Dosing 11.7 Conclusions and the Future of Precision Medicine in Oncology Chapter 12 Chemopreventive Agents 12.1 Introduction 12.2 Potential Mechanisms of Chemoprevention 12.2.1 Effect on Metabolic and Other Enzymes 12.2.2 Effect on Cellular Transport 12.2.3 Reduction of Inflammatory Processes 12.2.4 Induction of Apoptosis 12.2.5 Induction of Cell-Cycle Arrest 12.2.6 Inhibition of Cellular Proliferation 12.2.7 Inhibition of Cellular Invasion and Metastasis 12.2.8 Inhibition of Angiogenesis 12.2.9 Epigenetic Modifications 12.2.10 Effect on Glucose Metabolism 12.2.11 Estrogen and Androgen Modulation 12.3 Challenges Associated with the Evaluation of Chemopreventive Agents 12.3.1 Variability of the Contents of Phytochemicals in Plants 12.3.2 Limitations of In Vitro and In Vivo Studies 12.3.3 Bioavailability 12.3.4 Side Effects 12.3.5 Synergistic Effects of Mixtures of Chemopreventive Agents 12.3.6 Limitations of Retrospective Human Studies 12.3.7 Clinical Evaluation of Chemopreventive Agents 12.4 Naturally Occurring Chemopreventive Agents 12.4.1 Flavonoids and Related Compounds 12.4.1.1 Quercetin 12.4.1.2 Apigenin 12.4.1.3 Tangeretin 12.4.1.4 Naringin 12.4.1.5 Silibinin 12.4.1.6 Epigallocatechin-3-gallate (EGCG) 12.4.2 Chalcones 12.4.2.1 Xanthohumol 12.4.3 Xanthones 12.4.3.1 Mangostin 12.4.4 Phytoestrogens 12.4.4.1 Isoflavones 12.4.4.2 Coumestans 12.4.4.3 Lignans 12.4.4.4 Effect of Dietary Xenoestrogens on Breast Cancer Treatments 12.4.5 Alkaloids 12.4.5.1 Berberine 12.4.5.2 Capsaicin 12.4.5.3 Matrine 12.4.5.4 Piperine 12.4.5.5 Sanguinarine 12.4.5.6 Tetrandrine 12.4.6 Glucosinolates 12.4.6.1 Indole-3-carbinol 12.4.7 Terpenoids 12.4.7.1 Monoterpenoids 12.4.7.2 Diterpenoids 12.4.7.3 Triterpenoids 12.4.7.4 Tetraterpenoids 12.4.8 Curcumin 12.4.9 Organosulfur Compounds 12.4.9.1 Sulforaphane 12.4.9.2 Allicin 12.4.9.3 Ergothioneine 12.4.10 Phenolic Acids 12.4.10.1 Gallic Acid 12.4.10.2 Ellagic Acid 12.4.10.3 Caffeic Acid 12.4.10.4 Rosmarinic Acid 12.4.10.5 Chlorogenic Acid 12.4.11 Antioxidants 12.4.11.1 Ascorbic Acid (Vitamin C) 12.4.12 The “Mediterranean Diet” 12.4.12.1 Oleic Acid 12.4.12.2 Oleocanthal 12.4.12.3 Carotenoids (Tetraterpenoids) 12.4.12.4 Resveratrol 12.5 Synthetic Chemopreventive Agents 12.5.1 Aspirin 12.5.2 NSAIDs 12.5.2.1 Ibruprofen 12.5.3 Estrogen Inhibitors 12.5.4 Metabolic Agents 12.5.4.1 Metformin 12.5.5 Statins 12.6 Conclusions Index