Anticancer Therapeutics E-Book

Adam Todd

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 807

Veröffentlichungsjahr: 2017

Beschreibung

An integrated presentation of the basic science and clinical applications of anticancer agents

Aimed at both undergraduate and postgraduate readers, this unique text provides readers with a fully-integrated presentation of all aspects of the science of anticancer drugs, including their chemistry, pharmacology, and clinical applications.

After heart disease, cancer is the number one killer worldwide, and the tumor microenvironment is forever changing, creating an ever-greater demand for safer, more effective anticancer agents. In response to that demand, the $100 billion cancer drug market continues to grow, with our increased understanding of cancer leading to new drugs being used clinically almost every year.

Anticancer Therapeutics is divided into three sections. Section 1 is an introduction to cancer and therapeutics, and covers the etiology and cellular and molecular basis of cancer. In Section 2, the authors focus on the anticancer agents — their discovery, synthesis, mode of action, mechanisms of resistance, and adverse reactions. Section 3 focuses on specific cancers, explaining how and why the various agents discussed in Section 2 are used, both individually and in combination, to treat different cancers.

• Integrates aspects of basic science, including chemistry and pharmacology and clinical medicine in relation to cancer therapeutics

• Written by an author team comprising specialists in medicinal chemistry, pharmacology, and oncology
• Features full-color images throughout illustrating how drugs bind to cellular targets and exert their pharmacological effect
• Divided into three sections, covering the etiology and cellular and molecular basis of cancer, anticancer agents, and drug applications for different cancers.

Providing the reader with an integrated understanding of all aspects of the science of anticancer agents, this is an ideal textbook for undergraduates studying medicine, nursing, medicinal chemistry, pharmacy, pharmacology and other allied heath / life sciences. It is also a valuable bench reference for pharmacists, medics, and pharmaceutical researchers working in both academia and industry.

Leseprobe

Table of Contents

Cover

Title Page

Preface

References

Section 1: Introduction

1.1 The Global Burden of Cancer

References

1.2 Cancer Staging and Classification

1.2.1 Benign Tumour (or neoplasm)

1.2.2 Malignant Tumour (or cancer)

1.2.3 Tumour Nomenclature and Classification

1.2.4 Cellular Differentiation and Tumour Grade

1.2.5 Tumour Invasion and Metastasis

1.2.6 Clinical Staging of Cancer

References

1.3 Cellular and Molecular Basis of Cancer

1.3.1 Oncogenes

1.3.2 Tumour Suppressor Genes

1.3.3 Role of Epigenetics and Gene Promoter Regulation in Tumourigenesis

1.3.4 Multistage Tumourigenesis

1.3.5 Oncogene Addiction

1.3.6 Hallmarks of Cancer

1.3.7 Principles of Cancer Treatment

References

Section 2: The Anticancer Agents

2.1 Agents Which Act Directly on DNA

2.1.1 Nitrogen Mustards and Nitrosoureas

References

2.1.2 Temozolomide

References

2.1.3 Platinum‐containing agents

References

2.1.4 Gemcitabine

References

2.1.5 Camptothecin and Its Analogues

References

2.1.6 Podophyllotoxins

References

2.1.7 Anthracyclines [1]

References

2.1.8 Epigenetic Targeting Agents [1]

References

2.2 Antimetabolites

2.2.1 Cytarabine

References

2.2.2 Methotrexate

References

2.2.3 5‐Fluorouracil

References

2.2.4 6‐Mercaptopurine

References

2.3 Antimicrotubule agents

2.3.1 Taxanes

References

2.3.2 Vinca Alkaloids

References

2.4 Anti‐hormonal agents

2.4.1 Bicalutamide

References

2.4.2 Tamoxifen

References

2.4.3 Anastrozole [1]

References

2.5 Kinase Inhibitors

2.5.1 Discovery

2.5.2 Synthesis

2.5.3 Mode of Action

2.5.4 Mechanism of Resistance [32]

2.5.5 Adverse Drug Reactions

References

Section 3: The Cancers

3.1 Breast Cancer

3.1.1 Epidemiology

3.1.2 Presentation

3.1.3 Diagnosis

3.1.4 Staging

3.1.5 Treatments

References

3.2 Colorectal cancer

3.2.1 Epidemiology

3.2.2 Presentation

3.2.3 Diagnosis

3.2.4 Staging

3.2.5 Treatments

References

3.3 Leukaemia

3.3.1 Epidemiology

3.3.2 Presentation

3.3.3 Diagnosis

3.3.4 Staging

3.3.5 Treatments

References

3.4 Lung cancer

3.4.1 Epidemiology

3.4.2 Presentation

3.4.3 Diagnosis

3.4.4 Staging

3.4.5 Treatments

References

3.5 Oesophageal Cancer

3.5.1 Epidemiology

3.5.2 Presentation

3.5.3 Diagnosis

3.5.4 Staging

3.5.5 Treatments

References

3.6 Ovarian cancer

3.6.1 Epidemiology

3.6.2 Presentation

3.6.3 Diagnosis

3.6.4 Staging

3.6.5 Treatments

References

3.7 Pancreatic Cancer

3.7.1 Epidemiology

3.7.2 Presentation

3.7.3 Diagnosis

3.7.4 Staging

3.7.5 Treatments

References

3.8 Prostate Cancer

3.8.1 Epidemiology

3.8.2 Presentation

3.8.3 Diagnosis

3.8.4 Staging

3.8.5 Treatments

References

3.9 Skin Cancers

3.9.1 Epidemiology

3.9.2 Presentation

3.9.3 Diagnosis

3.9.4 Staging

3.9.5 Treatments

References

3.10 Testicular cancer

3.10.1 Epidemiology

3.10.2 Presentation

3.10.3 Diagnosis

3.10.4 Staging

3.10.5 Treatments

References

Index

End User License Agreement

List of Tables

Section 1-Chapter 2

Table 1.2.1 Nomenclature of benign and malignant tumours.

Table 1.2.2 Histopathological grading of malignant tumours.

Section 1-Chapter 3

Table 1.3.1 Functional role of viral oncogenes, including retroviral origin and host species.

Table 1.3.2 Classification systems for genes involved in tumourigenesis.

Table 1.3.3 Examples of targets of oncogene addiction and the associated targeted therapy (adapted from [44,45]).

Section 2-Chapter 2

Table 2.1.7.1 Recommended cumulative maximum anthracycline doses.

Section 2-Chapter 3

Table 2.3.1.1 Grading for low erythrocyte, neutrophil and platelet levels, according to the Common Toxicity Criteria for Adverse Events, as proposed by the US National Cancer Institute [23].

Section 3-Chapter 1

Table 3.1.1 The seventh revision of the

T

N

M

classification of breast cancer, as proposed by the Union for International Cancer Control.

Table 3.1.2 Breast cancer number staging, as derived from T (tumour), N (nodal), and M (metastatic) status.

Section 3-Chapter 2

Table 3.2.1 The seventh revision of the TNM classification of colorectal cancer, as proposed by the Union for International Cancer Control.

Table 3.2.2 Colorectal cancer number staging, as derived from T (tumour), N (nodal) and M (metastatic) status: the equivalent Dukes’ staging is also shown.

Table 3.2.3 The different

de Gramont

chemotherapy regimens used in the treatment of metastatic colorectal cancer.

Section 3-Chapter 3

Table 3.3.1 Five‐year survival according to leukaemia type (for

C

L

L

and

C

M

L

in patients under the age of 14 years as there is no meaningful survival data as these diseases are rare in this subgroup).

Section 3-Chapter 4

Table 3.4.1 The seventh revision of the

T

N

M

classification of lung cancer, as proposed by the Union for International Cancer Control.

Table 3.4.2 Lung cancer number staging, as derived from T (tumour), N (nodal) and M (metastatic) status.

Section 3-Chapter 5

Table 3.5.1 The seventh revision of the

T

N

M

classification of oesophageal cancer, as proposed by the Union for International Cancer Control.

Table 3.5.2 Oesophageal cancer number staging, as derived from T (tumour), N (nodal), and M (metastatic) status.

Section 3-Chapter 6

Table 3.6.1 The

FIGO

staging system for ovarian cancer.

Table 3.6.2 The seventh revision of the

T

N

M

classification of ovarian cancer, as proposed by the Union for International Cancer Control.

Table 3.6.3 Ovarian cancer number staging, as derived from T (tumour), N (nodal), and M (metastatic) status.

Table 3.6.4 Five‐year survival rates for epithelial ovarian cancer (note that these statistics are based upon the old

FIGO

staging system, not the most recent version).

Section 3-Chapter 7

Table 3.7.1 Signs and symptoms associated with functioning

endocrine

pancreatic tumours.

Table 3.7.2 The seventh revision of the

T

N

M

classification of pancreatic cancer, as proposed by the Union for International Cancer Control.

Table 3.7.3 Pancreatic cancer number staging, as derived from T (tumour), N (nodal), and M (metastatic) status.

Table 3.7.4 Pancreatic cancer 5‐year survival rates.

Section 3-Chapter 8

Table 3.8.1 The seventh revision of the

T

N

M

classification of prostate cancer, as proposed by the Union for International Cancer Control.

Table 3.8.2 Prostate cancer stages, as derived from T (tumour), N (nodal), M (metastasis), PSA level, and Gleason score.

Table 3.8.3 Risk categories for localised prostate cancer.

Section 3-Chapter 9

Table 3.9.1 The seventh revision of the

T

N

M

classification of non‐melanoma cancer, as proposed by the Union for International Cancer Control.

Table 3.9.2 Non‐melanoma skin cancer stages, as derived from T (tumour), N (nodal), and M (metastatic) status.

Table 3.9.3 The seventh revision of the

T

N

M

classification of malignant melanoma cancer, as proposed by the Union for International Cancer Control.

Table 3.9.4 Malignant melanoma skin cancer stages, as derived from T (tumour), N (nodal), and M (metastatic) status.

Section 3-Chapter 10

Table 3.10.1 Serum tumour markers.

Table 3.10.2 The seventh revision of the

T

N

M

classification of testicular cancer, as proposed by the Union for International Cancer Control.

Table 3.10.3 Testicular cancer number staging, as derived from T (tumour), N (nodal), M (metastasis), and S (serum) status.

List of Illustrations

Section 1-Chapter 1

Figure 1.1.1 Estimated age‐standardised (a) cancer incidence and (b) cancer‐related mortality rates per 100,000 population in regions of the world in 2012 [3]. Northern Europe incorporates the UK and Scandinavia; South‐Central Asia incorporates Iran, Iraq, Afghanistan, Pakistan, and India; Eastern Asia incorporates China, Taiwan, Japan, North Korea, South Korea, and Mongolia; South‐eastern Asia incorporates Laos, Myanmar, Philippines, Thailand, Vietnam, Malaysia, Singapore, and Indonesia.

Figure 1.1.2 Estimates of the 20 most commonly diagnosed cancers Worldwide in 2012 (http://globocan.iarc.fr/Pages/fact_sheets_population.aspx). CNS, central nervous system.

Section 1-Chapter 2

Figure 1.2.1 Nomenclature of mesenchymal‐derived tumours.

Figure 1.2.2 Nomenclature of epithelial tumours.

Figure 1.2.3 Colonic adenocarcinoma. (a) Surgically resected caecum, indicating a tumour (white mass) around two‐thirds of the colonic circumference. The tumour was diagnosed histopathologically as a moderately differentiated adenocarcinoma: (b) low magnification; (c) high magnification. This malignant tumour had invaded from the epithelial layer of the caecum through the underlying muscle tissue.

Figure 1.2.4 Cervical squamous dysplasia. Whereas the epithelium is normal and stratified on the left of the image, from the centre across to the right the cells are dysplastic, with a disorderly pleomorphic appearance and abnormally large nuclei. The dysplastic process involves the full thickness of the epithelium, but the basement membrane remains intact. (Courtesy of Ed Uthman from Houston, TX, USA under the Creative Commons Attribution 2.0 generic licence.)

Figure 1.2.5 Microscopic view of transitional cell carcinomas of the urinary bladder, indicating different levels of cellular differentiation and tumour grade. Increased pleomorphism and increased nuclear‐to‐cytoplasmic ratio is visible with increasing grade and decreasing differentiated status.

Figure 1.2.6 Metastatic tumours in the liver. A cross‐section of liver containing several pale tumour deposits, originating from primary pancreatic adenocarcinoma.

Figure 1.2.7 Identification by ultrasound imaging of hepatic metastases of an ovarian carcinoma (identified by the arrow).

Figure 1.2.8 CT scan (axial cross‐section) through the thorax. A large adenocarcinoma tumour mass is located in the periphery of the left lung. (Image provided by Yale Rosen under the Creative Commons Attribution‐Sharealike Licence 2.0 via Wikimedia Commons.)

Figure 1.2.9 CT scan through the upper abdomen. Characteristic appearance of metastatic deposits on a contrast‐enhanced axial CT scan. Deposits appear as negative defects against the normally enhanced liver. (Image provided by James Heilman under the Creative Commons Attribution‐Sharealike Licence 3.0 via Wikimedia Commons.)

Figure 1.2.10 MRI scan showing metastatic lung cancer deposit in brain. (Image provided by Nevit Dilmen under the Creative Commons Attribution‐Sharealike Licence 3.0.)

Figure 1.2.11 MRI scan showing a large brain‐stem tumour in a 4‐year old patient: (a) sagittal view, without contrast, and (b) axial view, with contrast. (Image provided by Tdvorak under the Creative Commons Attribution‐Sharealike Licence 4.0.)

Figure 1.2.12 PET/MRI imaging of metastatic colon cancer.

Top

, transaxial MRI indicating two low signal masses in the liver;

middle

, contrast‐enhanced (gadoxetate disodium) transaxial MRI image indicating enhancement of the liver masses, consistent with metastatic colon cancer;

bottom

, PET/MRI image indicating high‐intensity FDG activity, confirming the presence of malignant deposits. The specificity of the methodology is shown by the detection of a mass by MRI (red circle, top image) with lack of PET‐detectable metabolic activity (red circle, lower image). Mass identified as a benign haemorrhagic cyst. (Image obtained from Matthews

et al

. [35] under the Creative Commons Attribution License.)

Section 1-Chapter 3

Figure 1.3.1 Numbers of somatic mutations in representative human cancers. The genomes of a diverse group of

paediatric

and adult (including specific

female

and

male

) cancers were analysed by genome‐wide sequencing. Numbers in brackets indicate the median number of non‐synonymous mutations per tumour (adapted from [6]). NSCLC, non–small cell lung cancers; SCLC, small cell lung cancers; AML, acute myeloid leukaemia; ALL, acute lymphoblastic leukaemia.

Figure 1.3.2 Distribution of mutations in oncogenes and tumour suppressor genes. The distribution of

missense

and

truncating

mutations in a representative oncogene,

PIK3CA

, and suppressor gene,

RB1

. The data were collected from genome‐wide studies annotated in the COSMIC database (release version 61). PIK3CA, phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha; ABD,

N

‐terminal adaptor binding domain; RBD, Ras‐binding domain; C2, protein kinase C homology‐2 domain; RB, retinoblastoma; T‐Ag, SV40 large T‐antigen protein; E1A, adenovirus E1A protein; E4F1, transcription factor E4F1.

Figure 1.3.3 Familial adenomatous polyposis (FAP). Multiple intestinal polyps within the sigmoid colon indicative of FAP, as detected endoscopically. (Provided under the terms of the GNU Free Documentation License Version 1.2.)

Figure 1.3.4 The central role of the p53 tumour suppressor in the governance of cellular functions. p53 responds to a wide range of stress signals (some of which are shown here) and responds by either positively or negatively regulating diverse cellular processes, maintaining tumor suppression (protein structures from PDB,

2

IDs, 1TUP, and 1YCR).

Figure 1.3.5 Epigenetic control of gene transcription. DNA (red and blue helices) wrapped around an octamer of histone proteins creates a nucleosome. (a) DNA methylation and modification of histone tails, by removal of acetyl groups, induces a closed‐chromatin configuration and transcriptional repression. (b) Demethylation of DNA and addition of acetyl (Ac) groups to histones relax chromatin, allowing transcriptional activation. Acetylation is regulated by opposing actions of

histone acetyltransferases (HATs)

and

deacetylases (HDACs)

. Methyl‐binding proteins, such as

MECP2 (methyl‐CpG‐binding protein)

, target methylated DNA and recruit HDACs. Ac, acetyl; Me, methyl; 5mC, 5‐methylcytosine; P, phosphate. (DNA–protein structure from PDB, ID 5B2J.)

Figure 1.3.6 Multistage tumourigenesis in the development of colorectal carcinoma. Tumour initiation is a result of gaining mutations in the adenomatous polyposis coli (

APC

) tumour suppressor gene. Mutations in an oncogene, such as

K‐Ras

, increases the hyperproliferative capacity, genomic instability, and survival advantage of the benign adenoma. Further progressive mutations (and epigenetic modifications) in several other genes, such as the

PIK3CA

oncogene and pathways associated with the transforming growth factor‐beta (TGF‐β) signalling pathway (e.g. SMAD4) or cell cycle and apoptosis (e.g. p53) thereafter cause tumour progression and malignant development. Although depicted as a linear process, the accumulation of the genetic changes can occur in any order, until all required molecular pathways are affected.

Figure 1.3.7 Hallmarks of cancer and enabling characteristics

Figure 1.3.8 Molecular regulation of the cell cycle. The cell cycle comprises four (or five, if G

0

is included) phases, each regulated by the concerted activity of specific cyclins and CDKs. Binding of cyclin D to CDK4/CDK6 progresses the cell through the initial gap phase (G

1

) in preparation for DNA synthesis. Through G

1

, cyclin D‐CDK4/6 levels diminish and levels of cyclin E‐CDK2 increase. The cell then arrives at the G

1

–S checkpoint, where an assessment of ‘readiness’ and DNA integrity is completed, prior to progression into the DNA synthesis phase (S phase). Degradation of cyclin E and release of CDK2 initiate S phase. Progression through S phase is achieved by cyclin A‐CDK2, thereafter the cell enters the second gap phase (G

2

) involving cyclin A‐CDK1. The cell reaches a second checkpoint (G

2

–M) to verify successful DNA synthesis and mitotic readiness. The level of cyclin B increases at the start of mitosis and diminishes at end of the M phase, with the inactivation of CDK1 due to decreasing cyclin B triggering completion of the cell cycle. Throughout the cell cycle, the activity and function of CDKs is further kept in check by endogenous inhibitors (p16

INK4a

, p27

kip1

etc.). After the cycle is completed, the cell either undergoes another replicate cycle or withdraws and enters quiescence (G

0

phase).

Figure 1.3.9 After stimulation of the

EGFR

by growth factors (ligands), it

dimerises

and a series of processes result in the activation of RAS, which then initiates a phosphorylation cascade of MAP kinases, leading to phosphorylation and activation of ERK (MAPK). Both RAS and RAF are often found to be mutated, resulting in their constitutive activation in various tumours. (Protein structures from PDB, IDs: 1NQL, 2M0B, and 2ITX.)

Figure 1.3.10 Extrinsic and intrinsic pathways of apoptosis. Cellular stress (e.g. DNA damage by radiotherapy/chemotherapy) activates the intrinsic pathway via

p53

; pro‐apoptotic

Bax

and

Bak

subsequently permeabilise the outer mitochondrial membrane, resulting in efflux of

cytochrome c

, which binds to the adaptor Apaf‐1 to recruit the initiator procaspase 9 into a signalling complex termed the

apoptosome

. Activated

caspase 9

then cleaves and activates the effector

caspases 3

,

6

, and

7

to trigger apoptosis. Cytotoxic immune cells produce pro‐apoptotic ligands such as TNF‐related apotosis‐inducing ligand (

TRAIL

), which binds to the pro‐apoptotic

death receptors

(DR4 and/or DR5) on the surface of a target cell. Ligand binding induces recruitment of an adaptor protein and the initiator

caspases 8

and

10

as pro‐caspases, forming a death‐inducing signalling complex. This eventually triggers the activation of the effector

caspases 3

,

6

, and

7

. (Constructed using protein structures from the PDB, IDs: 1NQL, 1TUP, 2BID, 2M0B, 2ITX, 4NBL, 4S0P, 5CIR, 5I9B, 5ITD, 5IY5, and 5FMJ.]

Figure 1.3.11 Tumour angiogenesis. Tumour cells release pro‐angiogenic factors (e.g.

VEGF

), which bind to receptors on the endothelial cells of pre‐existing blood vessels (

VEGFR

) and initiate their activation. This leads to secretion and activation of proteolytic enzymes, for example

MMPs

, which degrade ECM, allowing migration of endothelial cells. The existing vasculature is supported by pericytes, whereas the developing angiogenic blood vessel secretes growth factors, for example

platelet‐derived growth factor

(

PDGF

), which attracts supporting cells and pericytes to stabilise the new vessel. (Constructed using protein structures from PDB, IDs: 3MJG, 3V2A, 5B5O.)

Figure 1.3.12 Therapeutic targeting of the hallmarks of cancer. There are now many approaches in the clinic or in the development pipeline for the treatment of cancer, each of which targets one of the known or emerging hallmarks of cancer or the enabling characteristics. The targets indicated are indicative examples, with many more drugs being developed against different targets within most of these hallmarks. EGFR, epidermal growth factor receptor; HGF, hepatocyte growth factor; VEGF, vascular endothelial growth factor; PARP, poly‐(ADP ribose) polymerase.

Section 2-Chapter 1

Figure 2.1.1.1 Examples of

mustards

and a

nitrosourea

used clinically.

Figure 2.1.1.2 Sulfur and (the earliest) nitrogen mustards.

Figure 2.1.1.3 1‐Methyl‐3‐nitro‐1‐nitrosoguanidine (NSC‐9369).

Scheme 2.1.1.1 Original synthesis of melphalan.

Scheme 2.1.1.2 Original synthesis of cyclophosphamide [11].

Scheme 2.1.1.3 Synthesis of carmustine (BCNU) [13].

Scheme 2.1.1.4 Interstrand crosslink formation, using

N

7

‐guanine‐alkyl‐

N

7

‐guanine

16

as an example.

Scheme 2.1.1.5 The metabolic activation of cyclophosphamide.

Scheme 2.1.1.6 Activation of the nitrosoureas to bifunctional alkylators [21,22].

Scheme 2.1.1.7 Mechanism for the formation of interstrand crosslinks from nitrosoureas [24,25].

Figure 2.1.1.4 Interstrand crosslink repair during the G1 phase.

Figure 2.1.2.1 The

imidazo

tetrazinones

mitozolomide and TMZ.

Scheme 2.1.2.1 Original imidazotetrazinone synthesis [3,6].

Scheme 2.1.2.2 Synthesis of substituted imidazotetrazinones via nor‐TMZ

7

[7].

Figure 2.1.2.2 The anticancer agents dacarbazine and TMZ.

Scheme 2.1.2.3 Metabolic activation of dacarbazine.

Scheme 2.1.2.4 Conversion of TMZ to the methyldiazonium ion.

Scheme 2.1.2.5 Adducts from the TMZ alkylation of DNA.

Figure 2.1.2.3 Hydrogen bonding in

G

–

C

and

O

6

‐methyl G

–

T

(

O

6

‐MeG

‐

T

) base pairs.

Figure 2.1.2.4 Base flipped

O

6

‐methylguanine

in the active site of

O

6

‐alkylguanine DNA‐alkyltransferase

(PDB 1 T38) [22].

Scheme 2.1.2.6 Removal of

O

6

‐alkyl adducts by MGMT [21].

Figure 2.1.2.5 BER pathway for removal of

N

3

‐methyladenine

.

Figure 2.1.3.1 The platinum anticancer agents.

Scheme 2.1.3.1 Preparation of cisplatin by the method of Dhara [10].

Scheme 2.1.3.2 Synthesis of carboplatin [11].

Scheme 2.1.3.3 Synthesis of oxaliplatin [12].

Figure 2.1.3.2 Mechanism of action of cisplatin (adapted from Kelland [14]).

Scheme 2.1.3.4 Formation of cisplatin–DNA GpG adducts.

Figure 2.1.3.3 X‐ray structure of high‐mobility‐group protein 1 (HMG1) binding to cisplatin‐modified DNA (PDB 1CKT), showing GpG adduct [17]. DNA strands,

red

and

blue

; HMG1,

pink

; Pt,

grey

; ammonia ligands,

purple

.

Figure 2.1.3.4 NER mechanism. HR23B, human homologue of yeast Rad23 protein; XPA, C, F and G,

Xeroderma pigmentosum

complementation group A, C, F and G proteins; ERCC1, excision repair cross‐complementing rodent repair deficiency complementation Group 1 protein; XRCC1, X‐ray repair cross‐complementing protein 1; PCNA, proliferating cell nuclear antigen; Lig 3, DNA ligase IIIα; Polδ, ε, κ, DNA polymerases δ, ε, κ; TFIIH, transcription factor II human; RPA, replication protein A.

Scheme 2.1.4.1 Metabolism of gemcitabine [1].

Scheme 2.1.4.2 Original synthesis of gemcitabine [2].

Scheme 2.1.4.3 Masked chain termination by gemcitabine [6,7].

Scheme 2.1.4.4 Proposed mechanism for nucleotide diphosphate reduction to deoxynucleotide diphosphate by

RNRs

[10].

Scheme 2.1.4.5 Gemcitabine inhibition of RNRs [11].

Figure 2.1.5.1 Camptothecin, topotecan, and irinotecan.

Scheme 2.1.5.1 Formation of the sodium salt of CPT.

Scheme 2.1.5.2 Synthesis of (

S

)‐CPT [6].

Scheme 2.1.5.3 Conversion of CPT to topotecan.

Scheme 2.1.5.4 Irinotecan and its metabolite SN38.

Figure 2.1.5.2 Crystal structure of the B‐DNA dodecamer C‐G‐C‐G‐A‐A‐T‐T‐C‐G‐C‐G (PDB 2BNA) [11].

Figure 2.1.5.3 Crystal structure of a DNA–TOP I complex (PDB 1A36) [12].

Figure 2.1.5.4 TOP I‐catalysed cleavage of DNA supercoils (adapted from [10]). (a) TOP I acting on supercoiled DNA via a cleavage (or cleavable) complex to give relaxed DNA in preparation for replication. (b) Overview of the relaxation process at the cleavage complex, showing nicking (cutting of one strand), rotation of the strand, and religation.

Scheme 2.1.5.5 DNA strand nicking/religation by TOP I.

Figure 2.1.5.5 CPT intercalation into base‐pairs flanking the DNA cleavage site [16].

20

To prevent the religation of the scissile strand, the X‐ray structure was determined with a thiodeoxyguanine residue at the 5′‐end of the DNA strand.

Figure 2.1.5.6 DNA–TOP I–CPT ternary complex (PDB 1T8I). DNA strands are shown in

red (scissile)

and

blue (non‐scissile)

, and TOP I in

pink

. Carbon atoms of CPT are

grey

, those of TOP I amino acid residues are

green

, and those of the non‐scissile DNA strand adenine are white. The distances (in Å) between proposed hydrogen bonded contacts are shown by dashed lines [15,16].

Figure 2.1.5.7 Collision of replication fork with TOP I cleavage complex, generating TOP I irreversible complex and double‐strand breaks (adapted from [10]). In both the leading and lagging strands, the last bases paired by the DNA polymerase are coloured.

Figure 2.1.6.1 Podophyllotoxins.

Figure 2.1.6.2 Podophyllotoxin (PBG) and

4′‐

d

emethyl

e

pi

p

odophyllotoxin

b

enzylidene

g

lucosides (DEPBG).

Scheme 2.1.6.1 Semi‐synthetic route to DEP from podophyllotoxin [7].

Scheme 2.1.6.2 Conversion of DEP to 4′‐demethylepipodophyllotoxin glucoside (DEPG) [9].

Scheme 2.1.6.3 Cyclic acetal formation to give etoposide or teniposide [10].

Figure 2.1.6.3 TOP II‐catalysed DNA decatenation, with the DNA gate (G), formed by the TOP II double‐strand cleavages in the red/blue duplex, highlighted in yellow. The transported segment (T) of the purple/orange duplex moves through the G segment from back to front, thereby decatenating the DNA duplex circles [12,13].

Figure 2.1.6.4 Crystal structure of TOP II (PDB 4GFH) [15].

Figure 2.1.6.5 TOP II reaction cycle

Figure 2.1.6.6 Crystal structure of the ternary cleavage complex formed between etoposide, DNA and TOP II (PDB 3QX3). The two TOP II monomeric units are shown in

orange

and

pink

[14].

Figure 2.1.6.7 Close up of

etoposide

–DNA–TOP II complex, showing the scissile strand on right and the increased separation between the 3′‐OH and TYR821‐phosphate bond which prevents religation (PDB 3QX3). For clarity, only some of the DNA bases and the TYR821 of the TOP II (white) are shown. Etoposide has a sequence specificity for cytosine (dC) at the 3′‐terminus (‐1 base) [14].

Figure 2.1.7.1 Anthracycline anticancer agents.

Figure 2.1.7.2 Rhodomycin A.

Figure 2.1.7.3 Daunomycinone (aglycone)and daunosamine.

Scheme 2.1.7.1 Wong synthesis of racemic daunomycinone [10,11].

Scheme 2.1.7.2 Functionalisation of ring

A

[11]. Note that these steps were not simultaneous in the original synthesis as some of the other functional group interconversions in rings

B–D

take place at the same time. To simplify this scheme, only ring

A

is shown and the ⧙ indicates that we are not concerning ourselves with what is happening in the remainder of the anthraquinone skeleton. PTSA,

para

‐toluenesulfonic acid, an acid catalyst.

Scheme 2.1.7.3 Swenton asymmetric synthesis of (+)‐daunomycinone [9].

Scheme 2.1.7.4 Annelation of rings

C

and

D

via Michael addition of an

isobenzofuranone anion

19

onto

enone

18

[9].

Scheme 2.1.7.5 Mechanism for the regiospecific formation of daunomycinone via the Michael addition.

Figure 2.1.7.4 Intercalation of daunomycin (white) into DNA (PDB 1D10): (a) looking from the minor groove along the main axis of the anthraquinone and (b) the major groove on the left, the minor groove on the right [16].

Figure 2.1.8.1 Epigenetic targeting agents.

Figure 2.1.8.2 Polar small molecule inducers of cytodifferentiation.

Scheme 2.1.8.1 Original synthesis of decitabine [13,14].

Scheme 2.1.8.2 Synthesis of azacitidine [16].

Scheme 2.1.8.3 Original synthesis of vorinostat [17].

Figure 2.1.8.3 The crystal structure of a nucleosome containing CpG methylated DNA viewed (a) from above and (b) from the side: histone 2a proteins (H2a; two shades of yellow), histone 2b proteins (H2b; two shades of green), histone 3 proteins (H3; two shades of pink), and histone 4 proteins (H4; two shades of turquoise), [PDB 5B2J].

Figure 2.1.8.4 The structures of (a) heterochromatin (which contains high levels of 5‐methylcytosine [5mC]) and (b) euchromatin (showing acetylated [Ac] histone lysines).

Scheme 2.1.8.4

DNMT

‐catalysed methylation of cytosine (residues shown in

blue

are part of the enzyme active site and

B

represents a phosphate group from the DNA backbone) using SAM as the methyl group donor [27].

Figure 2.1.8.5 Cytosine (C) flipped out of the double helix and into a pocket of the

Hha

I methyltransferase

, leaving behind an unpaired guanine (G) (PDB 3MHT). AH represents

S

‐adenosyl‐L‐homocysteine (AdoHcys) [28].

Scheme 2.1.8.5 Activation of the azanucleosides [30].

Scheme 2.1.8.6 Inhibition of DNMT by azacytidine [30].

Scheme 2.1.8.7 Demethylation of DNA by TET enzymes [34].

Scheme 2.1.8.8

Acetyl

ation of a lysine residue on a histone tail by histone acetyltransferases (HATs)

33

using acetyl‐CoA as the co‐factor [36].

Scheme 2.1.8.9 Proposed mechanism for histone deacetylation [37].

Figure 2.1.8.6 Vorinostat binding to histone deacetylase, showing (a) the hydroxamic group binding to the zinc atom (grey) and (b) the narrow tunnel leading to the zinc [PDN 4LXZ] [38].

Figure 2.1.8.7 Structural requirements for HDAC inhibitors.

Scheme 2.1.8.10 Decitabine activation and deactivation.

Section 2-Chapter 2

Figure 2.2.1.1 Cytarabine (ara‐C, cytosine arabinoside).

Figure 2.2.1.2 Spongothymidine (ara‐T, thymidine arabinoside).

Scheme 2.2.1.1 Original synthesis of ara‐C via 2,2'‐anhydrocytidine [3].

Scheme 2.2.1.2 Intracellular

activation

(by phosphorylation to its monophosphate [MP], then diphosphate [DP] and triphosphate active form [TP]) and

deactivation

(by deamination) of cytarabine [5].

Figure 2.2.2.1 The relationship between aminopterin, methotrexate, pemetrexed, raltitrexed, and folic acid.

Scheme 2.2.2.1 One‐pot synthesis of folic acid, aminopterin, or methotrexate [6,11].

Figure 2.2.2.2 Tautomerism and ionisation in the pteridine fragment of MTX.

Scheme 2.2.2.2 Conversion of folic acid

4

to enzyme co‐factors

N

5

,

N

10

‐CH

2

‐FH

4

7

,

N

5

,

N

10

‐CH‐FH

4

8

, and

N

10

‐CHO‐FH

4

9

. DHFR, dihydrofolate reductase; SHMT, serine hydroxymethyltransferase. MTHFD1 exhibits three different activities: (a) methylenetetrahydrofolate dehydrogenase, (b) methylenetetrahydrofolate cyclohydrolase, and (c) formyltetrahydrofolate synthetase.

Scheme 2.2.2.3 Interconversion of folate coenzymes (C1 donors) during pyrimidine and purine biosynthesis. DHFR, dihydrofolate reductase; MTX, methotrexate.

Scheme 2.2.2.4 GART‐catalysed formylation.

Scheme 2.2.2.5 AICART‐catalysed formylation.

Figure 2.2.2.3 Ternary complexes of (a) folic acid (F) [PDB 2W3M] and (b) MTX [PDB 1U72] with human DHFR (

blue ribbon

) and NADPH.

Scheme 2.2.2.6 Mechanism for the DHFR‐catalysed reduction of dihydrofolic acid [15].

Figure 2.2.2.4 Folinic acid.

Figure 2.2.2.5 Examples of oral mucostitis associated with MTX therapy: (a) ulceration of the right buccal mucosa and (b) ulceration of the lower labial mucosa. ([21], permissions obtained.)

Scheme 2.2.3.1 5FU and the conversion to its active form FdUMP.

Scheme 2.2.3.2 Part of the

de novo

synthesis of pyrimidines and the structure of 5‐fluoroorotic acid.

Scheme 2.2.3.3 Synthesis of 5FU [3].

Scheme 2.2.3.4 Simplified mechanism for the

thymidylate

synthase (TS)

‐catalysed methylation of dUMP to dTMP showing the likely involvement of

conserved amino acid residues

Figure 2.2.3.1 dUMP bound to the active site of human TS [6], showing catalytic residues (PDB 3HB8).

Scheme 2.2.3.5 Metabolism of 5FU.

Scheme 2.2.3.6 Conversion of capecitabine to 5FU [7].

Scheme 2.2.3.7

Thymidylate synthase (TS)

inhibition by 5FU.

Figure 2.2.3.2 Palmar‐plantar erythrodysesthesia (or hand‐foot syndrome) associated with capecitabine therapy: (a) erythema commonly associated with hand‐foot syndrome and (b) the skin blistering, cracking, and peeling (http://www.cancernetwork.com/articles/dermatologic‐adverse‐events‐associated‐systemic‐anticancer‐agents, (https://en.wikipedia.org/wiki/Chemotherapy‐induced_acral_erythema

).

Figure 2.2.4.1 6‐Mercaptopurine, showing the thioenol (containing a mercapto [thiol] group) and thioamide tautomeric forms.

Scheme 2.2.4.1 Synthesis of 6MP [3].

Scheme 2.2.4.2 Conversion of 6MP into its active forms: TIMP, MeTIMP, and TGMP. HGPRT1, hypoxanthine‐guanine phosphoribosyltransferase 1 (HGPRT1); TPMT, thiopurine

S

‐methyltransferase; IMPDH, inosine monophosphate dehydrogenase; GMPS, guanine monophosphate synthetase; TIMP, thioinosine monophosphate; MeTIMP, 6‐methylthioinosine monophosphate; TXMP, thioxanthosine monophosphate; TGMP, thioguanosine monophosphate [6,7].

Scheme 2.2.4.3 Conversion of IMP to AMP.

Scheme 2.2.4.4 Conversion of PRPP to PRA, catalysed by PPAT.

Scheme 2.2.4.5 Conversion of TGMP to dTGMP.

Figure 2.2.4.2 Futile cycle of DNA mismatch repair induced by incorporation of 6TdG.

Section 2-Chapter 3

Scheme 2.3.1.1 Identification of the components of paclitaxel via methanolysis and X‐ray structure determination [4].

Figure 2.3.1.1 Taxane anticancer agents.

Figure 2.3.1.2 10‐Deacetylbaccatin III

5

: (a) showing the relationship to the paclitaxel core and (b) three‐dimensional representation showing the three secondary hydroxyl groups (at C7, C10, and C13).

Figure 2.3.1.3

Taxus baccata

(created 8 Mar 2008 by Frank Vincentz; http://commons.wikimedia.org/wiki/File:Taxus_baccata_01_ies.jpg).

Scheme 2.3.1.2 Semi‐synthesis of paclitaxel from 10‐deacetylbaccatin III [7]. DPC, di‐2‐pyridyl carbonate; DMAP, 4‐dimethylaminopyrdine.

Scheme 2.3.1.3 Synthesis of docetaxel by the β‐lactam coupling method [9].

Scheme 2.3.1.4 Mechanism for β‐lactam ring‐opening.

Figure 2.3.1.4 Structure–anticancer activity relationship for taxane anticancer agents [10].

Figure 2.3.1.5 Eukaryotic cell cycle. Mitosis stages:

P

, prophase;

M

, metaphase;

A

, anaphase;

T

, telophase;

C

, cytokinesis.

Figure 2.3.1.6 Sister chromatids (duplicated chromosome pair).

Figure 2.3.1.7 The stages involved in mitosis.

Figure 2.3.1.8 Microtubule (b) formation by the polymerisation of tubulin heterodimers (a) and the taxane binding site (c).

Figure 2.3.1.9 Paclitaxel (grey/red/blue ball and stick model) binding to the β‐tubulin subunit of an α,β‐tubulin dimer (PDB 1JFF).

GDP

and

GTP

are shown bound into the

β

‐ and

α

‐tubulin subunits [16].

Figure 2.3.1.10 Spontaneous bruising (a) and bleeding (b) associated with thrombocytopenia (https://en.wikipedia.org/wiki/Thrombocytopenia).

Figure 2.3.2.1 The vinca alkaloids in clinical use.

Scheme 2.3.2.1 Coupling of catharanthine and vindoline using Polonovski‐type conditions [8].

Scheme 2.3.2.2 Conversion of anhydrovinblastine to vinorelbine [10].

Figure 2.3.2.2

Vinblastine

binding at the plus end of microtubules. Vinblastine binds with greatest affinity at the extreme end of the microtubule (a) and with decreased affinity to tubulin which is buried within the lattice (b).

Figure 2.3.2.3 Vinblastine binding at the region between

β

‐ and

α

‐tubulin subunits (PDB 5J2T) [16].

Section 2-Chapter 4

Figure 2.4.1.1 The non‐steroidal anti‐androgenic agent bicalutamide.

Scheme 2.4.1.1 Testosterone reduction to dihydrotestosterone by 5α‐reductase.

Figure 2.4.1.2 The synthetic non‐steroidal anti‐androgens flutamide and its metabolite hydroxyflutamide [6].

Scheme 2.4.1.2 Original synthesis of bicalutamide [11].

Scheme 2.4.1.3 Synthesis of (

R

)‐bicalutamide [12].

Figure 2.4.1.3 X‐ray crystal structure of dihydrotestosterone (DHT) binding to the ligand binding domain of the AR showing (a) the helices and methionine 895 (M) and tryptophan 741 (W), and (b) important amino acids (R752, Q711, N705, and T877) and key water molecules for hydrogen bonding (PDB 4OEA) [15].

Figure 2.4.2.1 The selective oestrogen‐receptor modulator (SERM) tamoxifen.

Figure 2.4.2.2 The primary female sex hormone, 17β‐oestradiol.

Figure 2.4.2.3 The first synthetic non‐steroidal anti‐oestrogen, ethamoxytriphetol.

Scheme 2.4.2.1 Synthesis of tamoxifen isomers.

Scheme 2.4.2.2 Stereoselective tamoxifen synthesis [13].

Figure 2.4.2.4 Binding of (a) 17β‐oestradiol (PDB 1ERE) [16] and (b) hydroxytamoxifen (PDB 3ERT) [14] within the ER LBD. (17β‐oestradiol and tamoxifen are represented by silver/red ball‐and‐stick diagrams.)

Figure 2.4.2.5 (a) Hydrogen bonding (white lines) of 17β‐oestradiol (PDB 1ERE) [16] and (b) hydrogen bonding (white lines) and salt bridge formation (yellow line) by 4‐hydroxytamoxifen (PDB 3ERT) [14] within the ER LBD.

Scheme 2.4.2.3 Phase I metabolism of tamoxifen to 4‐hydroxytamoxifen and endoxifen [21,22].

Figure 2.4.3.1 The aromatase inhibitor anastrozole.

Figure 2.4.3.2 The common structural features of the progestogens, androgens, and oestrogens.

Figure 2.4.3.3 The aromatase inhibitors aminoglutethimide and fadrozole.

Scheme 2.4.3.1 The production of estrogens from androgens through the action of aromatase (CYP19) and 17‐β‐hydroxysteroid dehydrogenase (17β‐HSD).

Scheme 2.4.3.2 Synthesis of anastrozole [12,15].

Scheme 2.4.3.3 Oxidation of a substrate (

R‐H

) by CYP450. 1, Ferric‐haem CYP450 binds reversibly with substrate (

R‐H

) resulting in an enzyme‐substrate type complex; 2, the substrate complex undergoes a one‐electron reduction to a ferrous complex. The

electron

originating from NADPH and transferred by flavoprotein (NADPH‐CYP450 reductase) from a FNMH

2

/FADH complex; 3, the reduced complex binds oxygen as the sixth ligand to form an oxyCYP450 (ferric) complex; 4, oxyCYP450 is reduced to a ferric peroxyCYP450 complex (again requiring the transfer of an

electron

from the flavoprotein); 5, ferric peroxyCYP450 undergoes heterolytic cleavage to give water and the catalytically active intermediate; 6, abstraction of a hydrogen from the substrate to give a carbon‐based radical (

R

•); 7, radical combination (

R

• and •

O

H) gives the oxidised product (

R

O

H) and the regenerated initial complex.

Figure 2.4.3.4 Androstenedione bound to active site of human placental aromatase (PDB 3EQM) [17,18].

Figure 2.4.3.5 The triazole antifungal fluconazole binding to the haem‐iron of CYP51 (PDB 1EA1) [19].

Section 2-Chapter 5

Figure 2.5.1 Receptor kinase inhibitors.

Scheme 2.5.1 Phosphorylation on tyrosine is catalysed by tyrosine kinases.

Figure 2.5.2 Cartoon representations of the structure of (a) the

inactive EGFR

(constructed using PDB files 1NQL, 2M0B, and 2ITX) and (b)

the dimeric active EGFR

with bound TGF‐α [yellow] (constructed using PDB files 1IVO, 2M0B, and 2GS6). The

dimerisation arm

is shown in cerise and the structures of the regions in black have not been determined.

Figure 2.5.3 Examples of the downstream EGFR signalling pathways [12,13]. PI3K, phosphoinositide 3‐kinase; AKT, protein kinase B; JAK, Janus kinase; STAT, signal transducer and activator of transcription.

Figure 2.5.4 General structure of the natural product erbstatin and the synthetic tyrphostins.

Figure 2.5.5 Anilinoquinazoline EGFR tyrosine kinase inhibitors.

Figure 2.5.6 The indolin‐2‐ones semaxinib (SU5416; a selective VEGFR‐2 inhibitor) and orantinib (SU6668; a selective PDGFR‐β inhibitor).

Scheme 2.5.2 Preparation of the quinazoline portion of gefitinib [24].

Scheme 2.5.3 Gefitinib synthesis [20].

Scheme 2.5.4 Knorr pyrrole synthesis [22].

Scheme 2.5.5 Sandmeyer isatin synthesis [25].

Scheme 2.5.6 Sunitinib synthesis [22].

Figure 2.5.7 X‐ray structure of gefitinib bound to the ATP‐binding site of the EGFR kinase domain showing (a) methionine 793 (M), to which it forms its only hydrogen bond, and threonine 790 (T), and (b) the key amino acids for the interaction of ATP with the receptor. (PDB 2ITY) [26].

Figure 2.5.8 VEGFR‐2 in (a) the active DFG

in

(PDB 3B8R) [30] and (b) the inactive DFG

out

(PDB 4AGD) [31] conformations. Some of the residues in the ATP binding pocket are shown at the rear (labelled in pink).

Figure 2.5.9 Sunitinib binding to the ATP‐binding site of the VEGFR‐2 showing (a) the amino acids responsible for ATP‐binding and (b) the effect of sunitinib binding on the conformation of the activation loop (PDB 4AGD) [31].

Figure 2.5.10 Hair‐related changes associated with erlotinib therapy: (a) 3 weeks after starting erlotinib treatment showing an acneiform rash; (b) the same patient one year later, showing significant improvement in the rash, but development of thin, fine brittle hair

Figure 2.5.11 Increased eyelash growth in a patient taking erlotinib (a condition often referred to as eyelash trichomegaly); images were taken at 2 month intervals

Section 3-Chapter 1

Figure 3.1.1 Anatomy of the breast, showing the ducts and lobules. In

D

C

I

S

the cancer cells are contained within the ducts, while in

L

C

I

S

the cancer cells are contained within the lobules (http://archive.cnx.org/contents/d4af489c‐1473‐45a2‐ad71‐9db44d79d355@1/ou‐human‐physiology‐anatomy‐and‐physiology‐of‐the‐female‐reproductive‐system).

Figure 3.1.2 Example of an inverted nipple associated with breast cancer (http://images.sciencesource.com/preview/14758222/SQ1847.html). Reproduced with kind permission of Science Source.

Figure 3.1.3

Peau d’orange

observed in breast cancer (https://sites.google.com/site/breastproblems/breast‐cancer/symptoms).

Figure 3.1.4 Mammogram of a breast revealing a tumour.

Figure 3.1.5 An MRI scan showing a large invasive breast tumour in a 64‐year‐old female patient (a) before chemotherapy and (b) after chemotherapy. You can see how after chemotherapy the tumour reduced in size, while the blood vessels supplying the tumour have also significantly reduced in size (http://www.nature.com/articles/srep33832 under Creative Commons Attribution 4.0 International License).

Figure 3.1.6 Lymphoedema of the left arm post breast surgery (http://www.intechopen.com/books/breast‐reconstruction‐current‐perspectives‐and‐state‐of‐the‐art‐techniques/treatment‐of‐breast‐cancer‐related‐lymphedema‐using‐combined‐autologous‐breast‐reconstruction‐and‐au).

Section 3-Chapter 2

Figure 3.2.1 (a) A healthy bowel, imaged by a barium enema. (b) An ‘apple core sign’ suggestive of colorectal cancer, imaged by a barium enema. This is where a short segment of the colon has abrupt shouldered margins, resembling an apple core (https://en.wikipedia.org/wiki/Double‐contrast_barium_enemahttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769347/http://www.suggest‐keywords.com/Y29sb24gc3RyaWN0dXJl/).

Figure 3.2.2 A polyp identified in the colon during sigmoidoscopy screening (https://en.wikipedia.org/wiki/Colonoscopy).

Section 3-Chapter 3

Figure 3.3.1 A schematic representation showing the development of different blood cells. (https://en.wikipedia.org/wiki/Haematopoiesis#/media/File:Hematopoiesis_simple.svg).

Figure 3.3.2 Carcinogenic metabolites of benzene.

Figure 3.3.3 Skin lesions associated with leukaemia cutis (http://www.dermnetnz.org/topics/leukaemia‐cutis).

Source:

Reproduced with kind permission of DermNet NZ.

Figure 3.3.4 A bone marrow aspiration showing acute myeloid leukaemia. Note the small rod‐shaped structures within some of the blasts. These are known as Auer rods and consist of crystalline forms of myeloperoxidase (https://en.wikipedia.org/wiki/Auer_rod#/media/File:Myeloblast_with_Auer_rod_smear_2010‐01‐27.JPG).

Figure 3.3.5 A piece of chromosome 9 and a piece of chromosome 22 break off and swap places. A new gene, known as the

BCR‐ABL

gene, is formed on chromosome 22. The changed chromosome 22 is abnormally shorter than usual and is called the Philadelphia chromosome.

Section 3-Chapter 4

Figure 3.4.1 Histopathological images of lung cancer showing large cell carcinoma (a) and small cell lung carcinoma (b). Note the large, round cells in the top image, compared to the bottom image (https://en.wikipedia.org/wiki/Large‐cell_lung_carcinoma) (https://en.wikipedia.org/wiki/Small‐cell_carcinoma). Used under CC‐BY‐3.0 https://creativecommons.org/licenses/by‐sa/3.0/deed.en.

Figure 3.4.2 Some of the chemicals found in cigarette smoke.

Figure 3.4.3 DNA adduct formation with

acrolein

(a carcinogen present in cigarette smoke). See Wang

et al

. for more information [11].

Figure 3.4.4 (a) Finger clubbing and (b) superior vena cava obstruction showing distended veins in the chest, both of which can be associated with lung cancer (http://en.wikipedia.org/wiki/Nail_clubbing

,

https://commons.wikimedia.org/wiki/File:Superior.vena.cava.syndrome.aak.jpg

).

Figure 3.4.5 The various diagnostic techniques used in a patient who had suspected lung cancer: (a) a chest X‐ray showing a mass in the right lung, (b) a 4 cm tumour confirmed by a CT scan, (c) a contrast enhanced CT scan demonstrating enlarged lymph nodes near to the tumour, and (d) PET‐CT staging showing the high metabolic activity of the tumour (shown by the yellow/orange colour) but no nodal involvement. The tumour eventually was staged as T2aN0M0 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351680/).

Source:

Cortuesy of Xiu‐Xia Song, Director, Editorial Office, Baishideng Publishing Group Inc.

Figure 3.4.6 Survival rates for patients with NSCLC according to stage

Figure 3.4.7 A chest X‐ray showing SCLC without chemotherapy (left) and response 3 weeks after one cycle of chemotherapy (right)

Section 3-Chapter 5

Figure 3.5.1 Adenocarcinoma of the oesophagus seen by endoscopy (http://www.ddc.musc.edu/public/diseases/esophagus/esophageal‐cancer.html).

Figure 3.5.2 X‐rays showing (a) a normal barium swallow and (b) an abnormal barium swallow showing a large oesophageal carcinoma (http://misc.medscape.com/pi/iphone/medscapeapp/html/A277930‐business.html, https://www.justintimemedicine.com/CurriculumContent.aspx?NodeID=3288).

Figure 3.5.3 Scans of a 39‐year‐old man with an adenocarcinoma of the oesophagus. Top left, a fused CT/PET scan shows an oesophageal tumour (white arrow); top right, CT and fused CT/PET scans showing sites of bone metastases (two white arrows); bottom, axial CT (left) and fused PET/CT (right) images show a hypermetabolic focus within the right gluteus medius muscle (arrow) in keeping with a soft‐tissue metastasis. Note that when CT scan is used alone, the scans appear entirely unremarkable and show no sign of metastatic disease [10].

Figure 3.5.4 An endoscopy showing Barrett’s oesophagus (the Barrett’s tissue appears red, compared to the pink‐coloured normal oesophagus tissue) (http://www.aafp.org/afp/2004/0501/p2113.html).

Section 3-Chapter 6

Figure 3.6.1 A transvaginal ultrasound showing an ovary with small cysts (the black dots).

Figure 3.6.2 The PARP inhibitor olaparib.

Section 3-Chapter 7

Figure 3.7.1 Examples of jaundice that could be due to pancreatic cancer. Note the yellow sclera in the right‐hand image (https://en.wikipedia.org/wiki/Jaundice, https://phil.cdc.gov/phil/details.asp).

Section 3-Chapter 8

Figure 3.8.1 The anatomical location of the prostate gland (http://www.medicalillustration.com.au/portfolio/colour_illustration.html#../images/colour_illustrations/image01.jpg).

Figure 3.8.2 A visual representation of the Gleason scale (https://commons.wikimedia.org/wiki/File:Gleasonscore.jpg).

Figure 3.8.3 Prostate cells with a Gleason grade of 4 (left) and 5 (right) (http://www.wikiwand.com/en/Gleason_grading_system). Used under CC‐BY‐3.0 https://creativecommons.org/licenses/by‐sa/3.0/.

Figure 3.8.4 The anti‐androgens abiraterone (and its prodrug form abiraterone acetate) and enzalutamide.

Section 3-Chapter 9

Figure 3.9.1 (a) A basal cell carcinoma and (b) a squamous cell carcinoma (http://en.wikipedia.org/wiki/Basal‐cell_carcinoma#mediaviewer/File:BCC_Nodular_type.jpg and http://en.wikipedia.org/wiki/Squamous‐cell_carcinoma#mediaviewer/File:Squamous_Cell_Carcinoma.jpg).

Figure 3.9.2 A malignant melanoma (from:http://en.wikipedia.org/wiki/Melanoma#mediaviewer/File:Melanoma.jpg).

Figure 3.9.3 (a) Acute and (b) chronic skin damage associated with sun exposure (https://uk.pinterest.com/wbossmd/skin‐health‐avoiding‐sun‐damage/ https://en.wikipedia.org/wiki/Sunburn).

Figure 3.9.4 An example of Bowen's disease on the finger (https://en.wikipedia.org/wiki/Bowen%27s_disease#/media/File:Bowen11.jpg).

Figure 3.9.5 The hedgehog inhibitors cyclopamine and vismodegib.

Section 3-Chapter 10

Figure 3.10.1 Germ cell tumour of the testis, consisting of embryonal cell carcinoma (1), teratoma (2), and seminoma (3) (https://radiopaedia.org/articles/testicular‐teratoma).

Source:

Courtesy of A. Prof Frank Gaillard. Reproduced with kind permission of Radiopaedia.

Figure 3.10.2 An ultrasound of normal, healthy testicles (left) and a testicle with an embryonal carcinoma (right).

Source:

Reproduced with kind permission of Dr. Greetsma,”http://www.ultrasoundcases.info/Slide‐View.aspx?cat=583&case=2517”.

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Anticancer Therapeutics

From Drug Discovery to Clinical Applications

ADAM TODD

Newcastle University, UK

PAUL W. GROUNDWATER

University of Sydney, Australia

JASON H. GILL

Newcastle University, UK

This edition first published 2018© 2018 John Wiley & Sons Ltd

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Library of Congress Cataloging‐in‐Publication Data

Names: Todd, Adam, 1982– author. | Groundwater, Paul W., author. | Gill, Jason H., 1973– author.Title: Anticancer therapeutics : from drug discovery to clinical applications / Dr. Adam Todd, Professor Paul W. Groundwater, Dr. Jason H. Gill.Description: First edition. | Hoboken, NJ : Wiley, 2017. | Includes bibliographical references and index. |Identifiers: LCCN 2017024305 (print) | LCCN 2017025861 (ebook) | ISBN 9781118696217 (pdf) | ISBN 9781118696200 (epub) | ISBN 9781118622124 (cloth)Subjects: | MESH: Neoplasms–drug therapy | Neoplasms–physiopathology | Antineoplastic Agents | Drug DiscoveryClassification: LCC RC270.8 (ebook) | LCC RC270.8 (print) | NLM QZ 267 | DDC 616.99/4061–dc23LC record available at https://lccn.loc.gov/2017024305

Cover design by WileyCover image: (right) © Xray Computer/Shutterstock; (left top & left buttom) Courtesy of Adam Todd, Paul W. Groundwater & Jason H. Gill

FOR OUR CHILDREN

Preface

By the year 2020 estimates suggest that almost one in two of us will suffer from cancer at some stage in our lives [1]. This is an understandably frightening statistic, especially when we consider that, globally, cancer results in more deaths than HIV/AIDS, tuberculosis, and malaria combined [2]. In 2012, around 14.1 million new cases of cancer were diagnosed (with this figure expected to rise to 19.3 million by 2025) and 8.2 million people died from cancer [3]. On a more positive note, however, increasing numbers of people are now surviving cancer; in 2012 an estimated 32.5 million people were alive 5 (or more) years after their original diagnosis and by 2020, it is thought almost 40% of people suffering from cancer will not die from the disease, but from another cause, such as cardiovascular disease [1,3].

These days, one of the greatest temptations for any patient who has just been diagnosed with cancer must be to search the internet for information relating to survival rates. There are many excellent resources for people who have cancer, but until a patient’s cancer has been fully classified, statistics are meaningless and, even after staging, median survival rates are the best which can be offered. In addition, an internet search for news items on cancer cures will result in many hits, but these should be tempered by the knowledge that cancer refers to a diverse group of diseases, affecting different organs and systems of the body, and a single cure (or even one for more than one group of related cancers) is, therefore, extremely unlikely.

Since its use was first described over 74 years ago, chemotherapy has contributed to significant improvements in survival rates for patients suffering from a range of different cancers, with a number of cancers now considered, and even managed, as long‐term conditions as opposed to acute illnesses. A good example of this is prostate cancer; through the use of chemotherapy, men now live with this condition for many years without the cancer affecting their quality of life. Unfortunately, however, this progress is not evident for all cancers and, as we shall see, the survival rates for pancreatic cancer, to take one example, have remained roughly the same for many years and the prognosis for patients with this disease is still incredibly poor.

The complexity of cancer mirrors the complexity of the human body itself. The improvement in survival rates (which are required to address the increasing numbers of us who will get cancer) relies on advances in our understanding of normal cellular functioning and how these processes can go wrong in the development of cancer. It is these types of advances that have informed the treatment regimens (comprising combinations of surgery, radiotherapy, and chemotherapy) and resulted in increased survival rates for many different cancers. For example, in the UK, in 1992, 21% of patients diagnosed with cancer died from another cause; by 2010 this figure had risen to 35%, and by 2020 it is projected to reach 38% [1]. These statistics are very encouraging and show the progress we have made against this hugely challenging and complex disease. A vast array of people, including medicinal chemists, molecular biologists, clinical trialists, health economists, and oncologists, are working to continue this significant progress. It is quite unusual to make a one‐off landmark discovery that significantly changes the way cancer is managed overnight (although this can happen and a good example is the discovery of platinum therapy in the treatment of testicular cancer). What is more common is that, through high‐quality research and robustly designed clinical trials, we make small, but important steps in our understanding of how to best manage this disease.

In Section 1 of this book we give an introduction to the global burden of cancer, cancer classification, and the cellular and molecular basis of cancer. In Section 2 we describe the different classes of anticancer agents and include chapters on the discovery, synthesis, mechanism of action, and resistance for each class. In Section 3 we bring everything together and explore the clinical management of ten different cancers; importantly in this section, we consider the various screening approaches that may, or may not, be taken to help improve survival. We hope that the organisation of the book helps you to appreciate the sheer complexity of anticancer therapeutics and that cancer treatment is not – and never will be – a one size fits all approach. Like any book on anticancer agents, this text presents a snapshot of the agents used clinically at the time. There is no doubt that with the rapid progress being made in large‐scale data‐rich biology, yet more significant advances will be made against this disease, and that future texts (not necessarily further editions of this one) will have many more new anticancer agents (and targets) to discuss.

References

1

https://www.macmillan.org.uk/_images/cancer‐statistics‐factsheet_tcm9‐260514.pdf

(last accessed 21.8.2017).

2

Moten A, Schafer D, Ferrari M. Rededefining global health priorities: Improving cancer care in developing settings.

J Glob Health.

2014,

4

, 010304.

3

https://publications.cancerresearchuk.org/downloads/product/CS_REPORT_WORLD.pdf

(last accessed 21.8.2017).

Section 1Introduction

1.1The Global Burden of Cancer

In order for us to understand cancer and its treatment it is obviously important to define what is meant by the term ‘cancer’. The word is credited to Hippocrates, the Greek physician (460–370 BC), who used the words carcinos and carcinoma to describe non‐ulcer and ulcer‐forming growths. These words in Greek derive from the word for crab, and their use is believed to be due to the fact that the spreading nature and cellular projections of the growths observed were reminiscent of the shape of a crab. Later changes resulted in the use of the words cancer (Latin for crab) and oncos (Greek for swelling) to describe tumours, terms attributed to the Roman physicians, Celsus (28–50 BC) and Galen (130–200 AD), respectively. Interestingly, we still use all of these words to define malignancy, to discuss a tumour’s histological appearance, and as a description for medical specialists in this area (oncologists).

Although described as a single condition, cancer is actually a family of hundreds of different diseases. The distinction between the different types of cancer is extremely important since their treatment, management, and outcomes for the patient are very diverse (as we shall see in the later sections). Additionally, even within a single cancer ‘type’ there are significant issues with regards to treatment options and patient prognosis, as individual cancers of the same type can behave very differently from one another. The same can be said for the global distribution of cancer; there are different profiles of cancer types in different geographical regions, with different causative factors, different treatment options and successes, and different prognostic and survival rates. Invariably, across the globe, some cancer types and some patients will achieve some degree of remission, and some will be cured, but others will not, with treatment in their case focusing on extending life expectancy.

Cancer is a major worldwide public health problem, as indicated by the World Health Organization (WHO) identifying cancer as one of four leading threats to human health and development (the others being cardiovascular disease, chronic respiratory diseases, and diabetes) in 2008 [1]. In 2012, cancer incidence1 was estimated at 14.1 million people, cancer mortality2 was predicted at 8.2 million deaths, and cancer prevalence3 was estimated at 32.6 million people [2]. When we just consider these numbers it is difficult to appreciate the scale of the problem, and it is therefore important to put this into context. For instance, in 2012 the estimated population of the world was 7.05 billion people, and the risk of dying4 from cancer before age 75 was 10.5% [2].

Cancer is not a modern disease, being first identified and described around 5,000 years ago. What may be unexpected is that the frequency and occurrence of cancer are higher nowadays than about a century ago despite significant advances in cancer diagnosis, treatment, and management over this period. So how can that be? Are we seeing an increase in cancer cases? Are we really making progress with the treatment of these diseases? The answers to these questions relate to the way we consider and view cancer, and have a direct relationship to factors and successes outside of the cancer field. A major contributory factor in cancer appearing to become an increasing cause of mortality over the past century is our achievements in the treatment of other life‐threatening diseases. In the early 1900s cancer accounted for a small proportion of deaths, with the majority of deaths being due to infectious diseases such as pneumonia, tuberculosis, and polio. Since this time, medical progress and improvements in public health and hygiene have led to the significant reduction and elimination of infection as a major cause of death. This effect can be observed if we compare differences in cancer incidence and mortality in different regions of the world, particularly developed versus developing countries. In the developed countries of Europe, treatment for infectious diseases is highly successful and cancer appears to be a major mortality factor, for example mortality rates are greater than 150 per 100,000 and incidence rates are greater than 300 per 100,000 in Northern and Western Europe. We can compare this to the developing countries of Middle and Northern Africa, where infectious diseases are a major factor and treatment success is poor; here cancer mortality rates are below 90 per 100,000 and incidence rates are below 130 per 100,000 (Figure 1.1.1).

Figure 1.1.1