Cancer Chemotherapy E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Provides a clear and accessible summary of all stages and aspects of the discovery, design, development, validation and clinical use of anticancer drugs
This new edition provides an update on the current state of the art of cancer chemotherapy and clinical practice and presents new pipeline anticancer agents and promising therapeutic strategies that are emerging alongside new breakthroughs in cancer biology. Its unique approach enables students to gain an understanding of the pathological, physiological, and molecular processes governing malignancy, while also introducing the role of health professionals and scientists in the research and treatment of cancer.
Invaluable for its clarity and accessibility, Cancer Chemotherapy: Basic Science to the Clinic, 2nd Edition offers complete coverage of the scientific and clinical aspects of the creation, development, and administration of drugs or drug regimens used in the treatment of the disease. Chapters look at: cancer epidemiology and histopathology; carcinogenesis; current research; tumor hypoxia; antiangiogenic and antivascular agents; protein kinase and Ras blockers; new targets associated with development such as Hedgehog and Wnt signaling; stem cells; immunotherapy and oncolytic viruses; and more.
- Presents a clear, accessible, and comprehensive approach to cancer chemotherapy from basic science to clinical practice
- Offers a major update that reflects the latest developments in personalized chemotherapy
- Provides in-depth coverage of advances in biomarker diagnostics
- Includes new chapters/sections on bioinformatics and the ‘omic sciences’; pharmaceutical strategies used to achieve tumor-selective drug delivery; and cancer cell autophagy
- Combines descriptions of both clinical protocol and explanations of the drug design process in one self-contained book
- Features numerous diagrams and illustrations to enhance reader understanding
Aimed at upper undergraduate, graduate, and medical students, Cancer Chemotherapy: Basic Science to the Clinic, 2nd Edition is also an excellent reference for health professional, especially clinicians specializing in Clinical Oncology, and their patients who want to gain an understanding of cancer and available treatment options.
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Veröffentlichungsjahr: 2020
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Table of Contents
Cover
Preface
About the Companion Website
1 Cancer Epidemiology
1.1 Cancer Incidence and Mortality
1.2 Childhood Cancer
1.3 Global Epidemiology
1.4 Cancer Survival Rates
1.5 Summary and Conclusions
Further Reading
2 Cancer Histopathology
2.1 Cancer Morphology, Phenotype, and Nomenclature
2.2 Apoptosis
2.3 Necrosis
2.4 Autophagy and Others
2.5 Summary and Conclusions
Further Reading
3 Carcinogenesis
3.1 Initiation
3.2 Promotion
3.3 Progression and Environmental Carcinogenesis
3.4 Cell Cycle
3.5 Summary and Conclusions
Further Reading
4 Molecular Biology of Cancer
4.1 Oncogenes: Disruptors and Instigators
4.2 Cellular Oncogenes
4.3 Viral Oncogenes
4.4 Altered Oncogenic Products
4.5 Biological Carcinogens
4.6 Tumor Suppressor Genes
4.7 Familial Cancers and Cancer Syndromes
4.8 Summary and Conclusions
Further Reading
5 Cancer Metastasis
5.1 Detachment from the Primary Tumor
5.2 Migration of Cancer Cells from Primary Tumor
5.3 Intravasation of Tumor Cells into Vessels
5.4 Metastatic Transport
5.5 Extravasation
5.6 Growth of the Metastatic Tumor Mass
5.7 Summary and Conclusions
Further Reading
6 Health Professionals and Cancer Treatment
6.1 Pathology
6.2 Radiology
6.3 Biopsies
6.4 Surgical Treatment
6.5 Oncology Pharmacy
6.6 Oncology Nursing
6.7 Artificial Intelligence and Healthcare
6.8 Summary and Conclusions
Further Reading
7 Principles of Cancer Chemotherapy
7.1 Staging, Treatment, and Monitoring
7.2 General Types of Chemotherapy
7.3 Biomarker Uses and Limitations
7.4 Pharmacogenetics, Pharmacogenomics, Pharmacokinetics, Pharmacodynamics, and Personalized Medicine
7.5 Summary and Conclusions
Further Reading
8 Cytotoxic Compounds
8.1 Alkylating Agents
8.2 Intercalating Agents
8.3 Topoisomerase Blockers
8.4 Tubulin Disruptors
8.5 Summary and Conclusions
Further Reading
9 Antimetabolites and Hormonal Blockers
9.1 Nucleic Acid Analogs
9.2 Folate Analogs
9.3 Amino Acid Blockers
9.4 Hormone Modulators
9.5 Estrogen Antagonists
9.6 Aromatase Inhibitors
9.7 Antiandrogens
9.8 Endocrine Therapy
9.9 Summary and Conclusions
Further Reading
10 Cancer Research
10.1 Gel Electrophoresis Methods
10.2 Polymerase Chain Reaction
10.3 Molecular Cloning
10.4 Enzyme‐Linked Immunosorbent Assay, Immunohistochemistry, and Immunofluorescence
10.5 Mass Spectroscopy and Proteomics
10.6 Genomics, Transcriptomics, and Metabolomics
10.7 Microarrays
10.8 Cell Culture and Exogenous Expression Strategies
10.9 Protein Expression and Targeting
10.10 Animal Models
10.11 Delivery Systems
10.12 Resources
10.13 Summary and Conclusions
Further Reading
11 Clinical Trials
11.1 Clinical Trial Design
11.2 Clinical Trials Governance and Quality Assurance
11.3 Clinical Trial Ethics
11.4 Clinical Trial Study Schema
11.5 Measurement of Clinical Endpoints, Response, and Outcomes
11.6 Local and National Organization of Clinical Trials
11.7 Summary and Conclusions
Further Reading
12 Tumor Hypoxia
12.1 Effects of Hypoxia on Chemotherapy
12.2 Energy Reprogramming and the Warburg Effect
12.3 Hypoxia‐Inducible Factor
12.4 Lactate Dehydrogenase and Carbonic Anhydrase
12.5 Hypoxic Vascularization and Imaging
12.6 Bioreductive Drugs
12.7 Summary and Conclusions
Further Reading
13 Antiangiogenic and Antivascular Agents
13.1 History of Antiangiogenic Chemotherapy
13.2 Endogenous Integrin Blockers
13.3 Matrix Metalloproteinase Inhibitors
13.4 Synthetic Integrin Blockers
13.5 The Return of Thalidomide
13.6 Vascular Disrupting Agents
13.7 Antiangiogenic Antibodies
13.8 Summary and Conclusions
Further Reading
Note
14 Protein Kinase and Ras Blockers
14.1 Signal Transduction
14.2 Receptor Tyrosine Kinase Blockers
14.3 Nonreceptor Tyrosine Kinase Blockers
14.4 Receptor Serine/Threonine Kinase Blockers
14.5 Nonreceptor Serine/Threonine and Multiple Kinase Blockers
14.6 Ras and PLC Blockers
14.7 Summary and Conclusions
Further Reading
15 Modulating Global Gene and Protein Expression
15.1 Stress Protein Inhibitors
15.2 Proteasome Inhibitors
15.3 Ubiquitin Ligase Inhibitors
15.4 Histone Deacetylase Inhibitors
15.5 DNA Methylation Inhibitors
15.6 Summary and Conclusions
Further Reading
16 Stem Cells – Telomerase, Wnt, Hedgehog, Notch, and Galectins
16.1 Telomerase Blockers
16.2 Wnt Blockers
16.3 Hedgehog Blockers
16.4 Notch Blockers
16.5 Galectin Blockers
16.6 Summary and Conclusions
Further Reading
17 Immunotherapy and Oncolytic Viruses
17.1 Immunization
17.2 Immune Checkpoint Blockers
17.3 Chimeric Antigen Receptor T‐Cells
17.4 Oncolytic Viruses
17.5 Summary and Conclusions
Further Reading
18 Pharmaceutical Problems in Cancer Chemotherapy
18.1 Manifestation of Toxicity
18.2 Regimen‐Related Toxicity
18.3 Secondary Malignancies
18.4 Drug Resistance
18.5 Pharmaceutical Complications
18.6 Phlebitis and Venous Irritation
18.7 Health and Safety
18.8 National Guidance on the Safe Administration of Intrathecal Chemotherapy
Further Reading
Index
End User License Agreement
List of Tables
Chapter 2
Table 2.1 Hallmarks of cancer
Table 2.2 Examples of cancer nomenclature
Table 2.3 Morphologic and phenotypic changes observed in apoptosis and necrosis
Chapter 3
Table 3.1 Examples of carcinogenic compounds and tumor‐promoting agents
Chapter 4
Table 4.1 Some oncogenes, their general function, and cancers implicated
Table 4.2 Some oncogenic viruses and associated cancers
Table 4.3 Some tumor suppressors, their general function, diseases, and cancers ...
Chapter 5
Table 5.1 Some common cancers and metastatic sites
Chapter 6
Table 6.1 TNM staging for breast cancer
Chapter 7
Table 7.1 Summary of ESMO minimum clinical recommendations for breast cancer
Table 7.2 Summary of ESMO minimum clinical recommendations for nonsmall cell lun...
Table 7.3 Biomarkers, associated cancers, and general functions
Chapter 8
Table 8.1 Major classes and examples of cytotoxic anticancer compounds
Chapter 11
Table 11.1 Comparison of terminology relating to clinical trials in the UK and E...
Table 11.2 Roles and responsibilities of the clinical trial team
Chapter 13
Table 13.1 Examples of endogenous antiangiogenic compounds
Table 13.2 Matrix metalloproteinase (MMP), tissue inhibitor of matrix metallopro...
Chapter 14
Table 14.1 Examples of oncogenic receptor tyrosine kinase blockers
Table 14.2 Examples of oncogenic nonreceptor tyrosine kinase blockers
Table 14.3 Examples of agents that target receptor serine kinases
Table 14.4 Examples of oncogenic nonreceptor serine/threonine kinase blockers
Chapter 15
Table 15.1 HSP family members and representative inhibitors
Chapter 17
Table 17.1 Basic cell types of immune system
Table 17.2 Examples of immune checkpoint blockers and their targets
Table 17.3 Examples of oncolytic viruses
Chapter 18
Table 18.1 Emetogenic potential of single and combination anticancer agents
Table 18.2 Classification of anticancer agents according to potential to cause n...
List of Illustrations
Chapter 1
Figure 1.1 Statue of the Egyptian physician Imhotep (ca. 2600 BCE).
Figure 1.2 Worldwide cancer incidence by age. Statistics are shown for 2012.
Figure 1.3 Cancer rates over time. Invasive cancers from SEER 9 areas (San Fra...
Figure 1.4 Cancer incidence and mortality by tumor site. Numbers from IARC mem...
Figure 1.5 Childhood cancer incidence and mortality by tumor site. Worldwide n...
Figure 1.6 Cancer incidence and mortality by country. Incidence (
top
) and mort...
Figure 1.7 Most common cancers by country. Most common cancers for each countr...
Figure 1.8 Cancer survival rates. Age‐standardized one‐, five‐, and 10‐year ne...
Figure 1.9 Changes in cancer survival rates over time. Age‐standardized 10‐yea...
Chapter 2
Figure 2.1 Normal and cancerous human epithelium.
Figure 2.2 Cell and tissue morphology is altered and intercellular communicati...
Figure 2.3 Fundamental aspects of major pathways leading to cell death. Apopto...
Figure 2.4 Characteristic morphologic changes during cell death. These are exe...
Figure 2.5 Extrinsic and intrinsic pathways initiate caspase‐dependent cascade...
Figure 2.6 Bcl‐2 family members and apoptosis. Bcl‐2 proteins are located in t...
Chapter 3
Figure 3.1 Three stages of carcinogenesis. Cancer is usually initiated by chan...
Figure 3.2 G–C to A–T transition occurring when methylation of guanine allows ...
Figure 3.3 Coordinated cyclin‐dependent kinase activity controls cell prolifer...
Chapter 4
Figure 4.1 Cell junctions, architecture, and cancer signaling pathways. Cells ...
Figure 4.2 Intercellular communication and contact normalization. Cancer cells...
Figure 4.3 Ras mutations can promote cancer. The Ras GTPase is active when bou...
Figure 4.4 Formation of the Bcr‐Abl fusion oncogene by translocation of coding...
Figure 4.5 Mechanisms of transformation by the human papillomavirus. HPV produ...
Figure 4.6 Regulation of the p53 tumor suppressor protein. p53 activity is con...
Chapter 5
Figure 5.1 Cancer cells metastasize via lymphatic and blood vessels. For examp...
Figure 5.2 Melanoma cell metastasis in zebrafish embryos. DiI‐labeled melanoma...
Figure 5.3 Fundamental stages of metastasis. Metastasis involves detachment of...
Figure 5.4 The role of aquaporins in the formation of membrane protrusions dur...
Figure 5.5 Mechanisms of cell motility and matrix degradation. Cell membrane p...
Figure 5.6 Cooperativity of macrophages and tumor cells forming podosomes and ...
Figure 5.7 Extravasation of tumor cells by transendothelial migration or diape...
Chapter 6
Figure 6.1 Breast cancer pathology. Normal breast tissue is shown with progres...
Chapter 7
Figure 7.1 Facilitative glucose transporter Glut‐1 expression detected by immu...
Figure 7.2 Use of biomarkers to prescribe and monitor cancer treatment.
Figure 7.3 Factors affecting clinical response to anticancer agents.
Chapter 8
Figure 8.1 Cell cycle effects of classic cytotoxic chemotherapy compounds. Tub...
Figure 8.2 Soldiers and horses wore gas masks to protect them from poison gas ...
Figure 8.3 Structure of some common alkylating agents.
Figure 8.4 Alkylating agents produce reactive ethyleneimonium and carbonium io...
Figure 8.5 Dacarbazine and temozolomide are both prodrugs of the alkylating co...
Figure 8.6
Streptomyces peucetius
was isolated from soil around a thirteenth‐c...
Figure 8.7 Anthracyclines. (a) The classic anthracyclines doxorubicin, daunoru...
Figure 8.8 Doxorubicin (DOX) intercalates into DNA to cause major structural c...
Figure 8.9 Anthracyclines intercalate into DNA and produce superoxide and unst...
Figure 8.10 Anthracyclines form adducts with NH2 residues in guanine bases to ...
Figure 8.11 Anthracycline prodrugs. (a) Prodrugs of doxorubicin may be acid se...
Figure 8.12 Bleomycin, actinomycin D, and mitomycin C.
Figure 8.13 The systemic activation of bleomycin depends upon the binding of t...
Figure 8.14 The DNA fluorochrome 40‐6‐diamidine‐2‐phenyl indole (DAPI – shown ...
Figure 8.15 Structure of the minor groove binding agent trabectedin.
Figure 8.16 Hoechst 33342 labeling DNA in nuclei of human oral squamous cell c...
Figure 8.17 Minor groove binding agents in preclinical development.
Figure 8.18 Topoisomerase I inhibitors camptothecin and its derivatives topote...
Figure 8.19 Novel topoisomerase I inhibitors undergoing clinical evaluation.
Figure 8.20 The epipodophyllotoxin derivative topoisomerase II inhibitors etop...
Figure 8.21 Mitosis takes place during the M phase of the cell cycle. Nuclear ...
Figure 8.22 Vinca alkaloids vincristine, vinblastine, and vindesine, and their...
Figure 8.23 Taxanes paclitaxel and the semisynthetic derivatives docetaxel and...
Figure 8.24 Structures of some epothilones, desoxyepothilones, and the epothil...
Chapter 9
Figure 9.1 Some purine and pyrimidine nucleic acid analogs.
Figure 9.2 Capecitabine activation. Capecitabine is an orally administered pro...
Figure 9.3 Nucleic acid and folate antimetabolites. Pyrimidine, purine, and fo...
Figure 9.4 Folate and common analogs.
Figure 9.5 Folates and their analogs enter cells through the reduced folate ca...
Figure 9.6 Asparaginase depletes L‐asparagine in serum that is required for su...
Figure 9.7 Synthesis of androgens and estrogens from cholesterol. The conversi...
Figure 9.8 Regulation of gene expression by steroid hormones in estrogen recep...
Figure 9.9 Structure of several estrogen antagonists. These include selective ...
Figure 9.10 Estrogen antagonists can block binding of estradiol to its recepto...
Figure 9.11 Structures of the steroidal antiandrogen cyproterone acetate and t...
Figure 9.12 Interruption of the hypothalamus–pituitary axis. The hypothalamus ...
Chapter 10
Figure 10.1 Southern, Northern, and Western blotting can be used to study DNA,...
Figure 10.2 Polymerase chain reaction. DNA strands are melted, annealed to pri...
Figure 10.3 Plasmids and molecular cloning. Some common features of mammalian ...
Figure 10.4 ELISA, IHC, and IF protein detection. (
Left
) A “sandwich” ELISA pl...
Figure 10.5 Simplified model of microarray technology. Specific molecules (suc...
Figure 10.6 Effects of MASL on NCI 60 panel performed by the NIH DTP. Cells we...
Figure 10.7 MCF7 human mammary epithelial carcinoma cells exhibit different mo...
Figure 10.8 Blocking antibodies and expression constructs. Growth factors acti...
Figure 10.9 Dominant negative hypoxia‐inducible factor. A dominant negative co...
Figure 10.10 RNAi processing. Dicer cleaves miRNA into short fragments which g...
Figure 10.11 Gene targeting by homologous recombination. Targeting vectors con...
Figure 10.12 CRISPR technology. Guide RNA brings Cas9 nuclease to cleave targe...
Figure 10.13 Transgenic mouse keratitis‐ichthyosis‐deafness syndrome model. Mu...
Figure 10.14 Liposomes contain a hydrophilic lipid bilayer surrounding an aque...
Figure 10.15 Accumulation of stealth liposomes in solid tumors occurs by extra...
Chapter 11
Figure 11.1 The stages involved in the approval of an investigational drug fro...
Figure 11.2 Significant advances in cancer research from ancient times to the ...
Figure 11.3 Design to data lock – the clinical trials process.
Figure 11.4 Example of a site approval report which will be completed by a cli...
Figure 11.5 Generalized two‐arm study schema.
Figure 11.6 National Cancer Research Institute map of UK clinical trials units...
Figure 11.7 The NCI National Clinical Trials Network Structure includes five U...
Chapter 12
Figure 12.1 Chronic hypoxia occurs where distance from a functional capillary ...
Figure 12.2 Hypoxia affects glucose metabolism and microenvironmental pH in no...
Figure 12.3 Analogs of
D
‐glucose. Compounds such as 2‐deoxy‐ (2‐DG), 2‐fluoro‐...
Figure 12.4 Glucose conjugates are designed to achieve preferential uptake int...
Figure 12.5 HIF‐1 inhibitors include phenethyl isothiocyanate and acriflavine.
Figure 12.6 Examples of novel compounds identified as having HIF‐1 inhibiting ...
Figure 12.7 Compounds used to design agents that inhibit carbonic anhydrase. A...
Figure 12.8 Echo contrast‐enhanced power Doppler ultrasonography used to visua...
Figure 12.9 PET enhances tumor detection in combination with MRI.
Figure 12.10 DCE‐MRI images in a patient with liver metastasis from cholangioc...
Figure 12.11 Nitroimidazoles are similar in structure to the antimicrobial age...
Figure 12.12 Bioreductive drugs in clinical development include quinones such ...
Figure 12.13 Hypoxia‐dependent activation of the bioreductive agents tirapazam...
Chapter 13
Figure 13.1 Angiogenesis introduced a novel therapeutic strategy to treat canc...
Figure 13.2 Endogenous angiogenesis inhibitors produced from extracellular mat...
Figure 13.3 General structure of MMPs and ADAMs. Signal peptides are followed ...
Figure 13.4 Broad‐spectrum peptidomimetic agents marimastat and batimastat. Th...
Figure 13.5 Small molecule MMP inhibitors including tanomastat, BMS‐275291, te...
Figure 13.6 Pyrimidine trione‐based heteroaryl compound with selective MMP13 i...
Figure 13.7 Integrin signaling and the ECM. Integrins link the actin cytoskele...
Figure 13.8 Structure of cilengitide.
Figure 13.9 Thalidomide and lenalidomide.
Figure 13.10 Structure of colchicine (left) and combretastatin (right).
Figure 13.11 VEGF signaling pathway. VEGFA (and processed forms of VEGFD or VE...
Chapter 14
Figure 14.1 Signal transduction cascades. Simplified schematic overview of onc...
Figure 14.2 Receptor tyrosine kinase structure. Several receptors are shown wi...
Figure 14.3 Antibodies exemplified by trastuzumab and small molecule inhibitor...
Figure 14.4 Antibodies exemplified by bevacizumab and small molecule inhibitor...
Figure 14.5 Structures of v‐Src and c‐Abl. Src and Abl both contain an SH3 dom...
Figure 14.6 Jakanibs inhibit JAK kinase‐mediated STAT activation of oncogenic ...
Figure 14.7 TGFβ signaling and targeting. TGFβ binds to TGFβ R2 receptors, whi...
Figure 14.8 Tumor‐derived growth factors (TDGFs) include TGFβ, which c...
Figure 14.9 Structures of PKB/Akt kinase blockers PK‐2206, AZD5363, and RG7440...
Figure 14.10 Structures of mTOR blockers rapamycin, temsirolimus, everolimus, ...
Figure 14.11 CDKs phosphorylate Rb to promote cell cycle progression. Cells mu...
Figure 14.12 Farnesyltransferase inhibitors clavaric acid and tipifarnib.
Figure 14.13 Phospholipase C inhibitors include the alkyl‐lysophospholipid ede...
Chapter 15
Figure 15.1 Structure of the HSP27 blocker quercetin.
Figure 15.2 HSP70 structure. HSP70 contains an amino terminal nucleotide‐bindi...
Figure 15.3 HSP90 structure. HSP90 contains an amino terminal nucleotide‐bindi...
Figure 15.4 Representative HSP90 blockers include geldanamycin and radicicol d...
Figure 15.5 Protein ubiquitination. Ubiquitin (Ub) is activated by the ATP‐dep...
Figure 15.6 Structure of the proteasome.
Figure 15.7 Examples of chemotherapeutic proteasome blockers.
Figure 15.8 Nutlin 3.
Figure 15.9 Packaging of DNA into chromosomes depends upon the condensation of...
Figure 15.10 HDAC as an anticancer drug target. HAT (histone acetyl transferas...
Figure 15.11 HDAC inhibitors have histone deacetylation‐independent pharmacolo...
Figure 15.12 Structures of DNMT inhibitors 5‐azacytidine and 5‐aza‐20‐deoxycyt...
Chapter 16
Figure 16.1 Telomere end replication problem. DNA polymerases require a templa...
Figure 16.2 Telomere shortening leads to senescence. Telomere length is shorte...
Figure 16.3 Structure of hTERT and the telomerase blocker imetelstat (GRN163).
Figure 16.4 Canonical Wnt signaling pathway. Wnt binds FZD and its coreceptor ...
Figure 16.5 Silibinin and rottlerin are potential natural Wnt signaling blocke...
Figure 16.6 Canonical Hedgehog signaling pathway. Hedgehog (Hh) ligands bind t...
Figure 16.7 Examples of Hedgehog signaling blockers that target Smoothened (SM...
Figure 16.8 Teratogenic effects of the Smoothened blocker cyclopamine (
left
) d...
Figure 16.9 Notch signaling pathway. Notch is translated in the endoplasmic re...
Figure 16.10 γ‐secretase blockers used to inhibit Notch signaling.
Chapter 17
Figure 17.1 Ancient practice of inoculation by scratching matter from a smallp...
Figure 17.2 Dendritic cell loading. In this example, dendritic cells are extra...
Figure 17.3 Immune checkpoint receptors. Ligands B7‐1/2 and PDL1/2 target cyto...
Figure 17.4 Chimeric antigen receptors (CARs) are composed of an extracellular...
Figure 17.5 Bystander effect. Virus encoding HSV‐TK can phosphorylate ganciclo...
Chapter 18
Figure 18.1 The National Cancer Institute Common Terminology Criteria for Adve...
Figure 18.2 Sensor‐controlled scalp cooling device.
Figure 18.3 p‐Glycoprotein inhibitors.
Figure 18.4 The DNA repair enzyme
O
6‐alkylguanine‐DNA alkyltransferase (AGT) c...
Figure 18.5 Poly (ADP‐ribose) polymerase‐1 (PARP‐1) inhibitors that have been ...
Guide
Cover
Table of Contents
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Cancer Chemotherapy
Basic Science to the Clinic
Second Edition
Dr. Gary S. Goldberg, PhD
Associate ProfessorSchool of Osteopathic MedicineRowan UniversityStratford, New Jersey 08084USA
Dr. Rachel Airley, MRes PhD MRPharmS FHEA
Community pharmacist and former lecturer in pharmacology and cancer sciences Manchester, UK
With Illustrations by Tara M. Askin, BASenior Graphic DesignerSchool of Osteopathic MedicineRowan UniversityStratford, New Jersey 08084USA
Copyright
This edition first published 2020
© 2020 John Wiley and Sons Ltd
Edition History:
John Wiley and Sons (1e, 2009)
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.
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Library of Congress Cataloging‐in‐Publication Data
Names: Goldberg, Gary S., author. | Airley, Rachel, author.
Title: Cancer chemotherapy : basic science to the clinic / Dr. Gary S.
Goldberg, PhD, Associate Professor, School of Osteopathic Medicine,
Rowan University, Stratford, New Jersey, Dr. Rachel Airley, MRes PhD
MRPharmS FHEA, Community pharmacist and former lecturer in pharmacology
and cancer sciences, Manchester, UK ; with illustrations by Tara M.
Askin, BA, Senior Graphic Designer, School of Osteopathic Medicine,
Rowan University, Stratford, New Jersey.
Description: Second edition. | Hoboken, NJ : Wiley‐Blackwell, 2020. |
Revised edition of: Cancer chemotherapy / Rachel Airley. 2009. |
Includes bibliographical references and index.
Identifiers: LCCN 2019052331 (print) | LCCN 2019052332 (ebook) | ISBN
9781118963852 (paperback) | ISBN 9781118963838 (adobe pdf) | ISBN
9781118963845 (epub)
Subjects: LCSH: Cancer–Chemotherapy.
Classification: LCC RC271.C5 A35 2020 (print) | LCC RC271.C5 (ebook) |
DDC 616.99/4061–dc23
LC record available at https://lccn.loc.gov/2019052331
LC ebook record available at https://lccn.loc.gov/2019052332
Cover Images: Cancer cells: courtesy of Min Han;
Chemotherapy process: courtesy of Tara M. Askin;
DNA molecule © farakos/Getty Images; Cancer cells, cancer foci © ttsz/Getty Images; Process of cancer cell development © logo3in1/Adobe Stock Photo;
Lungs and Heart © olenka758/Adobe Stock Photo;
Human Body © robu_s/Adobe Stock Photo
Preface
When the first edition was published in 2009, we focused on classic anticancer agents and modern approaches targeting tumor hypoxia, angiogenesis, and signal transduction cascades. Each of these groups was represented by a small number of approved agents but offered the promise of a large number of drugs which at the time of writing were in preclinical and clinical development. Inevitably, a fair number of these agents have fallen by the wayside, but a significant number have progressed into treatment mainstays which have since been further explored in phase 3 clinical trials for an expanding range of indications.
Perhaps unlike other therapeutic specialties, the development of cancer chemotherapy progresses in a nonlinear fashion, where instead of older drugs falling out of vogue, new drugs are integrated into reengineered cancer treatment regimens with established chemotherapeutic agents and adjuvant treatment modalities. The constant flux of clinical trials in cancer allows treatments both old and new to be continually optimized, and the most promising to be trialed in cancer types suffering a paucity of treatments and which are slow moving in terms of improvements in prognosis. For this reason, this new edition now includes a more comprehensive discussion of the clinical trials process in cancer research (Chapter 11).
Although we have retained those anticancer strategies – old and new – that were included in the first edition, we have made additions according to our own perception of emerging and promising avenues in cancer research. Research into signaling pathways in the evolution of cancer pathology now means we have greater understanding of pathways such as Wnt, Hedgehog, and Notch and accordingly, we have discussed the status of their respective blocking agents (Chapter 16).
Immunotherapy is also gaining traction as a cancer treatment, and there are several approaches being developed to manipulate or exploit the host immune system (Chapter 17). To inform these new additions, we have made a number of updates to the chapters focusing on the molecular biology of cancer. Although we acknowledge that it is not possible to include all the latest developments in this area of science, we have tried to structure this section to underpin later discussions of the pharmacology of the newest anticancer agents discussed in this edition and based on our predictions of which major discoveries in tumor biology will become tomorrow's new targets for drug development.
In the 10 years since the publication of the first edition of this book, targeted agents have successfully traversed the experimental stages to become established treatments in the cancer armory. The treatment of cancer is often described as a battle, whether in the context of a patient's journey or the scientific community and cancer charities “standing up” to cancer. In truth, it is the highly individualized and complex molecular mechanisms controlling cancer formation and progression which will ultimately determine a patient's prognosis. In light of this, we have taken inspiration from Sun Tzu's The Art of War to create what we hope are thought‐provoking analogies between military strategy and the design and clinical use of cancer chemotherapy.
We hope this book is useful. We wrote it for everyone, including patients, clinicians, students, researchers, and the casual reader, with each section meant to stand on its own with clarity as a goal.
Rachel AirleyGary S. Goldberg
About the Companion Website
This book is accompanied by a companion website:
www.wiley.com/go/airley/cancerchemotherapy
The website includes:
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Powerpoints of all figures from the book for downloading
1Cancer Epidemiology
– Sun Tzu
Cancer is not a new disease. Humans are not the only species to get cancer. In fact, cancer is found throughout the animal kingdom. Therefore, hominids were likely to have suffered from cancer before the advent of Homo sapiens.
The history of cancer is evidenced by traditional medicines used by many cultures around the world. These “folk remedies” actually serve as the basis of many medical treatments used today. Many of these natural products are discussed in subsequent chapters of this book.
Perhaps the earliest reference to cancer can be found in the writings of the ancient Egyptian physician Imhotep from around 2600 BCE (see Figure 1.1). In papyrus documents dating from this period, Imhotep describes treating breast tumors with cauterization. The procedure was evidently less than successful since he instructs the reader, “Tumor against the god Xenus … do thou nothing there against.” Unfortunately, even today we are left with questions about whether side‐effects of some treatments are worse for patients than the disease.
Regardless of its history, cancer is a huge problem today, and is likely to become an even larger problem tomorrow. About 14 million people were diagnosed with cancer in 2012, and 18 million in 2018. This trend is daunting, with the number of new cases expected to reach 24 million by 2035.
1.1 Cancer Incidence and Mortality
Over 14 million people around the world are diagnosed with cancer each year, and this number is expected to rise. By current estimates, more than one in three people will develop a form of cancer at some point in their lifetime. Around 10 million people died from cancer in 2018. Thus, cancer kills an average of over 15 people every minute. A comprehensive understanding of cancer incidence and outcomes is an important step toward decreasing these numbers.
Figure 1.1 Statue of the Egyptian physician Imhotep (ca. 2600 BCE).
Source: https://upload.wikimedia.org/wikipedia/commons/d/d2/Imhotep.JPG.
Cancer incidence, defined as the number of new cases arising in a period of time, is gender and age specific. In males, prostate cancer is the most prolific, where over 1 million new cases were diagnosed in 2018, accounting for around 8% of all new cancer cases and 15% of all new cancer cases in men. In females, breast cancer continues to be the most common tumor type. Over 2 million new cases were diagnosed in 2018, making it the second most common cancer. Breast cancer represents about 12% of all new cancer cases, and 25% of all cancers in women.
Cancer incidence may be further defined by the lifetime risk of developing the disease. For instance, in females, the risk of developing breast cancer is 1 in 8. In males, the risk of developing prostate cancer is 1 in 6; however, 80% of men who are 80 years old are likely to have some stage of prostate cancer. Some other tumor types also show considerable gender‐related differences in cancer risk. For example, males are over twice as likely to develop lung cancer as women worldwide. However, lifestyle can be a factor for some of these differences. For instance, the chance of women getting lung cancer increases in countries such as the USA where women are more likely to smoke tobacco than in some other regions of the world.
Figure 1.2 Worldwide cancer incidence by age. Statistics are shown for 2012.
Source: Data from http://gco.iarc.fr/today.
Figure 1.3 Cancer rates over time. Invasive cancers from SEER 9 areas (San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, and Atlanta) age adjusted to 2000 USA population.
Source: Data from http://gco.iarc.fr/today.
In general, cancer risk increases with age, as shown in Figure 1.2. For example, less than 50 people per 100 000 under 39 years old were diagnosed with cancer in 2012. This number increased to over 1800 people between 40 and 64 years old, and over 3500 people older than 64 years. The rate of diagnosis in males 65 years or older rises most sharply with an incidence of over 4700 per 100 000.
Cancer is a major public health problem and is expected to become even worse. Cancer incidence rates have been steadily increasing over time. This is true for both males and females. However, regional spikes and dips can be seen in trends over time. For example, a spike in male cancers is seen in the 1990s in some areas of the United States, as shown in Figure 1.3. This spike has ebbed but incidence is still higher now than it was 40 years ago. In contrast, female cancer incidence has steadily climbed in these same areas over time.
Incidence rates of some types of cancer appear to be increasing more than others. Sites with annual cancer incidence increases of 1% of more include melanoma, renal, thyroid, pancreas, and liver. Meanwhile, although incidence rates are less than 1% per year, cancers such as non‐Hodgkin lymphoma, certain childhood cancers, leukemia, myeloma, testicular, and oral cancers are still on the increase. Cancer is the second leading cause of death in the USA and UK (behind heart disease). In fact, cancer causes about 25% of all the deaths in these countries.
Figure 1.4 Cancer incidence and mortality by tumor site. Numbers from IARC member countries (Germany, France, Italy, United Kingdom, USA, Australia, Austria, Belgium, Brazil, Canada, Denmark, Finland, India, Ireland, Japan, Norway, Netherlands, Qatar, Republic of Korea, Russia, Spain, Sweden, Switzerland, and Turkey) are shown for 2012.
Source: Data from http://gco.iarc.fr/today.
There are more than 200 different types of cancer but four particular tumor types constitute over half of all new cases diagnosed: breast, lung, colorectal, and prostate. In 2012, there were 14.1 million new cases of cancer diagnosed worldwide. As shown in Figure 1.4, these four cancers account for nearly 50% of these new cases (6.9 million), and are responsible for about half of all cancer deaths.
1.2 Childhood Cancer
Cancer in children is relatively rare. Less than one out of 1 million cancers are found in children under 15 years old. Nonetheless, children do get cancer. In 2012, over 160 000 children were diagnosed with cancer, and cancer killed about 80 000 children.
Leukemia is the most common form of pediatric cancer, followed by lymphomas and cancers of the central nervous system. These cancers were responsible for about 8 million deaths of children under 15 years old around the world in 2012. As shown in Figure 1.5, 35% of these deaths were caused by leukemias, compared to 12% by lymphomas and 14% by brain tumors.
Figure 1.5 Childhood cancer incidence and mortality by tumor site. Worldwide numbers for males and females up to 14 years old are shown for 2012. * All cancers exclude nonmelanoma skin cancer.
Source: http://gco.iarc.fr/today, August 2014.
Although pediatric cancers are rare compared to adult cancers, they can be devastating. Whereas adult patients who remain cancer free for five years are often considered to be “cured” since their chance of mortality after this time is consistent with other causes, this is not the case with children. Pediatric cancer patients can undergo remission only to have cancer emerge again at a relatively young age. Thus, consequences from childhood cancers can be especially brutal.
1.3 Global Epidemiology
Cancer is a global problem, but it is a larger problem in some countries than in others (Figure 1.6). North America, western Europe, Australia, and New Zealand have the highest incidence, while India, along with some countries in the Middle East and Central Africa, have lower incidences. These differences can result from population demographics and lifestyle factors. Age is also a primary risk factor. For example, India has a median age of 27 years, while the median age in the USA is 38 years. This difference in age demographics may account for the higher cancer incidence in the USA compared to India, though other factors such as a chemopreventive diet and exercise may also affect cancer incidence. For example, although Japan has a relatively high median age of 48 years, its cancer incidence rate is lower than that of the USA. This relatively low cancer rate of an elderly population has been attributed to the chemopreventive properties of soy beans and other foods in the Japanese diet.
Figure 1.6 Cancer incidence and mortality by country. Incidence (top) and mortality (bottom) per 100 000 people for all cancers are shown for 2018.
Source: http://gco.iarc.fr/today.
Overall, cancer mortality rates correlate with incidence, an effect shown in Figure 1.6. However, some intriguing observations arise from these comparisons. For example, the demarcation line between North and South Korea appears to delineate a difference in incidence and mortality between the two countries. While North Korea has a lower cancer incidence, it reports a higher mortality rate than South Korea. This apparent paradox may arise from incongruent options between healthcare systems in each country.
Figure 1.7 Most common cancers by country. Most common cancers for each country are shown as measured by incidence (top) and mortality (bottom) for 2018.
Source:http://gco.iarc.fr/today.
Figure 1.7 illustrates cancer incidence rates by site and country. Lung cancer has the highest incidence in most countries, followed by colorectal cancer in Russia, Australia, and regions of Africa and South America. Lung cancer also causes the most mortality around the world, followed by liver cancer in Mongolia, Thailand, and regions of Africa. However, some unique patterns arise from these data. For example, Papua New Guinea shows high levels of oral cancer that are not as prevalent in more western parts of the Indonesian islands, a difference attributed to the chewing of betel nut with tobacco by much of the population. Thus, lifestyle factors play a major role in the types of cancers seen, as well as cancer incidence and mortality rates.
1.4 Cancer Survival Rates
Cancer is a unique malady. While infectious diseases can be obliterated by medicines such as antibiotics, cancer treatments are not that simple and recurrence is far too common. Some consider a patient who is treated and still alive for some amount of time – generally five years – to be “cured.” However, current shifts in thought do not consider most patients to be cured of their cancer. Instead of being cured, these patients are called “survivors.” The question then becomes, “how long do they survive”?
As shown in Figure 1.8, the one‐, five‐, and 10‐year survival rates for all cancers average out to around 70%, 54%, and 50%, respectively. However, survival depends greatly on the type of cancer involved. Figure 1.8 shows one‐, five‐, and ten‐year survival rates for common cancers. Relatively high survival rates of 80% or more are seen in patients with some cancers including testicular, melanoma, breast, prostate, and Hodgin lymphoma.
However, some caveats arise from these numbers. Individual cases for each cancer should be taken into account. For example, while the survival rate for malignant melanoma is 90%, this survival rate drops to 16% after melanoma has metastasized to other sites beyond lymph nodes. Later chapters discuss cancer metastasis and the challenges this key element of cancer biology presents.
In contrast to early testicular, skin, and prostate cancers, some other cancer types including cancers of the esophagus, stomach, brain, lung, and pancreas are notoriously lethal. For example, pancreatic cancer has a five‐year survival rate of only 3%. These relatively low survival rates may result from the aggressive nature of these cancers combined with challenges in early detection technologies.
Progress in the early diagnosis and treatment of cancer has positively affected cancer survival rates, leading to a doubling of 10‐year overall cancer survival rates from 25% to 50% in the past 40 years (Figure 1.9). For example, tests for the biomarker prostate specific antigen (PSA) have increased the diagnosis of early asymptomatic prostate tumors. This early detection combined with better treatments has dramatically increased prostate cancer survival rates. This is reflected by the increase in 10‐year survival rates over the last 40 years from about 25% in 1971 to over 80% in 2011, as shown in Figure 1.9. Indeed, after prostate cancer mortality rates increased by around 50% during the 1980s, these advances have decreased mortality rates by about 30% since 1990 in Europe.
Figure 1.8 Cancer survival rates. Age‐standardized one‐, five‐, and 10‐year net survival rates are shown for common cancers in adults (aged 15–99) in England and Wales in 2010–2011. Breast and laryngeal data are shown for female and male only, respectively. NHL, non‐Hodgkin lymphoma.
Source:www.cancerresearchuk.org/cancer-info/cancerstats/survival/common-cancers, August 2014. Reproduced with permission of Cancer Research UK.
Figure 1.9 Changes in cancer survival rates over time. Age‐standardized 10‐year net survival rates are shown for common cancers in adults (aged 15–99) in England and Wales from 1971–1972 to 2010–2011. Breast and laryngeal data are shown for female and male only, respectively. Ten‐year survival for 2005–2006 and 2010–2011 was predicted by an excess hazard statistical model. Survival for bowel cancer is a weighted average derived from data for colon and rectum cancer. NHL, non‐Hodgkin lymphoma.
Source: www.cancerresearchuk.org/cancer-info/cancerstats/survival/common-cancers/#Trends, August 2014. Reproduced with permission of Cancer Research UK.
Breast cancer provides another example of progress in cancer treatments. Breast cancer screening procedures can detect tumors at very early stages. This early detection followed by improved treatments has increased 10‐year survival rates from about 40% in 1971 to nearly 80% in 2011, as shown in Figure 1.9.
Survival rates for some pediatric cancers have risen dramatically over time. Childhood cancer mortality rates decreased by an average of 2.6% per year between 1962 and 2001, essentially cutting the death rate in half. Nearly 72% of the childhood cancer cases diagnosed in the time period 1992–1996 survived over five years, and this number has increased to over 80% for patients diagnosed in the time period 2004–2010. Acute lymphoblastic leukemia provides a good example of how pediatric survival rates can be improved. The five‐year survival rate for this form of cancer, which accounts for three out of four cases of childhood leukemias, has gone from less than 10% in the 1960s to 80% of those diagnosed between 1992 and 1996, and over 90% of those diagnosed between 2000 and 2005. Such improvements are attributed to improved diagnostic techniques and the continual refinement and validation of combination chemotherapy regimens made possible by the steady enrollment of children into clinical trials.
In contrast to progress made in the detection and treatment of cancers such as breast and prostate, some other cancers have remained stubbornly lethal. For example, 10‐year survival rates for lung and pancreatic cancer have remained under 5% for the past 40 years. Nonetheless, progress in cancer detection and treatments has extended overall cancer survival rates and saves thousands of lives every year.
In clinical terms, cancer survival outcomes can be expressed in a number of ways. Overall survival simply notes patient survival, while “disease‐free” survival requires that cancer not be detected in a patient, and will exclude other causes of mortality. Meanwhile, “progression‐free” survival requires that the cancer may be detectable but does not progress or get worse. Thus, a patient may have a shorter disease‐free survival period than a progression‐free survival period. In clinical studies, overall survival is considered less specific as it can be affected by a variety of factors that can lead to death, including complications resulting from age and treatment‐related side‐effects.
1.5 Summary and Conclusions
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Cancer is not a new disease; it has been described in medical texts for thousands of years.
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Cancer is increasing from about 14 million cases per year to 24 million cases per year expected by 2035.
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Most cancers are found in people over 40 years old, but children can also get cancer.
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Lung, prostate, breast, liver, stomach, and skin are common cancer sites.
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Regional differences are seen in cancer incidence and type that can be related to genetics, lifestyles, and the environment.
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Improved methods for detection and treatment have increased cancer survival rates, particularly for certain cancers including prostate, breast, and lymphoma.
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Cancer survival depends on cancer types, and can be increased by improving methods for detection and treatment.
Further Reading
http://www.wcrf.org/cancer_statistics
http://seer.cancer.gov/statfacts
http://globocan.iarc.fr
http://seer.cancer.gov
http://www.cancerresearchuk.org/cancer-info/cancerstats
2Cancer Histopathology
– Sun Tzu
Tumors are characterized by a set of histologic changes displayed by the tumor cells themselves, as well as the microenvironment in which they develop. The general term used to describe a tumor is “neoplasm,” the literal meaning being new growth. A neoplasm refers to an abnormal mass of cells with uncoordinated or deregulated growth or cellular proliferation. Deregulated growth stems from a set of heritable changes in the expression of genes which control either cell division or cell survival. Tumors grow from a single founder cell by the process of “clonal expansion.”
Tumors are made up of two components: (i) proliferating cells composed of the actual cancer cells, called “parenchyma,” and (ii) surrounding cells, connective tissue, and blood vessels, called “stroma.” An example of normal and malignant tissue is shown in Figure 2.1. Tumor tissue is often laid out in tumor “nests,” surrounded by stroma which contains the vasculature necessary to supply oxygen and nutrients to the proliferating cells. Malignant progression depends on the ability of tumor cells to invade into surrounding tissue, a process influenced by the expression of enzymes such as matrix metalloproteinases that degrade surrounding host tissue. Advanced cancers will show progression to metastasis, which involves tumor cell “intravasation” into blood or lymphatic vessels where they move to sites distant from the primary tumor. Malignant progression also involves “angiogenesis” or the growth of a blood supply to provide oxygen and nutrients to the growing tumor.
Figure 2.1 Normal and cancerous human epithelium.
Source: Image courtesy of Dr Min Han.
2.1 Cancer Morphology, Phenotype, and Nomenclature
Cancer cells usually exhibit several “hallmarks of cancer” listed in Table 2.1. Effects of cancer on tissue cell morphology and differentiation are most noticeable from the pathologist's point of view. However, less morphologic hallmarks reveal key mechanisms that can be targeted by chemotherapy.
Table 2.1 Hallmarks of cancer
Hallmark
Normal
Cancer
Morphology
Normal
Abnormal
Differentiation
Functional
Nonfunctional
Growth signaling
Controlled
Uncontrolled
Growth inhibitory signals
Obedient
Disobedient
Immune recognition
Detected
Undetected
Immortality
No
Yes
Inflammation
Not induced
Induced
Motility
High
Low
Angiogenesis
None
Present
Genome
Stable
Unstable
Cell death
Sensitive
Resistant
Energy metabolism
Programmed
Reprogrammed
Communication
Intact
Disrupted
Figure 2.2 Cell and tissue morphology is altered and intercellular communication is disrupted in cancer cells. Cancer is usually accompanied by increased growth factor signaling, decreased formation of junctions between cells, and degradation of their surrounding extracellular matrix.
Transformation to malignancy causes alterations in cell morphology and phenotype that disrupt tissue architecture, as shown in Figure 2.2. Malignant cells become immortalized and lose their ability to communicate with surrounding cells in a coordinated fashion. This can result from a variety of events, including increased expression and activity of growth factor receptors. In a sense, these cells acquire the autonomy to grow in the absence of signals that are usually required to stimulate proliferation. Cancer cells also lose contact and communication with neighboring cells which inhibit excessive growth under normal circumstances by a phenomenon called “contact growth inhibition.” This is likely due to disruption of intercellular junctions formed by cadherins and connexins. As a result of this breakdown in communication with other cells in their microenvironment, tumor cells are usually dedifferentiated and despecialized. Cancer cells tend to lose the morphology and functionality that their nontransformed precursors would normally exhibit in their host tissue.
In contrast to normal cells, which require a basement membrane or solid surface to survive, tumor cells are capable of “anchorage‐independent growth.” The extracellular matrix is composed of different proteins, such as collagen and keratin, which are recognized by integrins to maintain normal epithelial cell survival. In contrast to fertile ground, malignant cells that do not require these signals may view their extracellular matrix as an encapsulating structure. Invasive cells produce matrix metalloproteinases that degrade their extracellular matrix in order to break out of their microenvironment, as illustrated in Figure 2.2.
Tumor cells that break out of their microenvironment can then enter blood or lymphatic vessels to colonize new sites by the process of “metastasis.” The extent of metastasis may be determined by the rate of angiogenesis, or new blood vessel growth, in the parenchyma and stroma. Indeed, growth factor signaling events between tumor cells and stroma cells can often augment the creation of these metastatic highways.
Cancer nomenclature depends upon the tissue of origin and whether it is benign or malignant (Table 2.2). Benign tumors usually have the suffix “oma,” whereas malignant tumors may be called a “carcinoma” if derived from epithelial tissue or an “adenocarcinoma” if derived from glandular tissue. Tumors of mesenchymal origin, such as muscle, are usually called “sarcoma.” It is also normal practice to state the tissue of origin. For example, a tumor arising from the buccal cavity that produces cells of identifiable squamous type would be described as an oral squamous cell carcinoma, as shown in Figure 2.1, while a tumor with a glandular pattern in the cervix would be classified as an adenocarcinoma of the uterine cervix.
As with living cancer cells, dying cancer cells also display characteristic morphologies. Cancer cell death is a central part of chemotherapy. This applies to both the tumor cells and the supporting stroma. Therefore, understanding how cells die is critical to developing effective treatments. Although complex and a field in itself, cell death can be broken down to some fundamental processes. In general, there are at least three ways to kill cancer cells: (i) apoptosis, (ii) necrosis, and (iii) autophagy.
