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METASTATIC DISEASES
Novel Approaches in Diagnosis and
Therapeutic Management
METASTATIC DISEASES
Novel Approaches in Diagnosis and
Therapeutic Management
Edited by
Sandeep Arora, PhD
Co-Edited by
Tapan Behl, PhD
Sukhbir Singh, PhD
Neelam Sharma, PhD
Saurabh Gupta, PhD
First edition published 2022
Apple Academic Press Inc. CRC Press
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Library and Archives Canada Cataloguing in Publication
CIP data on file with Canada Library and Archives
Library of Congress Cataloging‑in‑Publication Data

Names: Arora, Sandeep, 1967- editor. | Behl, Tapan, editor. | Singh, Sukhbir, 1984- editor. | Sharma, Neelam, 1986- editor. |
Gupta, Saurabh (Pharmacologist), editor.
Title: Metastatic diseases : novel approaches in diagnosis and therapeutic management / edited by Sandeep Arora ; co-edited
by Tapan Behl, Sukhbir Singh, Neelam Sharma, Saurabh Gupta.
Description: 1st edition. | Palm Bay, FL : Apple Academic Press, 2021. | Includes bibliographical references and index.
| Summary: “Metastatic Diseases: Novel Approaches in Diagnosis and Therapeutic Management opens new horizons
for exploring modern therapeutic entities and emerging targets for combating the deadly disease of cancer. The authors
provide a review of cancer along with descriptions of its molecular level mechanisms and emphasize the role of promising
new therapies, including herbal therapies that can be utilized for the treatment of metastatic diseases. The chapters look
at specific approaches that have been researched and developed and that have almost reached the standardization stage.
One of the approaches focuses on intracellular mechanisms, particularly proteins, and the pathway involving or being
regulated by the proteins that limit the metastatic cellular growths. In particular phosphoprotein enriched astrocytes are
being extensively tried. Also discussed is transerythretin protein, which has been significantly studied for its involvement
in formation and transportation of proteins in metastatic diseases. Other receptors and approaches examined include
CXCR4, autophagy-inhibiting drugs, phosphoprotein-enriched astrocytes, spatiotemporal genetic analysis, tyrosine
kinase inhibitors, and more. Also considered are advances in diagnostic systems like intra vital microscopy and molecular
imaging, which further add to the arsenal in metastatic diseases, diagnosis, and management along with techniques like
SAGA. These diagnostic methods and innovative methods of intervention by modification of epigenetic control of the
immune system using immune checkpoint inhibitor s and phytopharmaceuticals provide newer and better dimensions
to treatment of metastatic diseases. Key features: Discusses promising new therapies, including herbal therapies, for the
treatment of metastatic diseases Explains the new areas that are widely explored by scientists, researchers, and scholars
throughout the globe Explores new therapeutic molecules for cancer treatment The selection of appropriate treatment
strategies presented in this volume provide deep insight into the adverse effects and contraindications that will be of
immense benefit in the treatment and management of detrimental effects of this deadly disease. The volume will be
beneficial for major laboratories working on cancer research and will also serve as a guide for researchers to explore new
targets that can be beneficial for mankind”-- Provided by publisher.
Identifiers: LCCN 2020049549 (print) | LCCN 2020049550 (ebook) | ISBN 9781771889179 (hardcover) |
9781774638071 (softcover) | ISBN 9781003043249 (ebook)
Subjects: MESH: Neoplasm Metastasis--diagnosis | Neoplasm Metastasis--drug therapy
Classification: LCC RC263 (print) | LCC RC263 (ebook) | NLM QZ 203 | DDC 616.99/4--dc23
LC record available at https://lccn.loc.gov/2020049549
LC ebook record available at https://lccn.loc.gov/2020049550
ISBN: 978-1-77188-917-9 (hbk)
ISBN: 978-1-77463-807-1 (pbk)
ISBN: 978-1-00304-324-9 (ebk)
DOI: 10.1201/9781003043249
About the Editor
Sandeep Arora, PhD

Dean, Chitkara College of Pharmacy,
Chitkara University, Punjab, India; Professor,
Healthcare, Chitkara University, Rajpura,
Punjab, India
Sandeep Arora, PhD, MPharm, is Dean/Director of the

Chitkara College of Pharmacy at Chitkara University,
Punjab, India, as well Professor of Healthcare at
Chitkara University, Rajpura, Punjab, India. He is also an industrial consul-
tant. Dr. Arora is a seasoned pharma and academic professional with over
27 years of experience in pharma operations, quality management, academ-
ics, training, research, and consultancy planning and administration. An avid
researcher and writer, he has published four books and 150 research publi-
cations (h index 17). He holds 18 patents and four trademarks, and has one
registered company to his credit. He is an honorary editor of the journal
Advanced Drug Review, editor of the Journal of Pharmaceutical Technology,
Research, and Management, and honorary technical director and advisor to
Natural Solutions, Mumbai, India. He and his team has received an IEDC
(International Economic Development Council), Government of India, pro-
totyping grant for his project related to the management of acute respira-
tory distress syndrome in COVID during Novate+ 2020, held at Chitkara
University, Punjab, India. He and his team were shortlisted and eligible to
apply for sustainability allowance from the Startup Himachal HACKATHON
2020, his project held at Chitkara University. He has delivered sessions
as expert or keynote speaker and has chaired international conferences
(University of Florida, Pfizer-IPA CPD Sessions, OMICS, and Conference
Series Conferences at Thailand) on various topics relevant to pharmaceutical
industry trends, technology, phytopharmaceuticals, regulatory affairs, etc. In
addition to his pharmaceutical degrees, he also has certifications in business
development, business strategy, EHS, and pharmacy technology.
About the Co-Editors
Tapan Behl, PhD

Associate Professor, Department of Pharmacology,
Chitkara College of Pharmacy, Chitkara University,
Rajpura, Punjab, India
Tapan Behl, PhD, MPharm, is currently working as

an Associate Professor in the Department of Phar-
macology, Chitkara College of Pharmacy, Chitkara
University, Rajpura, Punjab, India. Dr. Behl carries a
professional experience of over eight years in academics and research. His
areas of interest include diabetes and associated complications, rheumatoid
arthritis, preclinical ethical considerations, molecular pharmacology, phar-
macotherapy for diabetic complications of the eye, drug transfusion across
ocular barriers, and neuropathic pain and rheumatoid arthritis. Dr. Behl has
more than 75 publications in various international and national journals
of repute. He is also the author of two international books and has various
book chapters to his credit. He has been invited as a guest speaker at various
international and national conferences. Dr. Behl represents India as a voting
delegate during the IUPHAR meeting and selection of IUPHAR 2026 in
Kyoto, Japan. Dr. Behl has received many prestigious honors and awards
for his work and academic excellence, including Academician of the Year
Award–2018, Fellow of Society of Biomedical Laboratory Scientists, etc. He
is also serving as a reviewer of many reputed journals in his field. Dr. Behl is
also engaged in guiding students for their doctoral (PhD) work.
viii About the Co-Editors
Sukhbir Singh, PhD

Associate Professor, Chitkara College of
Pharmacy, Chitkara University, Punjab, India;
Associate Head, Centre of Excellence,
Phytopharmaceutical, Chitkara College of
Pharmacy, Chitkara University, Punjab, India.
Sukhbir Singh, PhD in Pharmaceutical Science, is a

pharmaceutical research professional with more than
12 years of experience in academics and research. Presently, he is Associate
Professor and Associate Head, Centre of Excellence, Phytopharmaceutical, at
the Chitkara College of Pharmacy, Chitkara University, Punjab, India. He is
associated with industry-oriented courses held in collaboration with Chitkara
University and established pharmaceutical industries, such as Dr. Reddy’s
Laboratories. He has 100 publications in various national and international
journals (h-index 12 and I 10-index 13) and has published four books and 10
book chapters. He also has filed 12 patents to his credit. He has presented/
published 40 review/research abstracts in various national/international
conferences. He is also engaged with for consultancy projects on herbal/
homeopathic formulations. He is an associate editor of Open Access Journal
of Pharmaceutical Research. In 2017, he was been honored with a Research
Excellence Award by the Honorable Chancellor of Chitkara University. He
and his team has received an IEDC (International Economic Development
Council), Government of India, prototyping grant for his project related to
the management of acute respiratory distress syndrome in COVID during
Novate+ 2020, held at Chitkara University, Punjab, India. He and his team
were shortlisted and eligible to apply for sustainability allowance from the
Startup Himachal HACKATHON 2020, his project held at Chitkara Univer-
sity. He has guided 16 MPharmacy students and 6 PhD students. His areas of
interest in research are nanotechnology/liposome/niosomes/SEDDS based
formulation development and solubility enhancement of BCS class II drugs.
He has expertise in operation of various statistical analyses tools.
About the Co-Editors ix
Neelam Sharma, PhD

Associate Professor, Chitkara College of Pharmacy,
Chitkara University, Punjab, India; Associate Head,
Centre of Excellence, Pharma Tech and
Nanotechnology, Chitkara College of Pharmacy,
Chitkara University, Punjab, India
Neelam Sharma, PhD in Pharmaceutical Science, is a

pharmaceutical research professional with experience
of more than 10 years in academics and research. Currently, she Associate
Professor at the Chitkara College of Pharmacy, Chitkara University, Punjab,
and Associate Head, Centre of Excellence, Pharma Tech and Nanotechnology,
Chitkara College of Pharmacy, Chitkara University, Punjab, India. She has
90 publications in various national and international journals, three books,
and 10 book chapters, and has filed 12 patents to her credit (h-index 9 and
I-10-index 9. She has presented and published 40 review/research abstracts
in various national/international conferences. She is engaged in four consul-
tancy projects on herbal/homeopathic formulations. In 2016, she has been
awarded a Certificate of Inventorship for her novel invention. She has super-
vised 10 M. Pharmacy students, and three students are pursuing PhDs under
her guidance. She and her team (Dr. Sandeep Arora and Dr. Sukhbir Singh)
have an IEDC (International Economic Development Council), Government
of India, prototyping grant for the project related to the management of acute
respiratory distress syndrome in COVID during Novate+ 2020, held at Chit-
kara University, Punjab, India, with an opportunity to pitch for university
funding for research by Chitkara University Punjab. She and her team are
shortlisted and eligible to apply for sustainability allowance from Startup
Himachal HACKATHON 2020, for her project held at Chitkara University,
Punjab. Her areas of interest in research are novel drug delivery systems
such as nanoparticles, liposomes, phytosomes and solubility enhancement of
BCS class II drugs. She also has expertise in operation of various statistical
analyses tools.
Saurabh Gupta, PhD
Associate Head, Department of Pharmacology,
Chitkara College of Pharmacy, Chitkara University,
Punjab, India
Saurabh Gupta, PhD, is an Associate Head of the

Department of Pharmacology at Chitkara College of
Pharmacy, Chitkara University, India. His research
focuses on asthmatic pharmacology and cellular and
molecular biology. He is serving as an editorial member of several reputed
journals, including the Austin Journal of Pharmacology and Therapeutics,
World Journal of Pharmaceutical Research, and World Journal of Phar
macy and Pharmaceutical Sciences. He is also an expert reviewer for the
journals International Immunopharmacology and Journal of Physiology and
Pharmacology. He has authored over 30 international and national research
articles, two books, and a book chapter. Dr. Gupta is associated with many
professional bodies and is a CPCSEA nominee and an elective member
of the Indian Pharmaceutical Association, Madhya Pradesh State Branch,
Indore, India.
Contents
Contributors ......................................................................................................... xiii

Abbreviations..........................................................................................................xv
Preface.................................................................................................................. xxi
1. A Review on Cancer: From Clinical Perspective to Chemotherapy ......... 1

Sandeep Arora and Pooja Sharma
2. Phosphoprotein‑Enriched Astrocytes as Potential Anticancer

Agents............................................................................................................ 33
Sandeep Arora and Nidhi Garg
3. Autophagy‑Modulating Drugs as Complements to Cancer

Chemotherapy .............................................................................................. 47
Sandeep Arora and Sukhbir Singh
4. Transthyretin Protein in Renowned Metastatic and Other

Conditions..................................................................................................... 65
Sandeep Arora, Tapan Behl, and Kiranjeet Kaur
5. Role of CXCR4 Receptor Protein in Cancer Development and

Therapies ...................................................................................................... 77
Sandeep Arora and K. A. Shaima
6. C3D Complement System in Immunotherapy‑Based Cancer

Treatment...................................................................................................... 89
Sandeep Arora, Nidhi Garg, and Pooja Sharma
7. BH3 Mimetics ............................................................................................. 101

Sandeep Arora, Sukhbir Singh, and Neelam Sharma
8. Spherical Nucleic Acid Platform‑Based Drug Delivery for

Brain Cancer and Improved Blood‑Brain Barrier Crossing
for Alzheimer’s and Other Diseases ..........................................................117
Sandeep Arora, Saurabh Gupta, and Sukhbir Singh
9. Intra‑Vital Microscopy: A New Amelioration in Cancer

Immunotherapy Monitoring ..................................................................... 139
Sandeep Arora, Neelam Sharma, and Sukhbir Singh
xii Contents
10. Molecular Imaging: A New Advancement in Cancer

Immunotherapy Monitoring ..................................................................... 151
Sandeep Arora and Neelam Sharma
11. Spatiotemporal Genetic Analysis (SAGA) Technique for Cancer

Cell Biology Studies ................................................................................... 169
Sandeep Arora, Saurabh Gupta, and Neelam Sharma
12. Plant‑Derived Anti‑Malarial Compounds and Their Derivatives

as Anticancer Agents: Future Perspectives.............................................. 179
Sandeep Arora, Tapan Behl, and Samir Mehndiratta
13. Epigenetic Control of the Immune System and Its

Applications in Metastatic Diseases ......................................................... 197
Sandeep Arora, Sukhbir Singh, Neelam Sharma, Tapan Behl, and Nidhi Garg
14. Immune Checkpoint Inhibitors ................................................................ 207

Sandeep Arora, Saurabh Gupta, and Nidhi Garg
15. Tyrosine Kinase Inhibitors in Lymphocytic Leukemia .......................... 225

Sandeep Arora, Tapan Behl, Sukhbir Singh, Neelam Sharma, and Nidhi Garg
16. Cyclooxygenase‑1 (COX‑1) Inhibitors in the Management of

Neoplastic Disorders .................................................................................. 239
Sandeep Arora, Saurabh Gupta, and Suman Baishnab
17. Microfluidic Devices in Capturing Circulating Metastatic Cancer

Cell Clusters ............................................................................................... 261
Sandeep Arora, Ajmer Singh Grewal, Neelam Sharma, and Sukhbir Singh
Index .................................................................................................................... 279

Contributors
Sandeep Arora
Chitkara College of Pharmacy, Chitkara University, Punjab, India
Tapan Behl
Nidhi Garg
Ajmer Singh Grewal

Saurabh Gupta
Kiranjeet Kaur
Samir Mehndiratta
Taipei Medical University, Taipei, Taiwan
K. A. Shaima
Neelam Sharma
Pooja Sharma
Sukhbir Singh
Suman Baishnab
Abbreviations
67LR 67 kDa laminin receptor

A adenine
AA arachidonic acid
AAP activatable aptamer probe
AB2 isostructural aluminum diboride
ADPh antibody-dependent phagocytosis
Ag silver
AIDS acquired immune deficiency syndrome
AJCC American Joint Committee on Cancer
ALL acute lymphoid leukemia
AMBRA activating molecule in Beclin1-regulated autophagy
AML acute myeloidal leukemia
ANF atrial natriuretic factor
AOM azoxymethane
AP alternate pathway
ApoG2 apogossypolone
ASOs antisense oligonucleotides
ATG4 autophagy-related gene 4
Au gold
AuNP gold nanoparticles
BBB blood-brain barrier
BCG Bacillus Calmette-Guérin
Bcl-2 B-cell lymphoma 2
BCT bruceantin
BH3 Bcl-2 homology 3
BIF 1 Bax-interacting factor 1
BIM SAHB BIM stabilized α-helix of BCL-2
BM basement membranes
BTK Bruton’s tyrosine kinase
C cytosine
C1INH C1 inhibitor
C4bp C4b-binding protein
xvi Abbreviations
Ca2+ calcium ion

CAM chorioallantoic membrane
CaMKII calcium/calmodulin-dependent protein kinase II
cAMP cyclic adenosine monophosphate
CAR coxsackievirus-adenovirus receptor
CARD caspase activation and recruitment domain
CBC complete blood count
CFP cyan fluorescent protein
CHK1 check point kinase 1
CLL chronic lymphocytic leukemia
COX cyclooxygenase
CP classical pathway
CRC colorectal carcinoma
CsCl cesium chloride
CT computed tomography
CTAB cetyl trimethylammonium bromide
CTC circulating tumor cell
CTLA-4 cytotoxic T lymphocyte-associated antigen 4
CTLs cytotoxic T lymphocytes
Cy5 cyanine 5
CYP cytochrome P
DD death domain
DED death effector domain
DEP dielectrophoresis
DFCP double FYVE domain-containing protein
DHA dihyroxyartemisinin
DHFR dihydrofolate reductase
DNA deoxyribonucleic acids
DRAM damage-regulated autophagy modulator
ECOG Eastern Cooperative Oncology Group
EGFR epidermal growth factor receptor
EMT epithelial-to-mesenchymal transition
EpCAM epithelial cell adhesion molecule
EPR enhanced permeability and retention
ER endoplasmic reticulum
ERK1/2 extracellular signal-regulated kinases 1/2
ESCRT endosomal sorting complex required for transport
FACS fluorescence-activated cell sorters
FADD FAS associated death domain
Abbreviations xvii
FAP familial amyloid polyneuropathy

FDA Food and Drug Administration
Fe3O4 iron oxide
FH factor H
FISH fluorescent in situ hybridization
FOVs fields of view
FPs fluorescent proteins
G guanine
GB glioblastoma
GBM glioblastoma multiforme
GDP guanosine diphosphate
GFP green fluorescent protein
GLUT4 glucose transporter 4
GPCRs G-protein coupled receptors
GTP guanosine triphosphate
HBV hepatitis B virus
HCQ hydroxychloroquine
HDAC histone deacetylase
HDF human diploid fibroblast
HER human epidermal growth factor receptor
HIFU high intensity focused ultrasound
HIV human immunodeficiency virus
HSP70 heat shock protein 70
ICOS inducible co-stimulator
ICP-MS inductively combined plasma mass spectrometry
ICV intracerebroventricular
IgG immunoglobulins G
ILs interleukins
IVM intra-vital microscopy
JMD juxta membrane domain
JNK c-Jun N-terminal kinase
LAG3 lymphocyte activation gene 3
LMWHs low-molecular-weight heparins
LNA locked nucleic acid
LNPs lipid nanoparticles
LP lectin pathway
LPS lipopolysaccharide
LT liver transplantation
Mab monoclonal antibody
xviii Abbreviations
mAbs monoclonal antibodies

MAP mitogen-activated protein
MCL mantle cell lymphoma
MCTS multicellular tumor spheroid
MEKi mitogen-activated protein kinase inhibitor
MEN multiple endocrine neoplasia
MMIA multifunctional molecular imaging agents
MPM multi-photon microscopy
MRI magnetic resonance imaging
MSV multistage vector
MTIC monomethyl triazeno-imidazole-carboxamide
NaCl sodium chloride
NES nuclear exporting sequence
NPs nanoparticles
NSCLC non-small cell lung cancer
OFDI optical frequency domain imaging
PCR polymerase chain reaction
PD-1 programmed cell death protein 1
PDAC pancreatic ductal adenocarcinoma
PD-L1 programmed death-ligand 1
PDMS poly-dimethylsiloxane
PEA-15 phosphoprotein enriched astrocytes of 15 kDa
PEG polyethylene glycol
PET positron-emission tomography
PG prostaglandin
PH pleckstrin homology
PI phosphoinositide
PI3K phosphatidylinositol 3-kinase
PI3P phosphatidyl inositol-3-phosphate
PKC protein kinase C
PLD1/2 phospholipase D1 and D2
PML promyelocytic leukemia
PNA peptide nucleic acid
PNANs polyvalent nucleic acid nanostructures
PSMA prostate-specific membrane antigen
PTB protein tyrosine binding
PTEN phosphate and tensin homolog
Ptgs-1 prostaglandin-endoperoxide synthase 1
Ptgs-2 prostaglandin-endoperoxide synthase 2
Abbreviations xix
PYD pyrin domain

QD quantum dot
RAR-alpha retinoic acid receptor-alpha
RCC renal cell carcinoma
RFP red fluorescent protein
RGD arginine-glycine-aspartic acid
RNA ribonucleic acid
RNAi RNA interference
ROS reactive oxygen species
RSK2 ribosomal S6 kinase isozyme 2
RTKs receptor tyrosine kinases
RT-PCR reverse transcription polymerase chain reaction
SAXS small-angle X-ray scattering
sc simple cubic
SCA senile cardiac amyloidosis
SCLC small cell lung cancer
SDCM spinning disk confocal microscopy
SDF1 stromal development factor 1
SGKs SRC family kinases
SH2 SRC homology-2
SHG second-harmonic
siRNA small interfering RNA
SNA spherical nucleic acid
SNARE soluble N-ethylmaleimide-sensitive factor activating
protein receptor
SPECT single-photon emission computed tomography
SPIO super paramagnetic iron oxide
SR scavenger receptor
SSA senile systemic amyloidosis
T thymine
TCR T-cell receptors
TEM transmission electron microscopy
Th1 T lymphocyte and helper 1
TMD transmembrane domain
TMIA targeting molecular imaging agents
TNBC triple negative breast cancer
TNF tumor necrosis factor
TOR target of rapamycin
TORC1 TOR complex 1
xx Abbreviations
TP terminal pathway
TRAIL TNF-related apoptosis inducing ligand
TTR transthyretin
ULK UNC-51-like kinase
uPAR urokinase plasminogen activator receptor
USP10 ubiquitin-specific peptidase 10
USPIO ultra-small super paramagnetic iron oxide
UVRAG ultraviolet radiation resistance-associated gene
VEGF-A vascular endothelial growth factor A
VEGF-C vascular endothelial growth factor C
Vps18 vacuolar protein sorting protein 18
VSM vascular smooth muscle
WBCs white blood cells
WHO World Health Organization
WT wild-type
YFP yellow fluorescent protein
Preface
Metastatic diseases pose complicated issues in diagnosis and therapeutic

management because of the limitations or hindrances observed in identifying
the exact extent of nearby tissues’ spread and involvement. The approaches
in the management of metastatic diseases of various tissues are based on the
efforts to localize and target the therapy on the cancerous cells and avoiding
undue exposure of surroundings in the tissues, combining surgical, radio-
logical, and chemotherapeutic interventions based on biopsy, and imaging
for confirmation of metastatic stage.
Over the years, various oncolytic, anti-metabolite, and other agents have
been developed and used in combination with radio-, chemo-, and surgical
therapies, but with varying outcomes and post-treatment quality of life
efficacy.
These outcomes have encouraged drug discovery development and
clinical scientists to work on novel approaches for more efficacious and
targeted treatment of metastatic diseases. Some of these approaches have
been taken up for extensive development and have almost reached the stan-
dardization stage. One of the methods focuses on intracellular mechanisms,
particularly proteins, and the pathway involving or being regulated by the
proteins limiting the metastatic cellular growths. In particular, phospho-
protein-enriched astrocytes are being extensively tried. Also, transthyretin
protein has been significantly studied for its involvement in the formation
and transportation of proteins in metastatic diseases.
Specific receptors like CXCR4 are extensively investigated for their
chemokine-related inflammatory activity and involvement in angiogenesis
conditions and therapy managing the metastatic diseases.
Immune and inflammatory pathways, particularly the C3D complement
systems and their activation, are being extensively investigated for their
role in tumor-associated inflammation and possible ways to manage it.
BH3 mimetics and other agents have been investigated, which play a role
in apoptosis of normal and cancerous cells and help in designing therapies
for cancerous cells. Various delivery platforms like spherical nucleic acid
(SNA)-based drug delivery systems have been tried, making the therapies
for metastatic diseases more targeted.
xxii Preface
Advances in diagnostic systems like intravital microscopy and molecular

imaging have further added to the arsenal in metastatic diseases, diagnosis,
and management along with techniques like SAGA. These diagnostic
methods and innovative methods of intervention by modification of epigen-
etic control of the immune system, using immune checkpoint inhibitors and
use of phytopharmaceuticals have again given newer and better dimensions
to the treatment of metastatic diseases.
The selection of appropriate treatment strategies with deep insight into
the adverse effects and contraindications will prevent humanity from the
detrimental effects of this deadly disease along with its complications.
—Sandeep Arora, PhD
CHAPTER 1
A Review on Cancer: From Clinical

Perspective to Chemotherapy
SANDEEP ARORA and POOJA SHARMA
ABSTRACT
The primary trait of cancer is the unregulated growth and proliferation of

abnormal cells. The normal physiological mechanism of the cells is not carried
out with cancer cells, and they’re not responsive to average cell growth,
proliferation, and survival process sequences. The number of individuals
diagnosed with cancer was around 1.4 million in 2007. Therefore, healthcare
practitioners play an integral role in the diagnosis and treatment of cancer. To
control drug-induced toxicities, this becomes necessary for a cancer patient
to understand pharmacology and pharmacotherapy of chemotherapeutic
agents. Perceptive and skilled physicians contribute to public treatment in the
oncology unit. Carcinogenesis is a multistage mechanism that is genetically
regulated. Owing to mutated cells that are developed with the association of
carcinogens to normal cells, these mutated cells behave differently to their
environment; excessive production of tumor tissues produces characteristics
morphological and physiological changes in the initial phase of induction.
This chapter describes cancer from the scientific point of view of suggested
possible therapies.
1.1 INTRODUCTION
Unrestricted growth and spread of abnormal cells are the distinguishing

features of cancer. Being unresponsive to normal cell growth, proliferation,
and survival, cells’ normal physiological function is not performed by the
2 Metastatic Diseases
cancer cells. These cells can develop new tumors at a distant place by traveling
through blood or lymph (metastasis); they also have a property to occupy adja-
cent normal tissue and separate from the primary tumor (metastasize). Their
continuous growth and survival are promoted by their uncontrolled growth
and their potential to prompt the formation of a blood vessel (Alldredge et
al., 2012).
In 2007, the number of people diagnosed with cancer was about 1.4
million. It is essential to know anticancer drug pharmacology and phar-
macotherapy in a cancer patient to manage drug-induced toxicities. In the
oncology department, knowledgeable and trained health care professionals
contribute extensively to patient care (DiPiro et al., 2017).
1.2 ETIOPATHOGENESIS
1.2.1 STEPS INVOLVED IN CARCINOGENESIS
Carcinogenesis is a genetically controlled multistage process. In the initial

step of initiation, uncontrolled growth of neoplastic cells occurs due to
the mutated cells which are formed with the interaction of carcinogens
to normal cells, and these mutated cells respond differently to its envi-
ronment. This is then followed by promotion, i.e., the second phase, in
which cell alteration and mutated cell growth are observed over normal
cells, induced further by carcinogens. The only difference between the two
is that the promotion phase is reversible, whereas the initiation phase is
irreversible. It may also be seen as the pointer to future chemoprevention
strategies, including lifestyle and diet changes. Neoplastic growth marks
the last stage of carcinogenesis, termed as progression; it is characterized
by increased cell proliferation due to further genetic alteration. This phase
includes tumor invasion into local tissues and metastases development
(Calvo et al., 2005; Compagni and Christofori, 2000; Weston and Harris,
2003; Cotran et al., 1999).
1.2.2 CARCINOGENS
Chemical, physical, and biological agents constitute the three significant

carcinogens (Weston and Harris, 2003). Chemical agents are discussed in
Table 1.1 and are the associated cause of cancer. Also, ionization radiations
and ultraviolet rays make up a part of the physical agents. These radiations
A Review on Cancer: From Clinical Perspective to Chemotherapy 3
cause the free radical formation known to damage the DNA (deoxyribonu-
cleic acids) and result in mutations. Biological agents comprising of viruses
may also become a cause for cancer; for example, the Burkitt’s lymphoma
is caused by the Epstein-Barr virus, and cervical cancer is caused due to
the infection of human papillomavirus, age, gender, diet, growth factors,
and chronic irritation from the other promoters of carcinogens (Weston and
Harris, 2003).
TABLE 1.1 Cancer causing Drugs and Hormones in humans

Drug or Hormone Cancer Caused
Alkylating agents (e.g., chlorambucil, Leukemia
mechlorethamine, melphalan, and nitrosoureas)
Anabolic steroids Liver
Analgesics containing phenacetin Renal, Urinary bladder
Anthracyclines (e.g., doxorubicin) Leukemia
Antiestrogens (tamoxifen) Endometrium
Coal tars (topical) Skin
Estrogens:
• Nonsteroidal (diethylstilbestrol) Vagina/cervix, endometrium, breast
• Steroidal (estrogen replacement therapy, oral Endometrium, breast, liver
contraceptives)
• Immunosuppressive drugs (cyclosporine, Lymphoma, skin
azathioprine)
Source: Compagni and Christofori (2000).
1.2.3 GENES ENTAILED IN CARCINOGENESIS
Oncogenes and tumor suppressor genes are the genes associated with the
process of carcinogenesis.
1.2.3.1 ONCOGENES
Oncogenes originate from proto-oncogenes or normal genes and play a

significant role in carcinogenesis. All normal cells have proto-oncogenes,
which monitor cellular function (cell cycle). Exposure to any carcino-
genic agents causes an alteration in the genome of these proto-oncogenes
via chromosomal rearrangement, point mutation, or gene amplification
that, in turn, triggers the oncogenes. There is an increase in the prob-

ability of neoplastic transformation due to impaired cell growth, which
results in a distinct growth advantage to the cell. This is all due to the
oncogene’s activation that produces an abundance of the abnormal gene
product. HER (human epidermal growth factor receptor) is an example of
oncogenes. Epidermal growth factor receptor or ErbB-1, HER-3, HER-2,
and HER-4 are the four members present in this family having receptor
tyrosine kinases (RTKs). In several cancers, proliferation, metastasis,
angiogenesis, and cell survival happen once these receptors get activated,
causing the acquiring of specialized features and rapid multiplication of
cells through downstream signaling pathways and activation of receptor
tyrosine kinase (Gross et al., 2004).
1.2.3.2 TUMOR SUPPRESSOR GENES
Tumor suppressor genes control cellular growth and proliferation (Calvo

et al., 2005; Cotran et al., 1999; Weinberg, 1996). Failure to control cell
growth occurs due to the mutations caused by carcinogens. Retinoblas-
toma and p53 genes are examples of tumor suppressor genes. In almost
50% of cancer cases, mutation of p53 is the major cause (Weinberg,
1996). Different type of malignancies including, breast cancer, cancer of
the large intestine, lung, brain tumors, cervix, and anus; and osteogenic
sarcoma occurs due to uncontrolled growth because of the mutation
which stops the function of the normal p53 gene product from having
control over the cell cycle. The following are examples of oncogenes and
tumor suppressor genes (Table 1.2).
DNA repair gene (classified as tumor suppressor genes) is another
important gene in carcinogenesis; this gene helps to repair the damaged
DNA that may have developed during DNA replication (Cotran et al.,
1999). Lack of this gene may result in the mutation of genes that further
activate oncogenes via proto-oncogene. This condition can be seen in
familial cancer of the colon and breast. Cell cycle regulation is under the
stimulatory and inhibitory signals of oncogenes and tumor suppressor
genes (Calvo et al., 2005; Weinberg, 1996). Such genes control the cell
cycle clock.
TABLE 1.2 Summary of Tumor Suppressor Genes and Oncogenes
A Review on Cancer: From Clinical Perspective to Chemotherapy

Oncogenes
Gene Transcription Genes That Initiate Growth‑Promoter Genes
c-MYC N-MYC
Related Human Cancer Leukemia and breast, colon, gastric, Cancer found in adrenal glands, small cell lung carcinoma, and GBM
and lung carcinoma
Gene Growth Factor or Receptor Genes
Type Erb-B1 or Epidermal Growth Factor Erb-B2 or HER-2/neu RET
Receptor
Action/Activity Codes expressing the epidermal Helps in the coding of a Helps in the coding of a growth factor
growth factor (EGFR) receptor growth factor receptor receptor
Related Human Cancer GBM, breast, head, and neck, and Breast, prostate, bladder, Cancer of thyroid gland
large intestine carcinoma salivary gland, and ovarian
carcinoma
Gene Cytoplasmic Relays Genes for the Stimulatory Signaling Pathways
Type K-RAS N-RAS
Action/Activity Coding for guanine nucleotide-proteins with GTPase activity is
conducted
Related Human Cancer Lung, ovarian, large intestine, and pancreatic cancers Neuroblastoma, and acute leukemia
Gene Genes for Other Molecules
Type BCL-2 BCL-1 or PRAD1 MDM2
Action/Activity Codes for a protein that obstructs Codes for cyclin D1, which is Protein antagonist of p53 tumor
apoptosis a cell-cycle clock stimulator suppressor protein
Related Human Cancer Indolent B-cell lymphomas Breast, head, and neck cancers Sarcomas
5
TABLE 1.2 (Continued)
6
Tumor Suppressor Genes
Gene Protein Genes Whose Cellular Location is Unclear
Type BRCA1 BRCA2 VHL MSH2, MLH1, PMS1, PMS2, MSH6
Action/ DNA repair, DNA repair Regulator of protein stability DNA mismatch repair enzymes
Activity transcriptional
regulation
Related Breast and Breast cancer Renal cell cancer Hereditary nonpolyposis colorectal
Human ovarian cancer
Cancer cancers
Gene Protein Genes in Cytoplasm
Type APC NF-1 NF-2
Action/Activity Inhibition of the stimulatory RAS Inhibition of the stimulatory RAS
protein is coded by a signaling protein coded by a protein
pathway step for a protein
Related Human Cancer Colon and gastric cancer Neurofibroma and leukemia Meningioma, ependymoma, and
schwannoma
Gene Protein Genes in Nucleus
Type RB1 p53
Action/Activity Codes for the pRB protein, a master brake of the cell cycle Codes for the p53 protein, which
can halt cell division and induce
Metastatic Diseases
Apoptosis
Related Human Cancer Retinoblastoma Associated with a wide variety of
cancers
Source: Cotran et al. (1999); Weinberg (1996).
1.2.4 TUMOR CLASSIFICATION
A tumor may surface from any of these four-primary tissues: connective

tissue, epithelial tissue, lymphoid tissue, and nerve tissue. A benign tumor
is named by adding the suffix -oma to the cell type, while for malignant
sarcoma is added to the type of cell as a suffix (Table 1.3) exhibits the stan-
dard nomenclature of the tumor by the type of tissue (Cotran et al., 1999).
TABLE 1.3 Tumor Classification by the Type of Tissue

Tissue Origin Connective Tissue
Fibrous tissue Bone Smooth muscle Striated muscle
Benign Fibroma Osteoma Leiomyoma Rhabdomyoma
Malignant Fibrosarcoma Osteosarcoma Leiomyosarcoma Rhabdomyo-
sarcoma
Tissue Origin Connective Epithelial Neural Tissue
Tissue
Fat Surface Glandular tissue Glial tissue
epithelium
Benign Lipoma Papilloma Adenoma “Benign” gliomas
Malignant Liposarcoma Carcinoma Adenocarcinoma Glioblastoma
(squamous, multiforme,
epidermoid) astrocytoma
Tissue Origin Neural Tissue Mixed Tumors
Nerve sheath Melanocytes Gonadal tissue
Benign Neurofibroma Pigmented Teratoma
nevus (mole)
Malignant Neurofibro- Malignant Teratocarcinoma
sarcoma melanoma
Source: DiPiro et al. (2017).
Tumors are mainly of two types: benign and malignant. Benign tumors are
encapsulated, localized, and indolent non-cancerous growth. They are identical
to their parent cell and once removed, they have very less chance of recur-
rence whereas malignant tumor occupies and destroys the surrounding tissue.
These cells are genetically unstable and are unidentical of their cell of origin.
Moreover, they do not act like normal cells, and this is known as anaplasia. It
has a property to metastasize, and hence their recurrence chances are higher
than a benign tumor.
1.2.5 PATHWAY OF METASTASIS
Hematogenous and lymphatic pathways are the two main pathways. Other
rarely used modes of transmission include transabdominal spread and
dissemination. Neoplastic cells are continuously shredded into the systemic
or lymphatic circulations. This step occurs in the initial stage of the tumor
but increases with time. Not every shed cell is a metastatic lesion (Stetler-
Stevenson, 2005). The process of invasion and metastasis is a multistep
process. After neoplastic alteration, both the malignant cells and host tissue
are known to produce some substance that provokes new blood vessel forma-
tion in order to supply oxygen and nutrients to malignant cells; this process is
termed as angiogenesis or neovascularization (Folkman and Kalluri, 2003).
After that, tumor cells separate and spread into surrounding blood and lymph
vessels, but not all cells survive the circulation; hence, these circulated
cells should adhere to the vascular tissue and from that multiply inside the
lumen vessel. This potentiates and serves as “fertilizer” for the proliferation
of metastasis. Last, angiogenesis again stimulates continued growth and
proliferation of cells. Figure 1.1 summarizes the functions acquired by a
cell to survive as well as mechanisms by which the cancer cell achieves this
function (Hanahan and Weinberg, 2000).
1.3 DIAGNOSING CANCER
The signs and symptoms vary and depend upon the type of cancer. The
clinical aspect for adults and children is discussed in Table 1.4.
1.3.1 PHASES OF CANCER
American Joint Committee on Cancer’s (AJCC’s) TNM system is used all over
the world to explain the type of cancer. General categorization is listed below:
1. Tumor (T): T (0–4) indicates the size and site of the tumor; i.e., the
way most of the tumor grows into surrounding areas. The bigger and
deeper the tumor, the more will be the aggregates.
2. Node (N): N (0–3) signifies the presence of cancer cells present
inside the lymph nodes or not.
TABLE 1.4 Cancer Clinical Presentation

Forewarning Signs of Cancer in adults • Discomfort in swallowing
• Unhealing abrasion
• Apparent difference in the size of mole
• Wheeziness
• Lump formation in mammary glands
• Bowel movement becomes irregular.
• Uncommon discharge or bleeding
Forewarning Signs of Cancer in Children • Visible lack of color in the skin
• Recurring fevers
• Nausea and headaches
• Continuous weight loss
• Inflammation in neck or abdomen
• Edema or constant soreness in bones
• Pupil becomes white
Source: American Cancer Society (2007).
Eluding Growth signal

apoptosis exhibit self
sufficiency
Insensitivity
Angiogenesis towards anti
is sustained growth signal
Immense Metastasis
potential for and tissue
replication invasion
FIGURE 1.1 Mechanism of tumorigenesis (American Cancer Society, 2007).

3. Metastasis (M): M represents the stage in which cancer has spread

to other parts of the body. M0 indicates that cancer has not spread,
whereas M1 describes that it has spread.
1.3.1.1 STAGE GROUPING OF CANCER

Along with TNM, cancer stages have been categorized into four categories:
stages I, II, III, and IV (Figure 1.2). However, in some cases, stage 0 may
also be present.
Stage 0 Stage 1
In-situ Cancer, this cancer has not spread Cancer in its early stage, it is identified as
in other tissues and is still located in the a small tumor that hasn’t spread much in
initial area. This is a curable stage. surrounding areas.
Stage 4 Stage 2 & 3

Advanced of cancer where it is Bigger tumor which has developed and
metastatic and had spread to other parts spread to the lymph nodes however other
of the body. body parts are not affected.
FIGURE 1.2 Stages of cancer.

Source: American Society of Clinical Oncology (ASCO).
1.4 TREATMENT OF CANCER

There are four major procedures for the treatment of cancer: surgery, radia-
tion, chemotherapy, and biological therapy. Surgery is the oldest method for
diagnosis and treatment of cancer. It is mainly recommended for a solid tumor
that is diagnosed early. Radiations were employed for the first time during
1800. Both surgery and radiation are the local treatment. Today most patients
have metastatic cancer, and these localized therapies cannot completely
eradicate the cancer cells. Hence the third treatment or the chemotherapy,
it reaches the circulation and cures the initial tumor and metastasis. Last
is biological therapy, also termed as immunotherapy or targeted therapies.
It basically involves the activation of the host’s immune system to fight
cancer. It usually uses naturally occurring cytokines, which are produced
by recombinant DNA technology. Interferons and interleukins (ILs) serve
as examples. Targeted therapies include monoclonal antibodies (mAbs),

tyrosine kinase inhibitors, and proteasome inhibitors (DiPiro et al., 2017).
Chances of recurrence of cancer after surgery or radiations are because some
of the primary tumors may have metastasized before it was diagnosed. Moreover,
these early metastases are too small and undetectable, so the name micrometas-
tases. Hence, adjuvant therapy is being introduced to eradicate micrometastatic
diseases following isolated treatments like radiation or surgery, or both. The prime
purpose of using systemic medical care is to minimize the recurrences figures
and extend survival. For example, additional methods are used in colorectal and
breast cancers. Most of the cancer management uses combined modalities, for
example, in the case of breast cancer (DiPiro et al., 2017).
1.4.1 CANCER MANAGEMENT PRINCIPLE: ONCOLOGY SURGERY

Patients with solid tumors are recommended surgery if the tumor is limited
to the origin site. Treating an individual with surgery requires a specific
ethical and psychological approach. Surgery as a means of cancer prevention
is detailed in Table 1.5.
TABLE 1.5 Surgery as a Means of Cancer Prevention

Characteristic Colitis ulcerosa Inherited colorectal Inherited breast carcinoma
Situations cancer
Cancer Cancer of colon Cancer of colon Cancer of mammary
glands
Treatment Colectomy Colectomy Mastectomy
Characteristic Undescended MEN1, MEN2 (Multiple endocrine neoplasia)
Situations testicles
Cancer Cancer of testicles Thyroid carcinoma
Treatment Orchidopexy Thyroidectomy
Source: DeVita et al. (1997).
Many surgical instruments have evolved, namely, fiberoptic endoscopy

and laparoscopy that has changed into a prerequisite for intraperitoneal
non-Hodgkin lymphoma’s diagnosis, and when combined with ultra-
sonography, plays a very crucial part in cancer staging, like pancreatic
and hepatic tumors (Berry and Maddern, 2000). Recently, nonoperative
techniques have evolved that destroy the tumors caused by physical or
chemical carcinogens such as arterial chemoembolization, cryotherapy,
etc. (Luck and Maddern, 1999).
1.4.2 PRINCIPLE OF CANCER MANAGEMENT: RADIATION THERAPY
Ionizing radiation is used in this therapy for the treatment of malignant illness.
Its high energy has 100 times more penetrating power than X-ray. Hence,
the deep-seated tumors are treated by this therapy with very less radiations
affecting the nearby areas (Partensky and Maddern, 1999; Price and Sikora,
2000). The penetrating power of radiotherapy is expressed as its energy and
is calculated in terms of electron volts (eV). The simplest equipment used
is a low energy orthovoltage machine, which can produce a beam of up to
250 KeV. The penetration of voltage is only 1–4 cm; hence, it is effective for
treating skin cancers and bone metastases. But using millivoltage causes skin
reactions. Another therapy called isotope-based radiotherapy uses sources
that emit rays to produce higher energy beams. In the earlier times, radium
was used for this purpose but later got replaced by cobalt as they produce
higher energy and seem dependable.
Nowadays, linear accelerators are used as a standard. In this, charged
subatomic particles or ions are accelerated to high speed by subjecting them
to a series of oscillating electric potentials along a linear beamline. These
machines can reliably produce beams of up to 20 MeV energy. It doesn’t
produce any skin reactions. Regarding the target, the dose is taken from
clinical examination, X-rays, MRI, and CT scans. Radical radiotherapy is
normally given in few regular doses in fractions 5 times a week. It enables the
tumor cells to get administered with a lethal dose, during which surrounding
cells get time to salvage and reconstruct the harm caused to the DNA due to
radiation. The matter that has been always debated is the upper hand of cobalt
machines as collated to the linear accelerators (Borras and Stovall, 1993).
“Short distance treatment” or the Brachytherapy is the technique in
which radioactive substance is placed directly in contact with the tumor. It
is effective for treating cervix cancer. In this procedure, cesium rods are put
inside the uterus and in the vagina radioactive material is inserted. It reduces
unwanted exposure of radiation in staff and relatives.
1.4.2.1 SIDE EFFECTS OF RADIOTHERAPY
Most people are tolerable to radiotherapy. Major adverse effects include

mucous membranes becoming edematous and painful, and skin reaction may
lead to severe cases of scarring and ulceration. Enteritis and diarrhea are
caused by abdominal radiations.
1.4.3 CHEMOTHERAPY
1.4.3.1 CELL CYCLE
Normal and cancer cells reproduce in the same manner, through the cell
cycle phenomenon. Figure 1.3 describes the cell cycle and the activity
of phases for commonly used antineoplastic agents (Buick, 1994). The
initial phase of the cell cycle termed as M phase is the Mitosis phase
that lasts about 30–60 min and cell division occurs in that phase.
After the first phase, the cell enters either to G0 or G1 phase. G0 is
a dormant phase called the resting phase. In phase G1, the cell manu-
factures necessary enzymes for DNA synthesis. Next is the S phase,
i.e., the synthesis phase, which lasts for 10–20 hrs. Flow cytometry is
an instrument that measures the percentage of cells in the S phase, and
it is the major signal for tumor cell proliferation. Then, after that, the
G2 phase or premitotic phase occurs for 2–10 hr. In this phase, the cell
prepares itself for cell division by manufacturing ribonucleic acid (RNA)
and specialized proteins, as well as the mitotic spindle apparatus. After
which, again, the M phase starts, and the cycle completes. The cell cycle
is controlled by external mitogens, including cytokines, hormones, and
growth factors and genes, namely proto-oncogenes and tumor suppressor
genes. Numerous anticancer drugs affect the proliferation of cells (both
normal and cancerous cells); these are called cell-cycle phase-specific
agents. The S phase is mainly affected by antimetabolites, and alkylating
agents have an effect on the multiphase of the cell cycle, for example,
nitrogen mustard. Cell cycle consideration is important for scheduling
chemotherapy; hence knowledge of the cell cycle is very crucial. At any
given time, the tumor cell may be at any particular phase in the cycle. The
phase-specific agents of the cell cycle are known as schedule dependent,
while cell-cycle phase-nonspecific drugs activity depends on their dose,
and hence these are called dose-dependent (Dang et al., 2003; Chabner et
al., 2001) (Figure 1.3).
1.4.3.2 MECHANISM OF ACTION OF ANTINEOPLASTIC AGENTS
A summary of the mechanism of action of various antineoplastic agents is

discussed in Table 1.6.
Phase G2
Topoisomerase
Inhibitors
Anti-tumor Antibiotics
Phase M
Taxanes
Vinca Alkaloids
Phase S
Antimetabolites
Cell Division
CELL CYCLE
Phase G0
Cell Growth
Alkylating Agents
Prepare for DNA
Platinum Derivatives
Phase G1 Replication
Hexam Ethylymelamine
Hormonal Agents
Anti-tumor Antibiotics
FIGURE 1.3 The cell cycle and the activity phases for commonly used antineoplastic agents
(DiPiro et al., 2017).
1.4.4 ANTINEOPLASTIC AGENTS
1.4.4.1 ANTIMETABOLITES
1.4.4.1.1 Pyrimidine Analogs
1. Fluorouracil (5‑FU): 5-FU is a fluorinated analog of the naturally occur-

ring pyrimidine uracil. It is a prodrug and metabolizes to an active form
called fluorodeoxyuridine monophosphate. In the presence of folates,
fluorodeoxyuridine monophosphate tightly binds and interferes with the
thymidylate synthase functions. This enzyme is essential for thymidine
production, one of the amino acids in DNA, and other. Other metabolites
of 5-FU, the triphosphate nucleotide, and causes hindrance in RNA
function. Both mechanisms produce the cytotoxic 5-FU (Pizzorno et al.,
2003).
2. Cytarabine: It forms an arabinose analog of cytosine. Its phos-
phorylation takes place in tumor cells to form active triphosphate
TABLE 1.6 Mechanism of actions of antineoplastic agents

Drugs Mechanism of Action
(Phosphonacetyl)-L-aspartate Inhibition of pyrimidine biosynthesis
Hydroxycarbamide Inhibition ribonucleotide reductase
Capecitabine 5-Fluoracil Inhibit dTMP synthesis
Cytarabine, Fludarabine, Cladribine and Inhibit DNA synthesis
Gemcitabine
Bleomycin Damages DNA
Cisplatin, Carboplatin and Dacarbazine Cross- linking of DNA
Vinea alkaloids and Taxanes Inhibit function of microtubules
6-Mercaptopurine Inhibition of biosynthesis of ring
6-Thioguanine Inhibition of interconversions of nucleotide
Methotrexate Inhibit purine ring biosynthesis
Teniposide, Irinotecan and Topotecan Damages DNA and prevent reconstruction
Dactinomycin and Anthracyclinrs Inhibition of synthesis of RNA
Source: DiPiro et al. (2017).
form. This active form inhibits DNA polymerase; it also inhibits

the replication of DNA. A deaminase enzyme, mainly cytidine
deaminase, opposes the activation of the active triphosphate form
by converting it into an inactive form. Renal impairment and
hepatic impairment cause the accumulation of a high level of active
form that causes neurotoxic effect (Pizzorno et al., 2003; Johnson,
2000; Smith et al., 1997).
3. Gemcitabine: It is a fluorine alternative deoxycytidine parallel associ-
ated with cytarabine in composition. Its mode of action is the same as
that of cytarabine. It inhibits DNA polymerase and also ribonucleotide
reductase. This enzyme converts ribonucleotides into the deoxyribo-
nucleotide forms. When compared to cytarabine, gemcitabine bioavail-
ability is more and also having greater penetration to the cell membrane
(Pizzorno et al., 2003; Johnson, 2000; Venook et al., 2000).
4. Azacytidine and Decitabine: Both antineoplastic agents were used
for the patient of myelodysplastic syndrome, a disorder of hemato-
poietic cell maturation that can progress to acute myeloid leukemia.
They both incorporate directly into DNA and inhibit the methyltrans-
ferase, which causes hypomethylation of DNA, resulting in cellular
differentiation and apoptosis (Silverman et al., 2002; McKeage and
Croom, 2006).
1.4.4.1.2 Purines and Purine Antimetabolites

1. 6‑Mercaptopurine and 6‑Thioguanine: They are the synthetic
analogs of the naturally occurring purines: guanine and adenine.
Both drugs are converted to ribonucleotides that result in inhibition
of biosynthesis of purine. It has been observed that co-administration
of these agents with purine increases interconversion reactions and
results in serious toxicity (Pizzorno et al., 2003).
2. Fludarabine Monophosphate: It is an analog of purine adenine.
It inhibits DNA polymerase resulting in chain termination, and also
inhibits transcription. Its toxicity is myelosuppression. It is basically
an immunosuppressive; thus, there is a chance of opportunistic infec-
tion resulting in a decline of the CD4 counts (Pizzorno et al., 2003;
Plosker and Figgitt, 2003).
3. Pentostatin and Cladribine: Both these agents are analogs of purine
nucleoside. Cladribine is converted to its working form that incorpo-
rates into DNA and causes inhibition of synthesis of DNA along with
chain termination. Pentostatin is an inhibitor of adenosine deami-
nase, this enzyme is important in the base metabolism of purine, and
a high concentration is found in the lymph tissue. Moreover, it also
causes immunosuppression; hence there is a chance of opportunistic
infections (Pizzorno et al., 2003; Johnson, 2000).
1.4.4.1.3 Antifolates
Folate is essential for DNA synthesis. Dietary folates are being converted
to tetrahydro forms, containing four hydrogens on the pteridine ring, this
conversion is carried out by dihydrofolate reductase (DHFR) enzyme,
and this tetrahydrofolate is essential for thymidylate and purine synthesis.
Deficiency of either thymidine or purines prevents the synthesis of DNA.
Methotrexate is an antifolate that inhibits the DHFR enzyme; lack of
tetrahydrofolate forms results in a deficiency of thymidine or purines that
alter the DNA synthesis. Resistance to antifolate caused by amplification of
DHFR slows the rate of thymidylate synthesis, decreased affinity of DHFR
for MTX, and lack of polyglutamation within tumor cells. Therapeutic
monitoring is a very crucial parameter for methotrexate. Cytotoxic effect of
methotrexate is observed as above 5 × 10–8 M. To recover from toxic effects
of this agent, Leucovorin is recommended until levels fall below 5 × 10–8 M
(Kamen et al., 2003).
1.4.4.2 DRUGS TARGETING MICROTUBULES
1.4.4.2.1 Vinca Alkaloids

Vinblastine, vinorelbine, and vincristine are natural alkaloids extract from
the vinca plant. These are inhibitors of mitosis. Both vinorelbine and vinblas-
tine cause myelosuppression with increasing dose, and vincristine shows
neurotoxic effects. They act on the tubulin protein that polymerizes to form
a microtubule. Vinca alkaloids cause an imbalance between polymerization
and depolymerization of microtubules. This result in the accumulation of
cell in mitosis and also induce apoptosis (Rowinsky, 2003).
1.4.4.2.2 Taxanes
Docetaxel and paclitaxel are natural plant alkaloid having antimitotic activity.
Paclitaxel is produced semi synthetically from the European yew plant, whereas
docetaxel is selected from 10-diacetyl baccatin III (Rowinsky, 2003). Taxanes
cause microtubule disassembling and stimulate tubulin polymerization, which
results in the formation of improper, non-functional toxicity. Moreover, taxanes
also inhibit the process of angiogenesis. Toxicity of docetaxel and paclitaxel
causes fluid retention and neurotoxicity, respectively (Krieger, 2002).
1.4.4.2.3 Topoisomerase Inhibitors
Topoisomerase is a key enzyme of DNA replication and transcription. It

forms a strand break to reduce the torsional strain during the process of DNA
unwinding. They form gaps through which DNA strands can pass, and then
they reseal. There are two types of Topoisomerase: II and I. Topoisomerase
I produces single-strand breaks, whereas topoisomerase II generate double-
strand breaks (Rubin and Hait, 2003). Anticancer drugs that attack the topoi-
somerase enzyme are camptothecins, anthracyclines, and epipodophyllotoxins.
1. Camptothecin Derivatives: It is a plant alkaloid isolated from Camp

totheca acuminata and has the potential of inhibiting DNA topoisom-
erase I. This drug produces severe toxicity. Its analogs are irinotecan
and topotecan and are synthesized in order to reduce toxicity and
improve therapeutic effects. Both these analogs inhibit the activity of
the topoisomerase I enzymes through the formation of SN-38 (Rubin
and Hait, 2003; Ulukan and Swaan, 2002; Raymond et al., 2002).
2. Etoposide and Teniposide: These are podophyllotoxin derivates

that are isolated from the mayapple or mandrake plant. It has two
mechanisms; first, it interferes with microtubule formation by
binding to tubulin, and second, it inhibits topoisomerase II, causing
the breaking of DNA strands (Rubin and Hait, 2003). Clinically it
was found that both are cross-resistant. It also affects the cell cycle,
i.e., they arrest the cells in S or early G2 phase. Hence, its effect is
shown much better in divided doses rather than a single dose.
3. Anthracene Derivatives: The members of anthracene derivatives
are daunorubicin, epirubicin, idarubicin mitoxantrone, and doxoru-
bicin, and out of them mostly used is doxorubicin. Also, they are
topoisomerase inhibitors. Intercalating agents are those compounds
that incorporate between DNA’s base pair. The planar group of
anthracene ring complex is responsible for intercalating with DNA.
Those results in changes in their structures that interfere with the
synthesis of DNA and RNA and also inhibit the topoisomerase II.
Moreover, anthracyclines also undergo electron reduction as a result
of which free radicals are formed. The final step needs iron. Iron
binds to anthracyclines, and their iron-anthracycline complexes bind
with the DNA and react quickly with hydrogen peroxide to produce
the hydroxyl radicals that actually responsible for cleaving the DNA.
Mitoxantrone has a similar mechanism as other derivatives, but their
potency for free radical formation is much less (Rubin and Hait,
2003; Danesi et al., 2002).
1.4.4.3 ALKYLATING AGENTS
This is the oldest and useful antineoplastic agent. All alkylating agents act
by forming a covalent bond of the alkyl group with the nucleophilic groups
of nucleic acids and proteins. The binding site of the alkyl group is a seven-
nitrogen group of guanines, this interaction causes cross-linking in the two
strands of DNA or between the two bases inside the same DNA strand that
causes the death of the cell and inhibits replication of DNA (Colvin, 2003).
1.4.4.3.1 Cyclophosphamide and Ifosfamide
These are nitrogen mustard derivatives. Both activated by mixed hepatic

oxidase enzymes, including the cytochrome P450 (CYP) 2B6 and CYP3A4/5
isoenzymes. The active metabolic product of cyclophosphamide is phos-

phoramide mustard, and another metabolite is 4-hydroxycyclophosphamide;
it is cytotoxic. Moreover, ifosfamide is hepatically activated to ifosfamide
mustard (Colvin, 2003).
1.4.4.3.2 Non-Classic Alkylating Agents
These are antineoplastic agents that act like alkylators, but their structure
does not resemble with classic alkylating agents. It includes dacarbazine,
procarbazine, temozolomide, the heavy metal compounds, and some anti-
tumor antibiotics (Colvin, 2003).
1. Dacarbazine, Procarbazine, and Temozolomide: Both dacarbazine

and procarbazine undergo demethylation to the same active inter-
mediate (monomethyl triazine-imidazole-carboxamide [MTIC]) that
interrupt in the replication of DNA by causing guanine methylation
and also inhibit DNA, RNA, and protein synthesis. Temozolomide can
easily cross the blood-brain barrier (BBB), hence can be therapeuti-
cally used for brain tumor tissue (Colvin, 2003; Stupp et al., 2001).
2. Heavy Metal Compounds: Heavy metals include platinum deriva-
tives, namely cisplatin, carboplatin, and oxaliplatin. They are used
in colorectal cancer. Their mechanisms involve the formation of
intra-strand cross-links or adduct between neighboring guanines,
this major illicit bending of DNA, and also cause damage to the
cells by damaging the normal conformation of DNA and prevent the
pairing of base-pair with each other. Toxicity includes nephrotox-
icity, ototoxicity, peripheral neuropathy, emesis, and anemia (Colvin,
2003). While carboplatin causes hematologic toxicity (Colvin, 2003;
Guminski et al., 2002).
1.4.4.4 MISCELLANEOUS AGENTS
1.4.4.4.1 Bleomycin
It is an antitumor antibiotic; basically, it is a mixture of fungal Streptomyces

species, and its strength is expressed in units of drug activity. One unit is
approximately equal to 1 mg of polypeptide protein. Its mechanism involves
the binding of iron bleomycin complex to DNA. This complex reduces to
form free radicals that cause the breaking of strands of DNA. It affects the
G2 phase of the cell cycle and also in mitosis (Lazo, 1999).
1.4.4.4.2 Hydroxyurea
It is a ribonucleotide reductase inhibitor; it targets the S phase of the cell

cycle, resulting in the formation of abnormal DNA strands (Pizzorno et al.,
2003).
1.4.4.4.3 L-Asparaginase
It is an enzyme produced by Escherichia coli and other bacteria. L-asparagine

is degraded by the enzyme L-asparaginase, which depletes existing supplies
and inhibits protein synthesis (Kurtzberg et al., 2003).
1.4.4.4.4 Arsenic Trioxide
It is effective for the treatment of acute promyelocytic leukemia (PML).

Also, it induces programmed cell death or apoptosis (Soignet et al., 2001).
1.4.5 PRINCIPLES OF PATIENT MANAGEMENT DURING

CHEMOTHERAPY
1.4.5.1 ASSESSMENT OF PATIENT FOR CHEMOTHERAPY
The four aspects of patient assessment are discussed in the following

subsections.
1.4.5.1.1 Patient’s Clinical Status and Performance
The Eastern Cooperative Oncology Group (ECOG) scale is used to grade

this (Oken et al., 1982).
Phase 0
• Fully active, able to carry on all pre-disease performance without
restriction.
Phase 1
• Restricted in strenuous physical activity but able to carry out work of
a light sedentary nature.
Phase 2
• Restricted in strenuous physical activity but able to carry out work of
a light sedentary nature.
Phase 3
• Capable of only limited self-care, confined to bed or chair more than
50% of waking hours.
Phase 4
• Completely disabled, cannot carry on any self-care, totally confined
to bed or chair.
Usually, patients with ECOG grade more than two are not considered
suitable for chemotherapy. The chemotherapy-sensitive cancers such as
lymphoma and small cell lung cancers (SCLCs) are the only exceptions.
1.4.5.1.2 Kind and Seriousness of Side Effects From Previous

Chemotherapy Cycles
Life-threatening side effects should be examined by the physicians. Firstly,

the type and severity of side effects should be ruled out. For example, it is
expected that peripheral neuropathy is common if a patient with breast cancer
undergoes taxane chemotherapy, but there is a need for dose reduction of the
subsequent cycle if the patient has a neutropenic fever in mid-cycle. The
precedent that is given by the NCI that contains the common terminologies
for the adverse events is applied for the grading of toxicity (Oken et al.,
1982).
1.4.5.1.3 Blood (Hematological) Parameters
The count of platelets that is greater than 100 x 109/L is required in the safer
management of chemotherapy. In the case of cisplatin and carboplatin, renal
function is important, and for docetaxel, liver function is important.
1.4.5.1.4 Non-Hematological Toxicity
The following are the common examples of non-hematological toxicity and

antineoplastic agents that need to be taken into consideration:
Diarrhea 5-FU-based, Irinotecan, Oxaliplatin, Taxotere
Neuropathy Cisplatin, Oxaliplatin, Taxanes, and Vinca alkaloids
Autotoxicity Cisplatin.
Renal Impairment Cisplatin.
Pulmonary Toxicity camptothecin and gemcitabine
The examination of the physical conditions to be followed, intravenous

infection sites, and side effects.
1.4.5.2 TERMINATION OF CHEMOTHERAPY
1. Cessation of treatment is necessary when there are any life-threat-

ening or severe dose-limiting toxicity.
2. Treatment may have to be stopped if the cancer is not curable and
other toxic side effects are caused.
3. Termination of therapy is required in case of deteriorating perfor-
mance status and organ function.
4. In order to improve symptom management, comfort and care unit
referral are done in the case of patients with metastatic disorders
even when they are currently undergoing treatment.
1.4.5.3 COMMON REACTIONS OR SIDE EFFECTS OF THE CHEMO

DRUGS
Some of the common adverse effects of the antineoplastic agents are

discussed in Table 1.7.
TABLE 1.7 Common Adverse or Side Effects of the Antineoplastic Agents

Drugs Used in Chemo Treatment Reactions/Side Effects
Cisplatinum/Platinol Functions of the kidney, levels of magnesium,
peripheral neuropathy
Gemcitabine Pneumonitis, peripheral edema
Taxol/Paclitaxel Peripheral neuritis, flu-like symptoms
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Sheep,” which were found to be so, and therefore the Devil must
needs have done it. But in this he neither nameth the place, time, nor
Author to avouch it, and therefore all reasonable Men may judge how
palpable a falsity it is, for then if true it would follow that none could
be safe, and that the Devil might kill immediately with swords or
knives, which he cannot do.
2. Whereas he De Lithias. c. 8. p. Observ. 2.
holdeth that the 75.
Devil doth bring or convey the things to be Hist.
injected near unto the place, and that he
offereth filth and poysons to his clients, that thereby he may
fermentally conjoin the Ideas of these formed in the imaginative
faculty with these. If the Devil be taken to be meerly and simply
incorporeal, then he cannot remove matter (as we have before
proved) and so cannot convey the things near to the object; and if he
be taken to be corporeal (as we have asserted) his help is needless,
because the Witches may do it themselves, as we find sufficient
stories of their hideing of strange and poysonous things under the
thresholds of houses and Churches; and to this purpose this same
Author telleth us this story: “A certain person (he saith) did by
custome use to make water in a corner of the Court, whereupon he
was afflicted with a bloody and cruel Strangury. And all the remedy
of the Physicians proved in vain, except that as often as he did drink
of Birch-Ale he did find a signal ease: But as oft as he rose and
walked, and made water in the same place, so often his pains did
return. At the last a pin of old black Oak-wood is espied to be fixed in
the place where he used to make water. Which being pulled forth and
burned he remained free from the bloody Strangury, by drinking Ale
of Birchen-twiggs. Also (he saith) that he remembred, that
Karichterus had written that he had loosed such kind of
inchantments by only pissing through Beesomes of Birch.” Now from
hence it is plain that this making water constantly upon this pin of
old black Oak-wood did cause his bloody Strangury, and that the
pulling of it up and burning of it, was with the help of the Birchen Ale
the cure; but it can no wayes be judged necessary that the Devil
should fix the Oak pin there, but that the Witch might do it himself.
Neither can it be thought to be any power given by the Devil to the
Oaken pin, that it had not by nature, for in probability it will
constantly by a natural power produce the same effect; only thus far
the Devil had a hand in the action, to draw some wicked person to fix
the pin there where the Man was accustomed to make water, thereby
to hurt and torture him, and so was only evil in respect of the end.
3. We observe and affirm that whatsoever Observ. 3.
effects are brought to pass by that which is
commonly called and accounted Witchcraft, if they be not brought to
pass by jugling, confederacy, delusion and imposture (as the most of
them are, if not all) then they are performed either by meer natural
causes, or the strength of the Witches fancy, and most vehement
desire of doing of mischief to those she hateth, or by both joined
together, and that Satan is no further an author or actor, but as he
leadeth and draweth the minds of the Witches to do such
mischievous actions, and pusheth on to seek about to learn of others
such secret poysons, charms, images and other hidden things, that
being used so or so, may produce such destructive ends as their
wicked and diabolical purposes are led to, and in this sense they are
his clients, and bounden vassals, and not otherwise.
4. The stories that he relateth are either Observ. 4.
all to be taken to be true, or none of them;
and if they be all alike equally to be credited, then it will undeniably
follow, that they were all alike produced by natural causes, and so no
need at all of the Devils assistance in performing of them, no more
than by working upon the minds of such as used those natural means
to a wicked and mischievous end. For first he giveth these instances
of things that were very strange that were voided either by vomit or
stool, by the ordinary power of nature, without suspicion of
diabolical cooperation, as the voiding of the piece of the brass
Cannon with its letters, with the Eele wrapped in its secundines: The
Dragon that the Oxe voided by taking three herbs, with a tail like an
Eele, a body like or of leather, with a Serpentine head, and not less
than a Partridge: The knife that the Thieves forced a man to swallow,
which he voided by an Apostume in the side, and was after sound:
also the arrow head of three fingers broad strucken into the back,
and after voided by stool, with diverse such which we recited before.
And that these being solid bodies should have penetrated and passed
through parts that are impatient of wounds, and in which a wound is
mortal, must of necessity be very wonderful, and might as soon and
upon as rational grounds be taken to be diabolical, as those that he
enumerateth to be so: For from these it is manifest that either nature
put to her last pinch doth make penetration of dimensions, or else so
inlarge the pores, that those solid bodies may pass without wound,
which (if seriously considered) is a stupendious operation and effect.
And as there needeth no cooperation of a diabolical power, for the
performing of these, no more needeth there any concurrence of
Devils to the others, that to that purpose he relateth. Only here is all
the difference: these are wrought by the ultimate endeavour of the
Archæus to save life; without the concurrence of external causes; the
others (that are therefore called diabolical) are commonly wrought
for a bad end, namely to hurt or to take away life, and have an
external cause, to wit, the force of the Witches imagination and
strong desire of doing of mischief, which is stirred up to that end by
Satan, and therefore in regard of the end are devilish, though they be
both wrought by the agency of nature, the one in the body of the
imaginant, the other in the body that the Witch intendeth to hurt by
the force of her imagination and vehement desire, whereby a seminal
Idea is created or formed, which is sufficiently operative to
accomplish the end intended.
5. The Syl. Syl. Cent. 10. p. Observ. 5.
arguments that he 556.
bringeth to prove penetration of dimensions to be in nature, or
something equivalent thereunto, seem to be strong and convincing.
For in the generation of things, whosoever shall seriously and strictly
mark, shall find (as he alledgeth) that the spirit of the Archeus
(though not altogether incorporeal) doth in the seeds of things
penetrate it self, and their parts one another, which he further
maketh good by the instance of Gold generated of water; for it must
of necessity be, that more than fifteen parts of water must fall in or
penetrate one another, that from thence one part of Gold may be
made, for weight is not of nothing, but argueth the matter ponderous
in the Ballance. Therefore naturally the water must so oft penetrate
its body as the Gold doth preponderate the water. And though it be
granted that the water hath pores, yet notwithstanding it cannot
contain so much as fourteen times, it whole. And therefore he
irrefragably concludeth: Est ergo ordinarium in natura, quod
aliquæ partes aquæ se penetrent in unicum locum. And this he
backs with an unanswerable story of a Woman that longing for
Muscles, did in greediness eat some of them with the shells twice or
thrice broken with her teeth, and that she brought forth a child with
the same half eaten shells, and a wound in the belly; therefore those
shells had penetrated the stomach, womb and secundines, or
otherwise the force of the Archeus had opened the pores and letten
them pass in an unconceiveable manner. So that if these things be
granted to be true (and we confess we know not how they can be
answered) then there need no diabolical power be brought to solve
the injecting of strange things into mens bodies, seeing nature is
sufficient of it self, and therefore we can allow no power at all unto
Devils in effecting these things (if they be truly done, and be not
delusions) but only in drawing the minds of the Witches to these
wicked and mischievous courses; and therefore the Lord Bacon said
profoundly and wisely these words: Ut in operationibus illis earumq;
causis error cavendus est, ita quoq; danda vel imprimis opera est,
ne effecta nobis imponant, temere judicantibus talia esse, quæ
eousq; nondum processerunt. Sic prudentes judices, præscripta
velut norma, fidem haberi temere nolunt confessionibus sagarum,
nec etiam factorum contra illas probationi. Sagas enim turbat
imaginationis vertigo, ut putent se illud facere, quod non faciunt,
populumq; hîc ludit credulitas, ut naturæ opera imputent fascino.
6. And to confirm this point he addeth far Observ. 6.
more stupendious matters of fact than the
former, of things that were within, being taken to without or invisibly
conveyed away, as the woman at Mechlin that saw the Souldier in a
conflict lose his hand, and forthwith brought forth a Daughter
wanting an hand, which was never found, and the wench died of the
Hæmorrhage. Another at Antwerpe seeing a Souldier begging with
his right arm shot off and bloody, forthwith brought forth a Daughter
wanting the right arm whose bloody shoulder the Chirurgeon cured,
and she was married after; and that the arm was never found, neither
did there appear any bones or putrefied matter into which the arm
might waste. Also another Woman going to see the Decollation of
thirteen men; did soon after bring forth a mature Child with a bloody
neck, the head no where appearing. I confess it would rack the
judgment even of the most credulous to the highest pitch to believe
these unparallel’d Stories; but the Author relating them as of his own
knowledge, and being a person of unquestionable veracity, I cannot
conceive how they can rationally be denied, especially finding Mr
Boyle to affirm, that in those experiments (much more relations of
matters of fact) that Helmont avouched upon his own knowledge, he
durst be his Compurgator. Who would not believe but that these
things could never have been done, but by a supernatural and
Diabolical power, but that this Author (to which all judicious persons
in reason may adhere) doth utterly deny, that the arm was either
pull’d away or conveyed none can tell whither, by Satan, and
therefore that in such a strange Paradox, trivial reasons are not to be
allowed; and it were too much sloathfulness to ascribe all effects unto
Satan, of which we are ignorant. And therefore if an hand, an arm,
nay an whole head, could be separated from the rest of the body, and
conveyed forth of the Womb by the Archeus or natural spirit,
thereunto excited by the impression of horror and terror in the
Women: In like manner by the same power of the natural spirit of
man or woman, excited by a vehement and fierce imagination to
revenge and to do mischief, may strange things be injected (if there
can be any sound proof of such a matter of fact) into the bodies of
such men or women as the Witches intend to do hurt unto, and yet
Satan hath no more hand in it, but only as a spiritual agent to move
the wills of those wicked and malicious people to do mischief unto
those that they hate, though without cause. And the great secret of
that which may be called Witching, is the learning of others, who
likewise have had it by tradition, the great force of imagination, and
the natural spirit with the ways and means how to excite it and exalt
it; herein stands the mystery of all Magick, and it becomes only evil
in the use and application, and they are to be condemned that use it
to such devillish ends, even as those that use those good Creatures
that nature doth produce to poysonous, wicked, and destructive
purposes. And lastly, here we may note, that if things or bodies that
are without may be injected into the bodies of others, by the force of
exalted, imagination and a vehement desire, then the same power
that doth inject them through skin, flesh and bones, must also be
able to bring them near to the place, and need not at all the
assistance of Satan, because it is far easier to carry them near the
place, than to thrust them into the body; and so this Author hath
here introduced the Devils aid to bring them to the place to no
purpose, and never yet proved either by reason or matter of fact, that
ever Satan did any such thing, and so is a meer supposition without
proof.
7. The other De occult. nat. Observ. 7.
matters of fact that mirac. l. 2. c. 40. p.
he relateth are 325.
prodigious, and Hist. De Tumor. l. 6. c.
are brought to prove that Satan is an actor 19. p. 158.
to convey these strange things into the bodies of men, and are these.
A piece of an Oxe Hide taken forth of a mans Arm, so also that
Equuleum, a Wood-Horse, or a four-footed board with a wheel and
ropes twice as broad as the gullet. Another that vomited up perhaps
two thousand pins conglomerated together, with filth and hairs;
another that vomited up, he being present, wooden Chips that had
been cut off with the Hatchet in smoothing of wood, with much slime
to the bigness of two fists, of which we shall note these Conclusions.
1. It doth no way appear (if these things be granted to be true, both
for matter and manner) neither doth he offer to prove it, that these
are any more than the former Diabolical, but only in the end, because
they are for the hurt and destruction of mankind and not otherwise;
and there being no proof of the Devils Cooperation any further but in
working upon the minds of those that are agents and instruments to
bring these things to pass, we may very well reject those things that
are supposed, but not proved. 2. The ejecting or voiding of such
strange things as here he hath related, doth not necessarily suppose
their injection or thrusting in, because they may be bred there by
natural Causes, so Worms of many sorts and strange Figures, also
Frogs, Dracunculos and Askers have been voided, and doubtlesly
bred there by natural causes, and were not injected or thrust in, and
for proof of this I refer the Reader to the relations of learned
Schenchius lib. 3. p. 363. of those strange sorts of Worms and other
Creatures that he from divers Authors sheweth have been vomited
up, which without all scruple, were not injected, but bred there. To
confirm this and to prove what strange things are sometimes bred in
Apostumes and Tumors, we shall translate a passage or two, and first
take this from Levinus Lemnius that learned and famous Physician
of Zeland, who writeth thus: “Also forth of sordid Ulcers and
Impostures (he saith) we have known that the fragments of nails,
hairs, shells, little bones and stones have been taken forth; which
were concreted and grown together forth of putrid humours: As also
little creatures, worms with tails, and little beasts of an
unaccustomed form, cast up by vomiting, especially in those who
were oppressed with contagious diseases, in whose urines I have
often discerned to swim little Animalcles like to Pismires, or to those
creatures we observe in the estival months to move in the celestial
dew here in England we call it Woodsoar, or Cuckow-spittle.” Take
another from that learned and expert Chirurgeon Ambrosius Paræus
where he is speaking of strange tumors, in these words: “Also in
these tumors being opened thou maist see bodies of all kinds, and far
differing from the common matter of Tumors, as stones, chalk, sand,
coals, cockles, ears of corn, hay, horn, hairs, flesh as well hard as
spongious, grisles, bones and whole Animalcles, as well living as
dead. The generation of which things (by the corruption and
alteration of the humors) will not much astonish us, if we consider,
that even as nature hath framed Man as a Microcosm forth of all the
seeds and elements of the whole great world, that he might be as it
were the lively image of that great world: So in that Microcosm,
nature hath willed, that all the species of all motions and actions
might be manifest, nature being never idle in us, as long as matter is
not a wanting to work upon.” So that it is most plain that these
strange things may be bred within, and so the opinion of injecting
them, is but a meer figment. 3. Neither can the vomiting up of such
strange things as he relateth, conclude necessarily that they were
injected either by the power of Satan or the Witch, because they may
be performed by jugling, sleight of hand, confederacy and the like, as
was manifest in the Boy of Bilson, and diverse that we have known,
that had made some numbers of others to believe that they had
voided strange things, as pins, needles, crooked-knitting-pricks,
moss, nails, and the like; but upon a strickt search, have but proved
delusions and sleight, such as our common Hocus Pocus Men use,
when they make the people believe they swallow a long pudding of
white tinn, and again pull it forth of their mouths, or in pulling
ribbins, or laces of diverse colours forth of their throats. 4. And again
the most of these relations are but commonly taken upon trust from
the affirmations of the by-standers who might be confederate parties,
or ignorant persons, and so easily deceived; and it appeareth not that
Helmont was by at the very instant when the children vomited up the
wooden horse, or four-footed board, but that it was the by-standers
that drew it forth, who might be parties to the cheat, or be
themselves deluded, and so aver it pertinaciously to others. For I
have in my practice known a young Wench about 9 or 10 years old,
who that she might be pittied and have an idle life, had made her
Father and Mother believe that quick worms came forth at her ear,
and also I taking her into mine own house she had perswaded all the
family that it was true, and did often open her head-cloaths, and
holding down her ear a quick worm would drop forth of the hair, who
notwithstanding by diligent watching, was found out to get them
privately from under stones or wood, and so did cunningly convey
them into her hair, but being discovered, was by due correction
reclaimed, and so the wonder ceased. And it is as common to mistake
things, either by absolute judging them to be such a thing indeed,
when it hath but some slender resemblance of it, or by judging a
thing to be really so, because of such a name but metaphorically
given unto it; so it is usual to call a Carcinoma in the highest degree
Lupus or a Wolf, because as a Wolf is a most voracious creature, so
this ulcer is the most devouring of all others; and therefore have we
known after that such have been by incision eradicated by our selves
and others, and exposed to the view of the vulgar people, they would
presently most earnestly affirm to others that they had seen it, and
that it was a living creature, and had mouth, eyes and ears; so far will
ignorant mistake induce credulity.
8. That the force Syl. Syl. Cent. 10. p. Observ. 8.
of imagination 583.
accompanied with the passions of horror, fear, envy, malice, earnest,
desire of revenge, and the like, is great upon the body imaginant, as
also upon the fœtus in the womb, is acknowledged by all. But that it
can at distance work upon another body, though denied by Fienus
and the whole rabble of the Schoolmen, yet is strongly proved by this
learned Author, and allowed of by all others that truly understood
the operations of nature, which we also take to be a certain truth, and
do assert that if those people that are esteemed Witches, do really
and truly (of which we utterly doubt) inject any of these strange
things into the bodies of men, that they are brought to pass meerly
by the imagination of the Witch, and the Devil acteth nothing in it at
all, but the setting of his will upon that mischief. As for the handling
the dispute concerning the manner of the injecting of these strange
things, so strongly pursued by this Author, Sennertus and others, we
shall totally supersede and suspend our judgment, until the ὅτι be
sufficiently proved (which yet lies under water, and unseen) and then
it will be time enough to dispute the manner, when the matter is
certainly made evident. Therefore we will shut up this with that
modest and grave advice of the Lord Bacon in these words: Ideo
cogemur in hac inquisitione ad nova experimenta confugere; ubi
directiones tantùm eorum præscribi possunt, non ulla positiva in
medium adferri. Si quis putet subsistendum nobis fuisse, donec
tentamentis res penitus innotuisset, (ut fecisse nos ubiq; probant
alii tituli) sciat dubia nos fide amplecti quæcunq; imaginationis
effecta circumferuntur, animum tamen esse illa per otium exigere
ad Lydium veritatis lapidem, id est, experimentorum lucem.
CHAP. XIII.
That the ignorance of the power of Art and Nature and such like
things, hath much advanced these foolish and impious opinions.
The opinions that we reject as foolish and impious are those we have
often named before, to wit, that those that are vulgarly accounted
Witches, make a visible and corporeal contract with the Devil, that he
sucks upon their bodies, that he hath carnal copulation with them,
that they are transubstantiated into Cats, Dogs, Squirrels, and the
like, or that they raise tempests, and fly in the air. Other powers we
grant unto them, to operate and effect whatsoever the force of
natural imagination joyned with envy, malice and vehement desire of
revenge, can perform or perpetrate, or whatsoever hurt may be done
by secret poysons and such like wayes that work by meer natural
means.
And here we are to shew the chief causes that do and have
advanced these opinions, and this principally we ascribe to mens
ignorance of the power of Nature and Art, as we shall manifest in
these following particulars.
1. There is nothing more certain than, that how great soever the
knowledge of Men be taken to be, yet the ultimate Sphere of natures
activity or ability is not perfectly known, which is made most
manifest in this, that every day there are made new discoveries of her
secrets, which prove plainly that her store is not yet totally
exhausted, nor her utmost efficiency known. And therefore those
Men must needs be precipicious, and build upon a sandy foundation,
that will ascribe corporeal effects unto Devils, and yet know not the
extent of nature, for no Man can rationally assign a beginning for
supernatural agents and actions, that does not certainly know where
the power and operation of nature ends.
2. And as it is thus in general, so in many particulars, as especially
in being ignorant of many natural agents that do work at a great
distance, and very occultly, both to help, and to hurt, as in the
weapon salve, the Sympathetick powder, the curing of diseases by
mumial applications, by Amulets, Appensions and Transplantions,
which all have been, and commonly are ascribed unto Satan, when
they are truly wrought by natural operations. And so (as we have
sufficiently manifested before) by many strange, and secret poysons
both natural and artificial, that have no bewitching power in them at
all, but work naturally, and only may be hurtful in their use through
the devilishness of some persons that use them to diverse evil ends.
3. There is nothing that doth more clearly manifest our scanted
knowledge in the secret operations of nature, and the effects that she
produceth, than the late discoveries of the workings of nature, both
in the vegetable, animal and mineral Kingdoms, brought dayly to
light by the pains and labours of industrious persons: As is most
evident in those many elucubrations, and continued discoveries of
those learned and indefatigable persons that are of the Royal Society,
which do plainly evince that hitherto we have been ignorant of
almost all the true causes of things, and therefore through blindness
have usually attributed those things to the operation of Cacodemons
that were truely wrought by nature, and thereby not smally
augmented and advanced this gross and absurd opinion of the power
of Witches.
4. Another great means in advancing De occult. Philos. l.
these Tenents hath been Mens supine 1. c. 2.
negligence in not searching into and experimenting the power of
natural agents, but resting satisfied in the sleepy notions of general
rules, and speculative Philosophy. By which means a prejudice hath
been raised against the most occult operations of nature, and natural
magick (which is (as Agrippa truly said) “The comprizer of great
power, full of most high mysteries, and containeth the most
profound contemplation, nature, power, quality, substance and
virtue of most secret things, and the knowledge of all nature) to be
condemned, as the work of the Devil and hellish fiends, which is the
handmaid and instrument of the Almighty.” And from this diabolical
pit of the ignorance of the power of nature (especially when assisted
by art) have sprung up those black and horrid lies in the mouths of
Erastus, Conringius and above all of Kircherus, denying the
possibility of the transmutation of metals, by the power of Art and
Nature, and ascribing the performance thereof by Paracelsus,
Lullius, Sendinogius and others to the Devil; so malevolent do men
grow when they are led by nescience and ignorance.
5. The ignorance of the strange and Vid. Theatr. Chym.
wonderful things that Art can bring to pass Vol. 5. p. 943.
hath been no less a cause, why the most admirable things that Art
bringeth to pass by it are through blind ignorance ascribed unto
Devils, for so have many brave learned Artists, and Mechanicians
been accused for Conjurers, as happened to Roger Bacon, Dr. Dee,
Trithemius, Cornelius Agrippa, and many others, when what they
performed was by lawful and laudable art. The strange things that
the Mathematicks and Mechanicks can perform are hardly to be
enumerated, of which were those most wonderful catoptrical glasses
mentioned by Nicero, Aquilonius, Baptista Porta and many others,
those wonderful engines in the shape of Birds, Men, Beasts, and
Fishes that do move, sing, hiss and many such like things mentioned
by Heron of Alexandria, and our Countryman Dr. Fludd; and those
that would have more ample satisfaction concerning the stupendious
things that are produced by art, may receive most large satisfaction
in reading that most learned and elaborate Epistle written as a
preface before the Book of Johannes Ernestus Burgravius called
Biolychnium vel de lampade vitæ et mortis, by Marcellus
Vranckheim Doctor of both laws, as also in reading that profound
and mysterious piece written by Roger Bacon, de admirabili
potestate artis et naturæ, et de nullitate magiæ, with the learned
notes of Dr. Dee upon it, of which he saith this: Ut videatur quod
omnis potestas magica sit inferior his operibus et indigna. And
therefore there can be nothing more unworthy, than for any man,
that pretendeth to any portion of reason, so far to dote, or suffer
himself to be led with ignorance and rashness, as to ascribe those
strange things that Nature and Art, or both joined together do
produce, unto Devils: And yet there is nothing that is more common
not only by the blind vulgar, but even by those that otherwise would
be accounted learned, and wise enough; pride and folly attendeth the
most of the Sons of Men.
6. Another gross mistake there is, in Hist.
supposing those strange things that are
performed by vaulters, tumblers, dancers upon ropes, and such like,
not possible to be done but by the assistance of the Devil, when they
are altogether brought to pass and effected by use, custome, exercise,
nimbleness and agility of body. And yet we have known some not
only of the popular rank, but many that thought themselves both
wise, learned and religious that have been so blind as to father these
things upon Devils and seriously to seem to believe, that the actors of
these things had made a league and compact with the Devil, by
whose help they performed them. And I do remember that a pretty
active young man, within these few years went about in this North
Countrey with a neat Bay Mare for money to shew tricks, which were
very odd and strange, for if she had been blindfolded, and several
pieces of money taken from several persons, and wrapped in a
cloath, the Mare would have given every one their own piece of
money; and this and many other feats she plaid, were not only by the
common people, but by others that should have been more wise,
judged to be performed by no other means but by the Devil, and
some were so stark mad as to believe and affirm that the Mare was
not a natural one, but that it was the Devil that plaid those strange
tricks in the shape of a Mare: when more sober judgments knew that
they were performed by the masters eye, and rod directing the Mare.
Error & credulitas multum in hominibus possunt.
7. In like manner are often both those that are learned, as well as
the vulgar most wofully imposed upon by the odd and strange feats
performed by Legierdemain, sleight of hand, and by wonderful
things brought to pass by subtile and cunning Impostors that act by
confederacy, and the like, of which we have given some instances
before in this treatise. And it was no evil piece of service, that Master
Scot did in his book of the discovery of Witchcraft, when he laid open
all the several tricks of Legierdemain and sleight of hand, thereby to
undeceive the ignorant multitude; and that is no less praise-worthy
that is performed by the Author of that little treatise called Hocus
Pocus junior, where all the feats are set forth in their proper colours,
so that the most ignorant may see how they are done, and that they
are miracles unknown, and but bables being discovered, which
treatise I could commend to be read of all Witchmongers and vain
credulous persons, that thereby their ignorance may be laid open,
and they convinced of their errors.
8. The ignorance or mistaking of these things, joyned with the
notions Men have imbibed from their infancy, together with
irreligious education, are the true and proper causes, that make so
many ascribe that power to Devils and Witches, that they neither
have, or ever had, or can ever bring into act. And therefore it
behoveth all that would judge aright of these abstruse matters, to
labour to understand the secret operations of nature, and the strange
works of art, to divest themselves of their false imbibed notions, and
truely and rightly to understand the Articles of the Christian Faith, to
be daily conversant in reading the Scriptures, they will then be more
fit to judge of these things, and not to call light darkness, nor
darkness light.
CHAP. XIV.
Of diverse Impostures framed and invented to prove false and

lying miracles by, and to accuse persons of Witchcraft, from
late and undeniable authorities.
In the treatise preceeding we have often made mention of delusions

and Impostures, which we shall largely handle in this place: and
though Mr. Glanvil, and others do object, that though many
pretended possessions or Witchcrafts have been proved to be meer
couzenings and impostures, yet therefore it will not follow that all are
so. To which we shall render these answers.
1. If it do not necessarily conclude, that they are all impostures, yet
it gives a most shrewd cause of dubitation that they may be so. And
the objection depends not upon a necessary connexion betwixt the
subject and predicate, for some being direct and palpable
Impostures, it is not of necessity, but by contingency or accident that
the others are not so, and ought first to have been proved, which
never yet was performed.
2. But we affirm that a general conclusion drawn from an inductive
argument is good and sound, where no instance can be clearly made
out to the contrary. But as yet no true instance, really and faithfully
attested, hath ever been brought to prove that any of these things
that we deny, were ever effected by diabolical power. For who were
ever by and present, that were persons of sincerity and sound
judgment, that could truly testifie and averr that the Devil in a visible
and corporeal shape made a contract with the Witch, or that he suckt
upon his, or her body, or that he had carnal copulation with them, or
that saw when the Witch was really changed into a Dog or a Cat, or
that they flew or were carried in the air? Seeing no instance can be
given to prove any of these to be undoubted truths, it must needs
follow that they are meer figments, or at the best all but absolute
Impostures. And again it is but precarious, and petitio principii, to
imagine that any persons have vomited up or voided strange things
that saw or knew that they were injected by Devils, for they were
either naturally bred there, or else were meer Impostures and
delusive Juglings.
And therefore we shall propose some Histories of strange and
prodigious cheats and Impostures from late and unquestionable
authorities, whereby all the rest may be judged and discerned; of
which take this for one.
“1. Elizabeth Vid. Stat. Pulton, Hist. 1.
Barton of Kent (by 25. year Henr. 8. c.
those that 12.
laboured to cry up The Pope. Vid Chron.
her horrible cheats for miracles, otherwise Hollingshead. Stow
An. Hen. 8. 25. p.
called the holy Maid of Kent) and others 1013.
were in the twenty fifth year of King Henry
the Eighth attainted of High Treason, for that under colour of
hypocrisie, Revelations and false Miracles practised by the said
Elizabeth, they conspired to impugne and slander the divorce
between the King and Queen Katherine his first Wife, and the last
Marriage between him and Queen Anne his second Wife, to destroy
the King, and to deprive him of his Crown.” Her false and feigned
miracles, and the subtile and cunning contrivances that were brought
to pass by the help of her confederate accomplices, and her and the
others open confession of them may be found at large in
Hollingshead, Stow, and the writings of Mr. Lambert, whither for
brevities sake I remit my reader, and shall only give it here in the
words of Speed, which are these: “The Romanists (he saith) much
fearing that Babel would down, if Queen Anne might be heard
against wicked Haman, sought to underprop the foundations thereof
with certain devices of their own: and that the same might pass
without note of suspicion, they laid their forgery even upon Heaven it
self; whose pretended oracle Elizabeth Barton (commonly called the
holy Maid of Kent) was made to be; and the pillars of this godless
Fabrick were Edward Bocking a Monk by profession, and Doctor of
Divinity, Richard Masters Parson of Aldington, the Town wherein
she dwelt; Richard Deering a Monk, Hugh Rich a Friar, John
Adestone and Thomas Abell Priests, put to their helping hands; and
Henry Gould Batchelor of Divinity, with John Fisher the reverend
Father of Rochester imployed their pains to dawb these downfalling
walls with their untempered morter. The Scribes that set their pens
for her miracles, were Edward Thwaites Gentleman, and Thomas
Lawrence Register, besides Haukherst a Monk, who writ a letter that
was forged to be sent her from Heaven; And Richard Risby and
Thomas Gould were the men that dispersed her miracles abroad to
the world. This holy Maid Elizabeth made a Votaress in Canterbury,
was taught by Bocking her Ghostly Father, and suspected Paramour,
to counterfeit many feigned trances, and in the same to utter many
virtuous words for the rebuke of sin, under which more freely she
was heard against Luthers doctrine, and the Scriptures translation,
then desired of many: neither so only, but that she gave forth from
God and his Saints by sundry suggestive Revelations, that if the King
proceeded in his Divorce, and second Marriage, he should not raign
in his Realm one month after, nor rest in Gods favour the space of an
hour. But the truth discovered by Gods true Ministers, this oracle
gave place as all other such did, when Christ by his death stopped
their lying mouths: For her self and seven of her disciples were
executed for Treason at Tiburn, and the other six put to their fines
and imprisonment.” To which he subjoineth this story of the like
nature. “With the like counterfeit Revelations and feigned
predictions this generation of hypocrites had brought Edward Lord
Stafford Duke of Buckingham, unto his unhappy end, by the working
of John de la Court his own Confessor, together with Nicholas
Hopkins a Monk of the Carthusian Order in the Priory of Henton in
Somersetshire, who by his visions from Heaven forsooth, heartned
him for the Crown; But before his own Coronet could aspire to that
top, he worthily lost both head and all upon Tower-hill for his
Treason, Anno Domini 1521. Unto such sins the world was then
subject, and into such conceits their reputed holiness had brought
them, not only among the simple and unlettered, but even with them
that seemed to be learned indeed: For by certain predictions
foreshewing a great deluge, Prior Bolton of S. Bartholomews in
London, was so fearful that he built himself a house upon the height
of Harrowhill, storing it with provisions necessary to keep himself
from drowning in Anno Dom. 1524.
2. And that we Stow’s Chron. p. Hist. 2.
may be certified 678.
how frequent and common these counterfeited Impostures have
been, and yet are practised, take this other from undoubted
authority. “The 15 of August being Sunday in the 16 of the raign of
Queen Elizabeth, Agnes Bridges a Maid about the age of 20 years,
and Rachel Pinder a Wench about the age of 11 or 12 years, who both
of them had counterfeited to be possessed by the Devil (whereby they
had not only marvellously deluded many people both Men and
Women, but also diverse such persons, as otherwise seemed of good
wit and understanding) stood before the Preacher at Pauls-cross;
where they acknowledged their hypocritical counterfeiting with
penitent behaviours, requiring forgiveness of God and the world, and
the people to pray for them. Also their several examinations and
Confessions were there openly read by the Preacher, and afterwards
published in print, for posterity hereafter to beware of the like
deceivers.” From whence we may take these two Observations.
1. We may from hence note, how subject Observ. 1.
the nature of man is both to deceive and to
be deceived, and that not only the common people, but also the wiser
and more learned heads may most easily be imposed upon. And, that
therefore in things of this nature, and the like, we cannot use too
much circumspection, nor use too much diligence to discover them.
2. We may note, that when such strange Observ. 2.
Impostures or false Miracles are pretended,
there is commonly some sinister and corrupt end aimed at, under the
colour of Religion, and that those that are most ready to publish such
things as true Miracles and Divine Revelations, are generally those
that did complot and devise them. And therefore the greater number
they be that cry them up, and the more esteem the persons are of
that blow abroad such things, the greater suspicion we ought to have
of the falsity and forgery of them. Always remembring that the
greater the fame and number of the persons are that conspire and
confederate together, the greater things they may bring to pass, and
be more able to deceive, as was manifest by the Priests attending the
Oracles; who, though they laboured to father their predictions upon
some Deity, yet it was manifest that it was nothing else, but their
own Confederacy, Impostures and Juglings.
3. But these Vid. A Book called, Hist. 3.
Diabolical A discovery of
Counterfeitings of fraudulent
practices
possessions, and concerning
the maintaining of pretended
the power of possessions.
dispossession and Vid. ibid. Dialog. 11.
casting forth of Devils, was not only upheld p. 352.
and maintained by the Papists to advance
their superstitious courses; but also in the said time of Queen
Elizabeth, there were divers Non-Conformists, to gain credit and
repute to their way, that did by publick writing labour to prove the
continuation of real possessions by Devils, and that they had power
by fasting and Prayer to cast them out. Of which number were one
Mr Darrell and his Accomplices, who not only writ divers Pamphlets
in the positive defence of that opinion, but also published certain
Narrations of several persons, that they pretended were really
possessed with Devils, which were cast forth by their means in using
Fasting and Prayer. Which writings were answered by Mr Harsnet
and others, and their Theory not only overthrown, but their practice
discovered to be counterfeiting and Imposture. Whereupon there
were divers persons suborned to feign and counterfeit possessions,
as William Sommers of Nottingham, who by the Exorcists was
reported to have strange fits, passions and actions; which are at large
described and set forth in that learned Treatise, Dialogical
Discourses of Spirits and Devils, written about the same time by
John Deacon and John Waller, Ministers, and of divers other
persons who likewise pretended the same counterfeit possessions.
And though the said forged and feigned possessions were strongly
maintained by their Abettors, and the matters of fact audaciously
asserted to be true; yet after the said Darrell and his Accomplices
were examined by the Queens Commissioners, all was made
apparent to be notorious counterfeiting, cheating and imposture,
both by the confession of Sommers himself, and by the Oaths of
several Deponents. Neither was that discourse containing the certain
possession of seven persons in one Family in Lancashire, at
Cheworth in the Parish of Leigh, in the Year 1594. (though believed
by many for a truth, because of the streight tale told by the said
Darrell in that Narrative) of any better grain, but full of untruths,
impossibilities, absurdities and contradictions.
4. Our next Vid. The cunning of Hist. 4.
instance shall be a the Boy of Bilson, p.
most strange 55.
imposture acted in the time of King James, and in a manner known
unto the whole Nation; that is of the Boy of Bilson in Staffordshire,
in the year 1620. by name William Perry, whose condition as he had
been taught, and so left by the Popish Priests, take as followeth. “This
Boy being about thirteen years old (but for wit and subtilty far
exceeding his age) was thought by divers to be possessed of the Devil,
and bewitched, by reason of many strange fits and much distemper,
wherewith he seemed to have been extreamly affected. In those fits
he appeared both deaf and blind, writhing his mouth aside,
continually groaning and panting, and (although often pinched with
mens fingers, pricked with Needles, tickled on his sides, and once
whipped with a Rod, besides other the like extremities) yet could he
not be discerned by either shrieking or shrinking to bewray the least
passion or feeling. Out of his fits he took (as might be thought) no
sustenance which he could digest, but together with it, did void and
cast out of his mouth, rags, thred, straw, crooked pins, &c. Both in
and out of his fits his belly (by wilful and continual abstinence
defrauding his own Guts) was almost as flat as his back, besides, his
throat was swoln and hard, his tongue stiff and rolled up towards the
roof of his mouth, insomuch that he seemed always dumb, save that
he would speak once in a Fortnight or three Weeks, and that but in
very few words.
“Two things there were which gave most just cause of presumption
that he was possessed and bewitched; one was that he could still
discern when that Woman (which was supposed to have bewitched
him) to wit Jone Cocke was brought in to any room where he was,
although she were secretly conveyed thither, as was one time tryed
before the Grand Jury at Stafford: The second, that though he would
abide other passages of Scripture, yet he could not indure the
repeating of that Text, viz. In the beginning was the word, &c. Jo. 1.
ver. 1. but instantly rolling his eyes and shaking his head, as one
distracted, he would fall into his usual fits of groaning, panting,
distraction, &c. In which plight he continued many months, to the

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Metastatic Diseases: Novel Approaches

in Diagnosis and Therapeutic

Novel Therapeutic Approaches Targeting Oxidative Stress

Diagnosis and Management of Pediatric Diseases

Modern Occupational Diseases Diagnosis, Epidemiology,

Physics Galaxy 2020 21 Vol 3A Electrostatics Current

Diagnosis and Management of Primary Bone Tumors-Volume

Rare Lung Diseases: A Comprehensive Clinical Guide to

Therapeutic Approaches in Cancer Treatment Asma Saleem

Applying Cognitive Behavioural Therapeutic Approaches

© 2022 Apple Academic Press, Inc.

CIP data on file with Canada Library and Archives

Library of Congress Cataloging‑in‑Publication Data

Sandeep Arora, PhD

Sandeep Arora, PhD, MPharm, is Dean/Director of the

Tapan Behl, PhD

Tapan Behl, PhD, MPharm, is currently working as

Sukhbir Singh, PhD

Sukhbir Singh, PhD in Pharmaceutical Science, is a

Neelam Sharma, PhD

Neelam Sharma, PhD in Pharmaceutical Science, is a

Saurabh Gupta, PhD, is an Associate Head of the

Contributors ......................................................................................................... xiii

1. A Review on Cancer: From Clinical Perspective to Chemotherapy ......... 1

2. Phosphoprotein‑Enriched Astrocytes as Potential Anticancer

3. Autophagy‑Modulating Drugs as Complements to Cancer

4. Transthyretin Protein in Renowned Metastatic and Other

5. Role of CXCR4 Receptor Protein in Cancer Development and

6. C3D Complement System in Immunotherapy‑Based Cancer

7. BH3 Mimetics ............................................................................................. 101

8. Spherical Nucleic Acid Platform‑Based Drug Delivery for

9. Intra‑Vital Microscopy: A New Amelioration in Cancer

10. Molecular Imaging: A New Advancement in Cancer

11. Spatiotemporal Genetic Analysis (SAGA) Technique for Cancer

12. Plant‑Derived Anti‑Malarial Compounds and Their Derivatives

13. Epigenetic Control of the Immune System and Its

14. Immune Checkpoint Inhibitors ................................................................ 207

15. Tyrosine Kinase Inhibitors in Lymphocytic Leukemia .......................... 225

16. Cyclooxygenase‑1 (COX‑1) Inhibitors in the Management of

17. Microfluidic Devices in Capturing Circulating Metastatic Cancer

Index .................................................................................................................... 279

Ajmer Singh Grewal

67LR 67 kDa laminin receptor

Ca2+ calcium ion

FAP familial amyloid polyneuropathy

mAbs monoclonal antibodies

PYD pyrin domain

Metastatic diseases pose complicated issues in diagnosis and therapeutic

Advances in diagnostic systems like intravital microscopy and molecular

A Review on Cancer: From Clinical

The primary trait of cancer is the unregulated growth and proliferation of

Unrestricted growth and spread of abnormal cells are the distinguishing

1.2.1 STEPS INVOLVED IN CARCINOGENESIS

Carcinogenesis is a genetically controlled multistage process. In the initial

Chemical, physical, and biological agents constitute the three significant

TABLE 1.1 Cancer causing Drugs and Hormones in humans

1.2.3 GENES ENTAILED IN CARCINOGENESIS

Oncogenes originate from proto-oncogenes or normal genes and play a

1. Camptothecin Derivatives: It is a plant alkaloid isolated from Camp