Cancer & its treatment

Prepared by :
Dr. Bharat Mishra, Ph.D
Associate Professor & Head
Department of Pharmacology
Nirmala College of Pharmacy,
Muvattupuzha.
E.Mail: bharatekansh@gmail.com
Dr. Bharat Mishra, Nirmala College of
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CANCER
Chemotherapy
Antineoplastic Agents

• The 30 trillion cells that constitute the adult
human body grow and differentiate to take on
their many specialized functions in a tightly
regulated fashion.
• They proliferate only when required, as a
result of a delicate balance between growth-
promoting and growth-inhibiting mechanisms
that are controlled by an intricate network of
intra- and extracellular molecules.
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• In stark contrast, cancer cells override these
controlling mechanisms and follow their own internal
program for timing their reproduction.
• Indeed, cancer cells can grow in an unrestricted
manner.
• And over time they can acquire the ability to migrate
from their original site, invade nearby tissues, and
form tumors (metastases) at distant organs.
• The primary tumor and its metastases become lethal
when they invade and disrupt tissues whose function
is vital for survival.
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Differences between: cancer and the normal cell
• (1) The cancer cell does not respect usual cellular
growth limits; the reason for this is that these
cells presumably do not require all the same
growth factors that are necessary to cause
growth of normal cells.
• (2) Cancer cells often are far less adhesive to one
another than are normal cells.
• Therefore, they have a tendency to wander
through the tissues, to enter the blood stream,
and to be transported all through the body,
where they form area for numerous new
cancerous growths.
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• (3) Some cancers also produce angiogenic factors
that cause many new blood vessels to grow into the
cancer, thus supplying the nutrients required for
cancer growth.
• Cancer tissue competes with normal tissues for
nutrients.
• Because cancer cells continue to proliferate
indeﬁnitely, their number multiplying day by day,
cancer cells soon demand essentially all the nutrition
available to the body or to an essential part of the
body.
• As a result, normal tissues gradually suffer nutritive
death. Dr. Bharat Mishra, Nirmala College of
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Cancer
• “One type of neoplasm (tumor), which is an
abnormal mass of tissue, the growth of cell
exceeds with that of normal tissues became
uncontrolled & persists in same excessive
manner even after the cessation of the stimuli”.
• Cancer is not one disease but many disorder that
share a profound growth dysregulation.
• Neoplasia literally means "new growth."
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• Cancer chemotherapy, can be curative in
certain neoplasms as testicular cancer, non-
Hodgkin's lymphoma, Hodgkin's disease, and
choriocarcinoma as well as childhood cancers
such as acute lymphoblastic leukemia,
Burkitt's lymphoma, Wilms‘ tumor, and
embryonal rhabdomyosarcoma.
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• Chemotherapy combined with initial surgery can
increase the cure rate in locally advanced early-
stage breast cancer, esophageal cancer, rectal
cancer, and osteogenic sarcoma.
• All cancers are not curable, so the hope lies in
learning more about its cause & pathogenesis
especially the molecular basis of the cancer.
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• Fundamental to the origin of all neoplasms is loss
of responsiveness to normal growth controls.
• There are more than 200 different types of
cancer, all of which are characterized by
abnormal cellular functioning.
• Normally, our cells undergo mitosis only when
necessary and stop when appropriate.
• A cut in the skin, for example, is repaired by
mitosis, usually without formation of excess
tissue.
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• The new cells ﬁll in the damaged area, and
mitosis slows when the cells make contact with
surrounding cells.
• This is called contact inhibition, which limits the
new tissue to just what is needed.
• A neoplasm is often referred to as a tumor, and
the study of tumors is called oncology.
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Cancer
• Two types:
1. Benign tumor: remain localised, can’t spread to
other sites, and it is generally amenable to local
surgical removal; the patient generally survives.
2. Malignant tumor: are collectively referred to as
cancers, the lesion can invade, destroy adjacent
structures and spread to distant sites (metastasize)
to cause death.
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• Benign tumors generally do not spread by
invasion or metastasis
• Malignant tumors are capable of spreading
by invasion and metastasis
Malignant versus Benign Tumors
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Benign Tumors
• In general, benign tumors are designated by
attaching the suffix -oma to the cell type from which
the tumor arises.
• A benign tumor arising in fibrous tissue is a fibroma;
a benign cartilaginous tumor is a chondroma.
• Examples of benign tumors are-
• Adenoma: is applied to benign epithelial neoplasms
showing gland patterns.
• Papillomas: are benign epithelial neoplasms,
growing on any surface, that produce microscopic or
macroscopic finger-like fronds.
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• A polyp: is a mass that projects above a mucosal
surface, & form a macroscopically visible structure.
• Although this term commonly is used for benign
tumors, some malignant tumors also may appear as
polyps.
• Cystadenomas: are hollow cystic masses; typically
they are seen in the ovary.
• Malignant Tumors
• Malignant neoplasms arising in mesenchymal tissue
or its derivatives are called sarcomas.
• A cancer of fibrous tissue origin is a fibrosarcoma,
and a malignant neoplasm composed of
chondrocytes is a chondrosarcoma.
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• Malignant neoplasms of epithelial cell origin
are called carcinomas.
• Examples of Carcinomas:
• Squamous cell carcinoma: would denote a
cancer in which the tumor cells resemble
stratified squamous epithelium.
• Adenocarcinoma: denotes a lesion in which
the neoplastic epithelial cells grow in gland
patterns.
• Poorly differentiated carcinoma: Sometimes
the tumor grows in an undifferentiated
pattern. Dr. Bharat Mishra, Nirmala College of
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• Mixed tumors: In some instances, however,
the stem cell may undergo divergent
differentiation, creating so-called mixed
tumors.
• The best example is mixed tumor of salivary
gland origin, also called as Pleomorphic
adenoma and Fibroadenoma of the female
breast is another common mixed tumor.
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• This benign tumor contains a mixture of
proliferated ductal elements (adenoma)
embedded in a loose fibrous tissue (fibroma).
• Although only the fibrous component is
neoplastic.
• Teratoma: which contains recognizable
mature or immature cells of more than one
germ-cell layer and sometimes all three
(ectoderm, mesoderm, and endoderm).
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• Normally present in the ovary and testis and
sometimes abnormally present in embryonic
linings.
• When all the component parts are well
differentiated, it is a benign (mature) teratoma.
• when less well differentiated, it is an immature,
potentially or overtly malignant teratoma.
• The terms lymphoma, mesothelioma,
melanoma, and seminoma are used for
malignant neoplasms.
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N
O
M
E
N
C
L
A
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U
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E
O
F
T
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M
O
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• Approximately 90-95% of all cancers
are sporadic.
• 5-10% are inherited.
CANCER AND GENETICS
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• Our cells are genetically programmed to have
particular life spans and to divide or die.
• One gene is known to act as a brake on cell
division; another gene enables cells to live
indeﬁnitely, beyond their normal life span, and to
keep dividing.
• Any imbalance in the activity of these genes may
lead to abnormal cell division.
• Often the malignant cells are carried by the
lymph or blood to other organs such as the liver,
where secondary tumors develop.
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• Cancer is caused in all or almost all instances by
mutation or by some other abnormal activation
of cellular genes that control cell growth and cell
mitosis.
• The abnormal genes are called oncogenes.
• As many as 100 different oncogenes have been
discovered.
• Also present in all cells, are, antioncogenes,
which suppress the activation of speciﬁc
oncogenes.
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• Therefore, loss of or inactivation of
antioncogenes can allow activation of oncogenes
that lead to cancer.
• Only a minute fraction of the cells that mutate in
the body ever lead to cancer.
• There are several reasons for this.
• First, most mutated cells have less survival
capability than normal cells and simply die.
• Second, only a few of the mutated cells that do
survive become cancerous.
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• Third, potentially cancerous cells are often, if not
usually, destroyed by the body’s immune system
before they grow into a cancer.
• People, taking immunosuppressant drugs after
kidney or heart transplantation, the probability of
developing cancer is ﬁvefold.
• Fourth, usually several different activated oncogenes
are required simultaneously to cause a cancer.
• For instance, one such gene might promote rapid
reproduction of a cell line, but no cancer occurs
because there is not a simultaneous mutant gene to
form the needed blood vessels.
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• Many trillions of new cells are formed each
year in humans, Why not, all of us, develop
millions or billions of mutant cancerous cells?
• The answer is, the incredible precision with
which, DNA replication takes place in each cell
before mitosis.
• and also the proofreading process that cuts
and repairs any abnormal DNA strand before
the mitotic process is allowed to proceed.
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• Yet, despite all these inherited cellular
precautions, probably one newly formed cell in
every few million still has signiﬁcant mutant
characteristics and forms large number of cancers
cells.
• The probability of mutations can be increased
manyfold when a person is exposed to following
factors:
• Ionizing radiation: such as x-rays, gamma rays,
and particle radiation from radioactive
substances, and even ultraviolet light can
predispose individuals to cancer.
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• Chemical substances(carcinogens): as aniline dye
derivatives.
• The carcinogen that currently cause the one quarter
of all cancer deaths are those in cigarette smoke.
• Physical irritants: such as continued abrasion of the
linings of the intestinal tract by some types of food.
• The damage to the tissues leads to rapid mitotic
replacement of the cells.
• The more rapid the mitosis, the greater the chance
for mutation.
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• Hereditary tendency:
• Certain types of viruses: can cause some kinds
of cancer including leukemia.
• DNA & RNA viruses causes mutations generaly in
lab animals.
• Oncogenic RNA viruses all appear to contain a
reverse transcriptase enzyme that permits
translation of the RNA message of the tumor
virus into the DNA code of the infected cell.
• A specific human retrovirus (HTLV-I) has been
identified as being the causative agent for a
specific type of human T cell leukemia.
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• Oncogenes
• Tumor suppressor genes
• DNA repair genes
Genes playıng role ın cancer
development
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Genes responsible for cancer
cell growth?
Normal
Cancer
Proto-oncogenes Cell growth
and
proliferationTumor suppressor genes
+
-
Mutated or “activated”
oncogenes Malignant
transformation
Loss or mutation of
Tumor suppressor genes
++
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ONCOGENES
• Oncogenes are mutated forms of cellular
proto- oncogenes.
• Proto- oncogenes code for cellular proteins
which regulate normal cell growth and
differentiation.
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Activation mechanisms of proto-oncogenes
proto-oncogene --> oncogene
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Class I: Growth Factors
Class II: Receptors for Growth Factors and Hormones
Class III: Intracellular Signal Transducers
Class IV: Nuclear Transcription Factors
Class V: Cell-Cycle Control Proteins
Five types of proteins encoded by proto-
oncogenes participate in control of cell growth:
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4. Nuclear
Proteins:
Transcription
Factors
5. Cell Growth
Genes
3. Cytoplasmic
Signal Transduction
Proteins
1. Secreted
Growth Factors
2. Growth Factor Receptors
Functions of Cellular Proto-Oncogenes
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A general signalling
pathway
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Tumor suppressor genes
• Another class of genes, which may be deleted
or damaged, resulting neoplastic changes.
• A single gene in this class, the p53 gene, has
been shown to have mutated from a tumor
suppressor gene to an oncogene in a high
percentage of cases of several human tumors,
including liver, breast, colon, lung, cervix,
bladder, prostate, and skin.
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p53
• Phosphyorylated p53 activates
transcription of p21 gene
• p21 Cdk inhibitor (binds Cdk-
cyclin complex --> inhibits kinase
activity)
• Cell cycle arrested to allow
DNA to be repaired
• If damage cannot be repaired
--> cell death (apoptosis)
• Disruption/deletion of p53 gene
• Inactivation of p53 protein
--> uncorrected DNA damage
--> uncontrolled cell proliferation --
> cancer
Ataxia telangictasia mutated
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Gene Mutation: Chromosomal changes in the genome of
cancer cells
Terminal
Deletion
Ring
Chromosome
Robertsonian
Translocation
Deletion Reciprocal
translocation
IsochromosomesInsertion Inversion
Duplication
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Nucleotide changes in the genome of cancer cells:
Nucleotide
Deletions
Nucleotide
Insertions
Nucleotide
Substitutions
http://www.tokyo-med.ac.jp/genet/cai-e.htm
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Growth rate
• Most benign tumors grow slowly, and most
cancers grow much faster, eventually
metastasizing and causing death.
• some benign tumors grow more rapidly than
some cancers.
• For example, the rate of growth of leiomyomas
(benign smooth muscle tumors) of the uterus is
influenced by the circulating levels of estrogens.
• They may increase rapidly in size during
pregnancy and cease growing or atrophy after
menopause.
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Tumor enlargement
• Tumors cannot enlarge beyond 1 to 2 mm in
diameter or thickness unless they are vascularized.
• Then oxygen and nutrients can diffuse from blood
vessels.
• The tumor fails to enlarge without vascularization
because hypoxia induces, apoptosis by activation of
TP53 .
• Neovascularization has a dual effect on tumor
growth:
 Perfusion supplies nutrients and oxygen,
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 And newly formed endothelial cells stimulate the
growth of adjacent tumor cells by secreting
polypeptides, such as insulin-like growth factors,
PDGF, granulocyte-macrophage colony-stimulating
factor (GM-CSF), and interleukin (IL)-1.
• Angiogenesis is required not only for continued
tumor growth but also for metastasis.
• Tumor-associated angiogenic factors may be
produced by tumor cells or may be derived from
inflammatory cells e.g are vascular endothelial
growth factor (VEGF) and basic fibroblast growth
factor.
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• Tumor cells not only produce angiogenic factors but
also induce antiangiogenesis molecules.
• Emerging pattern is that, tumor growth is controlled
by the balance between angiogenic factors and
factors that inhibit angiogenesis.
• Antiangiogenesis factors, such as thrombospondin-1,
may be produced by the tumor cells themselves, or
their production may be induced by tumor cells.
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• Hypoxia within the growing tumor favors
angiogenesis by release of hypoxia-inducible
factor-1 (HIF-1).
• HIF-1 controls transcription of VEGF.
• The transcription of VEGF also is under the
control of RAS oncogene, and RAS activation up-
regulates the production of VEGF.
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• Proteases are also involved in regulating the
balance between angiogenic and antiangiogenic
factors by releaseing basic fibroblast growth
factor.
• Because of the crucial role of angiogenesis in
tumor growth, much interest is focused on
antiangiogenesis therapy.
• Results of ongoing clinical trials with several
angiogenesis inhibitors seem promising, and
more are awaited.
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Metastasis
• The term metastasis explains the development of
secondary implants (metastases) discontinuous
with the primary tumor.
• Malignant neoplasms spread by one of three
pathways:
• (1) seeding within body cavities,
• (2) lymphatic spread,
• (3) hematogenous spread.
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1-Seeding of cancers
• Occurs when neoplasms invade a natural body
cavity.
• Carcinoma of the colon may penetrate the
wall of the gut and reimplant at distant sites in
the peritoneal cavity.
• A similar sequence may occur with lung
cancers in the pleural cavities.
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2-Lymphatic spread:
• Is more typical of carcinomas.
• The pattern of lymph node involvement depends
principally on the site of the primary neoplasm
and the natural lymphatic pathways of drainage
of the site.
• Lung carcinomas arising in the respiratory
passages metastasize first to the regional
bronchial lymph nodes, then to the
tracheobronchial and hilar nodes.
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3- Hematogenous spread:
• Is the most feared consequence of a cancer.
• It is the favored pathway for sarcomas, but
carcinomas use it as well.
• As might be expected, arteries are penetrated less
readily than are veins.
• The liver and lungs are the most frequently involved
secondary sites in such hematogenous dissemination.
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CANCER THERAPY
• Can be performed by-
• 1- Chemotherapy
• 2-Radiotherapy
• 3-Surgery
• 4-Biotherapy
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Biotherapy
• Can be effective against clinically apparent, even
bulky cancer.
• The term biotherapy encompasses the therapeutic
use of any biological substances.
• For the agents used in biotherapy the name given is
“Biological Response Modifiers (BRM)”
• These are the agents and approaches whose
mechanism of action involves the individuals own
biological responses.
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• BRM works through the diverse mechanisms as-
• (a) Augment the host’s defenses through the
administration of cells, natural biologicals, or the
synthetic derivatives thereof as effectors or
mediators (direct or indirect) of an antitumor
response;
• (b) Increase the individual’s antitumor responses
through augmentation or restoration of effector
mechanisms, or decrease a component of the
host’s reaction that is deleterious;
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• (c) Augment the individual’s responses using
modiﬁed tumor cells or vaccines to stimulate a
greater response, or increase tumor cell
sensitivity to an existing bio logical response;
• (d) Decrease transformation and/or increase
differentiation or maturation of tumor cells;
• (e) Interfere with growth-promoting factors and
angiogenesis inducing factors produced by tumor
cells;
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• (f) Decrease or arrest the tendency of tumor cells
to metastasize to other sites;
• (g) Increase the ability of the patient to tolerate
damage by cytotoxic modalities of cancer
treatment; and/or,
• (h) use biological molecules to target and bind to
cancer cells and induce more effective cytostatic
or cytocidial antitumor activity.
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Biologicals and Biological Response Modiﬁers
1: IMMUNOMODULATING AGENTS
• Alkyl lysophospholipids (ALP)
• Azimexon
• BCG
• Bestatin
• Brucella abortus
• Cornyebacterium parvum
• Cimetidine
• Sodium diethyldithiocarbamate
(DTC)
• Endotoxin
• Glucan
• ‘Immune’ RNAs
• Krestin
• Lentinan
• T-cell growth factors (‘TCGF’ –
interleukin 2 [IL-2
• Levamisole
• Muramyldipeptide (MDP),
tripeptide (MTP)
• Maleic anhydride-divinyl ether
(MVE-2)
• Mixed bacterial vaccines (MBV)
• Nocardia rubra cell wall skeletons
(CWS)
• Picibanil (OK432)
• Prostaglandin inhibitors (aspirin,
indomethacin)
• Thiobendazole
• Tuftsin
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2: Interferons and interferon
inducers
• Interferons (α, β, γ)
• Poly IC-LC
• Poly A-U
• GE-132
• Brucella abortus
• Tilorone
• Viruses
• Pyrimidinones
3: Thymosins
• Thymosin alpha-1
• Thymosin fraction 5
• Other thymic factors
4: Antigens
• Tumor-associated antigens
• Molecular vaccines
• Cell-engineered cellular
vaccines
5: Effector cells
• Macrophages
• NK cells
• Cytotoxic T cells
• LAK cells
• T helper cells
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5: Lymphokines, cytokines,
growth/maturation factors:
• Antigrowth factors
• Chalones
• Colony-stimulating factors (CSF)
• Growth factors (transforming
growth factor, TGF)
• Lymphocyte activation factor (LAF-
interleukin 1 [IL-1])
• Lymphotoxins (TNF, α, β, LT)
• Macrophage activation factors
(MAF)
• Macrophage chemotactic factor
• Macrophage cytotoxic factor (MCF)
• Macrophage growth factor (MGF)
• Migration inhibitory factor (MIF)
• Maturation factors
• Interleukin 3–18, etc.
• Thymocyte mitogenic factor (TMF)
• Transfer factor
• Transforming growth factor (TFR, α,
β)
6: Miscellaneous approaches:
• Allogeneic immunization
• Liposome-encapsulated biologicals
• Bone-marrow transplantation and
reconstitution
• Plasmapheresis and ex vivo
treatments (activation columns,
immunoabsorbents, and ultraﬁ
ltration)
• Virus infection of cells (oncolysates)
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Chemotherapy
• An understanding of cell-cycle kinetics is
essential for the proper use of antineoplastic
agents.
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The Cell Cycle
• Proliferating cells progress through a series of
checkpoints and defined phases called the cell
cycle.
• The cell cycle consists of-
• Presynthetic growth phase 1, or G1
• DNA-synthetic phase, or S
• Premitotic growth phase 2, or G2
• Mitotic phase, or M.
• Resting cells (cells that are not preparing for cell
division) are said to be in a subphase of G1 ie. G0.
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Cell cycle
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• Cyclins proteins control the Entry and progression of cells through the cell
cycle.
• Cyclins accomplish their regulatory functions by activating the
constitutively synthesized proteins called cyclin-dependent kinases
(CDKs), and CDKs inhibited by proteins such as p16.
• Different combinations of cyclins and CDKs are associated with each of the
important transitions in the cell cycle.
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• A specific example involves CDK1, which controls the critical
transition from G2 to M.
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• After cell division, cyclin B is degraded, until there is a
new growth stimulus and synthesis of new cyclins, the
cells do not undergo further mitosis.
• The cyclin-CDK complexes are also regulated by the
binding of CDK inhibitors.
• These are particularly important in regulating cell cycle
checkpoints (G1 → S and G2 → M).
• Points at which the cell checks whether its DNA is
sufficiently replicated and all mistakes repaired before
progressing.
• Failure to adequately monitor the accuracy of DNA
replication leads to the accumulation of mutations and
possible malignant transformation.
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• As an example, when DNA is damaged (e.g., by
ultraviolet irradiation), the tumor suppressor
protein TP53 is stabilized and induces the
transcription of CDKN1A, a CDK inhibitor.
• This arrests the cells in G1 or G2 until the DNA can
be repaired; at that point, the TP53 levels fall,
CDKN1A diminishes, and the cells can proceed
through the checkpoint.
• If the DNA damage is too extensive, TP53 will
initiate a cascade of events to convince the cell to
commit suicide.
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• Many of the most effective cytotoxic agents act
by damaging DNA.
• Their toxicity is greater during the S, or DNA
synthetic, phase of the cell cycle, while others,
such as the vinca alkaloids and taxanes, block the
formation of a functional mitotic spindle in M
phase.
• Conversely, slowly growing tumors with a small
growth fraction (for example, carcinomas of the
colon or lung cancer) often are less responsive to
cycle-specific drugs.
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• Anticancer agents have variable
pharmacokinetics and toxicity in individual
patients.
• The causes of this variability are not always
clear and often may be related to
interindividual differences in drug
metabolism, drug interactions, or bone
marrow reserves.
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Aim of treatment
• In malignant diseases, drugs are used with the aim of:
1. Cure or prolonged remission:
• Chemotherapy is the primary treatment modality that
can achieve cure or prolonged remission in:
• Acute leukemias
• Wilm's tumour g
• Ewing's sarcoma
• Retinoblastoma
• Rhabdomyosarcoma
• Seminoma , Mycosis fungoides,Choriocarcinoma ,
• Hodgkin's disease ,Lymphosarcoma
• Burkitt's lymphoma, Testicular teratomas
In childrens
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2. Palliation:
• Shrinkage of evident tumour, alleviation of
symptoms and life is prolonged by chemotherapy
in:
• Breast cancer, Chronic lymphatic leukemia
,Ovarian carcinoma, Chronic myeloid leukemia,
Endometrial carcinoma, Non-Hodgkin
lymphomas, Myeloma Head and neck cancers,
Prostatic carcinoma Lung (small cell) cancer.
• Many other malignant tumours are less sensitive
to drugs-life may or may not be prolonged by
chemotherapy are:
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• Colorectal carcinoma, Malignant melanomas
• Carcinoma pancreas, Bronchogenic carcinoma
• Carcinoma stomach (non small cell)
• Carcinoma esophagus, Hepatoma
• Renal carcinoma Sarcoma
3. Adjuvant chemotherapy
• Drugs are used to mop up any residual
malignant cells (micro metastases) after
surgery or radiotherapy.
• This is routinely employed now.
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CLASSIFICATION OF ANTICANCER DRUGS
A. Drugs acting directly on cells (Cytotoxic drugs)
1. Alkylating agents 2. Anti metabolites
a. Nitrogen mustards :
•Mechlorethamine (Mustine HCl)
•Cyclophosphamide
•Ifosfamide, Chlorambucil, Melphalan
a. Purine antagonist
• 6-Mercaptopurine (6-MP), Pentostatin
• 6-Thioguanine (6-TG),
• Azathioprine, Fludarabine, cladribine
b. Ethylenimine & methylamine:
•Thio-TEPA, Altretamine
b. Folate antagonist
• Methotrexate (Mtx), Pemetrexed
c. Alkyl sulfonate :
•Busulfan
d. Methylhydrazine derivative:
•Procarbazine
c. Pyrimidine antagonist
• 5-Fluorouracil (5-FU),
• Cytarabine (cytosine arabinoside)
•Capecitabine, Gemcitabine
e. Nitrosoureas:
•Carmustine (BCNU)
•Lomustine (CCNU) ,streptozotocin
3.Microtubule Inhibitors: a.Vinca alkaloids
• Vincristine (Oncovin),
• Vinblastine , vinorelbine
f. Triazine
•Dacarbazine (DTIC), temozolomide
•G. Platinum coordination complexes:
•Cisplatin, carboplatin,oxaliplatin
4. Microtubule Inhibitors: b.Taxanes
• Paclitaxel,
• Docetaxel
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5. Epipodophyllo toxin:
• Etoposide, Teniposide
3. Selective estrogen receptor modulators:
•Tamoxifen, Toremifene
6. Camptothecin analogues:
• Topotecan, Irinotecan
4. Selective estrogen receptor down regulators :
•Fulvestrant
7. Antibiotics:
Actinomycin D, (Dactinomycin)
Doxorubicin , Daunorubicin (Rubidomycin)
Mitoxantrone, Bleomycins, Mitomycin C
5. Aromatase inhibitors
•Letrozole,
•Anastrozole,
•Exemestane
8. Miscellaneous :
Hydroxyurea, L-Asparaginase, Imatinib,
Tretinoin, arsenic trioxide, Gefitinib,
erlotinib, Bortezomib, Interferon-alfa,
interleukin 2
6. Antiandrogen
• Flutamide,
• Bicalutamide
7. Androgens:Testosterone propionate,
fluoxymesterone
B. DRUGS ALTERING HORMONAL MILIEU 8. 5-α reductase inhibitor
• Finasteride, Dutasteride
1. Glucocorticoids :
• Prednisolone and others
9. GnRH analogues
•Nafarelin, Triptorelin, Leuprolide
2. Estrogens :
• Fosfestrol, Ethinylestradiol ,
Diethylstilbestrol
10. Progestins
• Hydroxyprogesterone acetate, megestrol
acetate, Hydroxyprogesterone caproateDr. Bharat Mishra, Nirmala College of
Pharmacy
10-01-17 81

Cell cycle effects of anticancer drugs
Pharmacy
10-01-17 82

TOXICITY OF CYTOTOXIC DRUGS
Profound effect on rapidly multiplying cells,
 because the target of action are the nucleic acids
and their precursors; and,
rapid nucleic acid synthesis occurs during cell
division.
Many cancers (especially large solid tumours)
have a lower growth fraction than normal bone
marrow, epithelial linings, reticuloendothelial (RE)
system and gonads.
So these tissues are particularly affected.
Pharmacy
10-01-17 83

1. Bone marrow
• Depression of bone marrow results in
granulocytopenia, agranulocytosis,
thrombocytopenia, aplastic anaemia.
• Infections and bleeding are the usual
complications.
Pharmacy
10-01-17 84

2. Lymphoreticular tissue
Lymphocytopenia and inhibition of lymphocyte
function,
results in suppression of cell mediated as well as
humoral immunity.
susceptibility to all infections is increased.
Particularly the opportunistic infections.
Examples as, fungi (Candida, Pneumocystis
jiroveci & others), viruses (Herpes zoster,
cytomegalo virus), and Toxoplasma.
Pharmacy
10-01-17 85

3. Oral cavity
Because of high epithelial cell turnover.
 Gums and oral mucosa are regularly subjected
to minor trauma, and breaches are common
during chewing.
 oral infections.
Thrombocytopenia may cause bleeding gums.
 Xerostomia due to the drug may cause rapid
progression of dental caries.
Pharmacy
10-01-17 86

4. GIT
• Diarrhoea, shedding of mucosa,
haemorrhages occur due to decrease in the
rate of renewal of the mucous lining.
• Nausea and vomiting, due to direct
stimulation of CTZ as well as generation of
emetic impulses from the upper g .i. t.
Pharmacy
10-01-17 87

5. Skin
 Alopecia occurs due to damage to the cells in hair
follicles.
 Dermatitis is another complication.
• 6. Gonads
 Inhibition of gonadal cells causes oligozoospermia
and impotence in males;
 inhibition of ovulation and amenorrhoea are
common in females.
 Damage to the germinal cells may result in
mutagenesis.
Pharmacy
10-01-17 88

• 7. Foetus
profoundly damage the developing foetus
abortion, foetal death, teratogenesis.
• 8. Carcinogenicity
Secondary cancers, especially leukaemias,
lymphomas and histocytic tumours.
due to depression of cell mediated and
humoral blocking factors against neoplasia.
Pharmacy
10-01-17 89

9. Hyperuricaemia
This is secondary to massive cell destruction
(uric acid is a product of purine metabolism).
 Gout and urate stones in the urinary tract
may develop.
Pharmacy
10-01-17 90

DRUG TREATMENT
Pharmacy
10-01-17 91

General mechanisms for drugs acting on cell growth components
dTMP = deoxythymidine monophosphate [slide no.77 &78]
Pharmacy
10-01-17 92

PALA =N-phosphonoacetyl-L-aspartate; TMP = thymidine monophosphate.
Pharmacy
10-01-17 93

Pharmacy
10-01-17 94

ALKYLATING AGENTS
• The major clinically useful alkylating agents
have a structure containing a
chloroethylamine, ethyleneimine, or
nitrosourea moiety.
Pharmacy
10-01-17 95

Mechanism of action
• The general mechanism of action of these
drugs involves intramolecular cyclization to
form an ethyleneimonium ion that may
directly or through formation of a carbonium
ion transfer an alkyl group to a cellular
constituent.
Pharmacy
10-01-17 96

• N3 of cytosine, and O6 of guanine, as well as
phosphate atoms and proteins associated with
DNA.
• The major site of alkylation within DNA is the
N7 position of guanine,
• however, other bases are also alkylated to
lesser degrees, including N1 and N3 of
adenine,
Pharmacy
10-01-17 97

• The latter effect leads to DNA strand breakage
through scission of the sugar-phosphate
backbone of DNA.
• These interactions can occur on a single strand
or on both strands of DNA through cross-
linking.
• Alkylation of guanine can result in miscoding
through abnormal base pairing with thymine
or in de-purination by excision of guanine
residues.
Pharmacy
10-01-17 98

Intramolecular cyclization
10-01-17 99
Ethyleneimonium ion
Carbonium Ion
Directly
Alkyl group
Transfer to DNA
N7 position of guanine
N1 and N3 of adenine,
N3 of cytosine
O6 of guanine
Phosphate atoms and
proteins associated
with DNA.
Abnormal base pairing
with thymine
de-purination by excision of
guanine residues.
Miscoding
Scission of the sugar-
phosphate backbone of DNA
DNA strand breakage

• Thus, Although alkylation can occur in both
cycling and resting cells, so the alkylating
agents are not cell cycle-specific.
• Cells are most susceptible to alkylation in late
G1 and S phases of the cell cycle and express
block in G2.
10-01-17
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100

Mechanisms of Resistance to Alkylating Agents
• Resistance develops rapidly as a single agent.
• Specific biochemical changes implicated as:
• Decreased permeation of actively transported
drugs (mechlorethamine and melphalan);
• Increased intracellular concentrations of
nucleophilic substances, principally thiols such
as glutathione, which can conjugate with and
detoxify electrophilic intermediates;
Pharmacy
10-01-17 101

• Increased activity of DNA repair pathways,
which may differ for the various alkylating
agents.
• Thus, increased activity of the complex
nucleotide excision repair (NER) pathway
seems to correlate with resistance.
• Increased rates of metabolism of the activated
forms of cyclophosphamide and ifosfamide to
their inactive keto and carboxy metabolites by
aldehyde dehydrogenase.
Pharmacy
10-01-17 102

Toxicities of Alkylating Agents
• Bone Marrow Toxicity:
• Most cause dose-limiting toxicity to bone marrow
elements.
• Most alkylating agents, including nitrogen mustard,
melphalan, chlorambucil, cyclophosphamide, and
ifosfamide, cause acute myelosuppression.
• Busulfan suppresses all blood elements, particularly
stem cells, and may produce a prolonged and
cumulative myelosuppression lasting months or even
years.
Pharmacy
10-01-17 103

• Carmustine and other chloroethyl
nitrosoureas cause delayed and prolonged
suppression of both platelets and
granulocytes.
• Both cellular and humoral immunity are
suppressed by alkylating agents, which have
been used to treat various autoimmune
diseases.
• Immunosuppression is reversible.
Pharmacy
10-01-17 104

• Mucosal Toxicity:
• Highly toxic to dividing mucosal cells, leading
to oral mucosal ulceration and intestinal
denudation.
• Cyclophosphamide, melphalan, and thiotepa
have the advantage of causing less mucosal
damage than the other agents.
Pharmacy
10-01-17 105

• Neurotoxicity
• CNS toxicity is manifest in the form of nausea
and vomiting, particularly after intravenous
administration of nitrogen mustard.
• Ifosfamide is the most neurotoxic of this class
of agents, producing altered mental status,
coma, generalized seizures, and cerebellar
ataxia.
Pharmacy
10-01-17 106

• Other Organ Toxicities
• May occur after prolonged or high-dose use;
can appear after months or years, and may be
irreversible and even lethal.
• All alkylating agents have caused pulmonary
fibrosis, usually several months after
treatment.
• The nitrosoureas and ifosfamide, after
multiple cycles of therapy, may lead to renal
failure.
Pharmacy
10-01-17 107

• Cyclophosphamide and ifosfamide release a
nephrotoxic and urotoxic metabolite, acrolein,
which causes a severe hemorrhagic cystitis.
• Cystitis a side effect that in high-dose regimens
can be prevented by coadministration of 2-
mercaptoethanesulfonate (mesna or MESNEX),
which conjugates acrolein in urine.
Pharmacy
10-01-17 108

• Ifosfamide in high doses for transplant causes
a chronic, and often irreversible, renal toxicity.
• Proximal, and less commonly distal tubules
may be affected, with difficulties in Ca2+ and
Mg2+ reabsorption, glycosuria, and renal
tubular acidosis.
10-01-17
Pharmacy
109

• All alkylating agents have toxic effects on the
male and female reproductive systems,
• causing an often permanent amenorrhea,
particularly in premenopausal women, and an
irreversible azoospermia in men.
10-01-17
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• Leukemogenesis:
• These agents are highly leukemogenic.
• Acute nonlymphocytic leukemia, often associated
with partial or total deletions of chromosome 5
or 7.
• Very common in Melphalan, the nitrosoureas,
and the methylating agent procarbazine .
• less common with cyclophosphamide.
Pharmacy
10-01-17 111

Cyclophosphamide
• A nitrogen mustard,
• Cytotoxic action is similar to that of other
alkylating agents.
• Therapeutic Uses
• Cyclophosphamide is administered orally or
intravenously.
Pharmacy
10-01-17 112

• As a single agent & adjuvant therapy, a daily
oral dose of 100 mg for 14 days has been
recommended for breast cancer, and for
patients with lymphomas and chronic
lymphocytic leukemia.
• A higher dosage of 500 mg intravenously
every 2 to 4 weeks in combination with other
drugs often is employed in the treatment of
breast cancer and lymphomas.
10-01-17
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• Common: Gastrointestinal ulceration, cystitis,
and,
• less common: pulmonary, renal, hepatic, and
cardiac toxicities (a hemorrhagic myocardial
necrosis) may occur after high-dose therapy
with total doses above 200 mg/kg.
• It is an essential component of many effective
drug combinations for non-Hodgkin's
lymphomas, ovarian cancers, and solid tumors
in children.
Pharmacy
10-01-17 114

• Complete remissions and presumed cures
have been reported when Cyclophosphamide
was given as a single agent for Burkitt's
lymphoma.
• It frequently used in combination with
methotrexate (or doxorubicin) and fluorouracil
as adjuvant therapy after surgery for
carcinoma of the breast.
• Because of its potent immunosuppressive
properties, it has been used to prevent organ
rejection after transplantation.
Pharmacy
10-01-17 115

Nitrosoureas
• The nitrosoureas appear to function by cross-
linking through alkylation of DNA.
• More effective against plateau phase cells
than exponentially growing cells,
• Slow effect in cycling cell progression in the
DNA synthetic phase.
Pharmacy
10-01-17 116

• Because of its ability to cross the blood–brain
barrier, carmustine is used with procarbazine
in the treatment of malignant gliomas.
• Nausea and vomiting, Leukopenia,
thrombocytopenia, and rarely hepatitis are
adverse effects of Lomustine and carmustine.
Pharmacy
10-01-17 117

Pharmacokinetics
• Highly lipid-soluble and cross the blood-brain
barrier, useful in the treatment of brain
tumors.
• After oral administration of lomustine, peak
plasma levels of metabolites appear within 1–
4 hours.
• Elimination through Urinary excretion.
Pharmacy
10-01-17 118

• One naturally occurring sugar-containing
nitrosourea, streptozocin, is interesting
because it has minimal bone marrow toxicity.
• This agent has activity in the treatment of
insulin-secreting islet cell carcinoma of the
pancreas.
Pharmacy
10-01-17 119

Toxicity of STZ
• Nausea is frequent.
• Mild, reversible renal or hepatic toxicity.
• In less than 10% of patients, renal toxicity may be
cumulative with each dose and may be fatal.
• Should be avoided with other nephrotoxic drugs.
• Hematological toxicity—anemia, leukopenia, or
thrombocytopenia—occurs in 20% of patients.
Pharmacy
10-01-17 120

Methylhydrazines
Procarbazine
• An orally active drug,
• it is used in combination regimens for Hodgkin’s and
non-Hodgkin’s lymphoma as well as brain tumors.
• it inhibits DNA, RNA, and protein biosynthesis;
• prolongs interphase;
• and produces chromosome breaks.
Pharmacy
10-01-17 121

• Oxidative metabolism of this drug by
microsomal enzymes generates azopro-
carbazine and H2O2 , which may be
responsible for DNA strand scission.
10-01-17
Pharmacy
122

• A variety of other drug metabolites are formed that may be
cytotoxic.
• One metabolite is a weak MAO inhibitor,
• and adverse events can occur when-
• Procarbazine is given with other MAO inhibitors, with
sympathomimetics, tricyclic antidepressants, antihistamines, CNS
depressants, antidiabetic agents, alcohol, and tyramine-containing
foods.
• There is an increased risk of secondary cancers.
• it is more carcinogenic than other alkylating agents.
Pharmacy
10-01-17 123

Triazenes
Dacarbazine (DTIC)
• Dacarbazine is a synthetic compound.
• Forms metabolite which is monomethyl derivative.
• This metabolite spontaneously decomposes to
diazomethane, which generates a methyl carbonium
ion that is cytotoxic .
• It is administered parenterally .
Pharmacy
10-01-17 124

• Used in the treatment of malignant
melanoma, Hodgkin’s lymphoma, soft tissue
sarcomas, and neuroblastoma.
• Main dose-limiting toxicity is
myelosuppression, but nausea and vomiting
can be severe in some cases.
10-01-17
Pharmacy
125

Alkyl Sulfonates
Busulfan
Pharmacological and Cytotoxic Actions
• It produces little effect on lymphoid tissue
and GIT.
• In high-dose regimens, pulmonary fibrosis,
gastrointestinal mucosal damage, and veno-
occlusive disease of the liver become
important.
Pharmacy
10-01-17 126

Therapeutic Uses
• Chronic myeloid leukemia, the initial oral dose of
busulfan varies with the total leukocyte count and
the severity of the disease.
• Daily doses from 2 to 8 mg for adults (60 g/kg for
children) are used to initiate therapy.
• High doses of busulfan with high doses of
cyclophosphamide, used to prepare leukemia
patients for bone marrow transplantation.
10-01-17
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127

• Anticonvulsants must be used concomitantly to
protect against acute CNS toxicities, including
tonic-clonic seizures, which may occur several
hours after each dose.
• Busulfan induces the metabolism of Phenytoin.
• So lorazepam are recommended as an alternative
to phenytoin.
Pharmacy
10-01-17 128

Clinical Toxicity
• Myelosuppressive properties, and prolonged
thrombocytopenia .
• Occasional nausea, vomiting, and diarrhea.
• Long-term use leads to impotence, sterility,
amenorrhea, and fetal malformation.
• Rarely, asthenia and hypotension, a syndrome
resembling Addison's disease.
Pharmacy
10-01-17 129

• High-dose busulfan causes veno-occlusive
disease of the liver, seizures, hemorrhagic
cystitis, permanent alopecia, and cataracts.
• The coincidence of veno-occlusive disease and
hepatotoxicity is increased by its
coadministration imidazoles and
metronidazole.
10-01-17
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130

Antimetabolites
• Structurally related to normal compounds that
exist within the cell.
• They generally interfere with the availability of
normal purine or pyrimidine nucleotide
precursors,
• either by inhibiting their synthesis
• or by competing with them in DNA or RNA
synthesis.
• Their maximal cytotoxic effects are in S-phase
therefore, cell-cycle specific.
Pharmacy
10-01-17 131

1. Folate antagonist
Methotrexate (Mtx)
• The vitamin, folic acid plays a central role in a
variety of metabolic reactions involving the
transfer of one-carbon units and is essential for
cell replication.
• Methotrexate (MTX) is structurally related to folic
acid and acts as an antagonist of that vitamin by
inhibiting dihydrofolate reductase 2 (DHFR) [the
enzyme that converts folic acid to its active,
coenzyme form, tetrahydrofolic acid (FH4)].
Pharmacy
10-01-17 132

Mechanism of action:
Pharmacy
10-01-17 133

Mechanism of action of methotrexate and the effect of
administration of leucovorin.
FH2 =dihydrofolate;
FH4 = tetrahydrofolate;
dTMP = deoxythymidine monophosphate;
dUMP = deoxyuridine mono phosphate.
Folic acid is obtained from dietary sources or from that
produced by intestinal flora.
It undergoes reduction to the tetrahydrofolate (FH4) form
catalyzed by intracellular nicotinamide-adenine dinucleotide
MTX has an unusually strong affinity for DHFR and
effectively inhibits the enzyme.
(FH4) : imprtant as carbon carrier for enzymatic processes
involved in synthesis of thymidylate, purine nucleotides,
and the amino acids serine and methionine.
Thereby interferes with the formation of DNA, RNA, and
key cellular proteins .
The inhibition of DHFR can only be reversed by a 1000-fold excess
of the natural substrate, dihydrofolate , or by administration of
leucovorin, which bypasses the blocked enzyme and replenishes
the folate pool.
Pharmacy
10-01-17 134

Enzymatic reactions that use folates.
Section 1 shows the vitamin B 12 -dependent reaction that allows most dietary folates to enter the
tetrahydrofolate cofactor pool. Section 2 shows the dTMP cycle. Section 3 shows the pathway by which folic
acid enters the tetrahydrofolate cofactor pool.
Pharmacy
10-01-17 135

• Folate Di hydrofolate Tetra hydrofolate
DHFR DHFR
Methionine
Glycine
Serine
Initiator tRNA
Purine Thymidine
RNA
DNA
Proteins
DNA
By donating carbon atom
Pharmacy
10-01-17 136

• MTX has an unusually strong affinity for DHFR and
effectively inhibits the enzyme.
• Intracellular formation of polyglutamate metabolites,
with the addition of up to 5–7 glutamate residues, is
critically important for the therapeutic action of
MTX.
• This process is catalyzed by the enzyme
folylpolyglutamate synthase (FPGS).
FPGS
• Glutamate residues Polyglutamate metabolites
Pharmacy
10-01-17 137

• MTX polyglutamates are selectively retained
within cancer cells, and they display increased
inhibitory effects on enzymes involved in de
novo purine nucleotide and thymidylate
biosynthesis, making them important
determinants of MTX’s cytotoxic action.
Pharmacy
10-01-17 138

Resistance:
• Nonproliferating cells are resistant to MTX,
probably because of a relative lack of DHFR,
thymidylate synthase, and/or the glutamylating
enzyme.
• Decreased levels of the MTX polyglutamate may
be due to its decreased formation or increased
breakdown.
• Resistance in neoplastic cells can be due to
amplification (production of additional copies) of
the gene that codes for DHFR, resulting in
increased levels of this enzyme.
Pharmacy
10-01-17 139

• The enzyme affinity for MTX may also be
diminished.
• Resistance can also occur from a reduced
influx of MTX, apparently caused by a change
in the carrier-mediated transport responsible
for pumping the drug into the cell.
Pharmacy
10-01-17 140

Therapeutic uses
• Against acute lymphocytic leukemia, choriocarcinoma,
Burkitt's lymphoma in children, breast cancer, and head
and neck carcinomas.
• In addition, low-dose MTX is effective as a single agent
against certain inflammatory diseases, such as severe
psoriasis and rheumatoid arthritis as well as Crohn's
disease.
• All patients receiving MTX require close monitoring for
possible toxic effects.
Pharmacy
10-01-17 141

Doses
• Methotrexate is apparently curative in
choriocarcinoma: 15-30 mg/ day for 5 days
orally or 20-40mg i.v. twice weekly.
• It is also useful in other malignancies,
rheumatoid arthritis, psoriasis and as
immunosuppressant.
• Marketed preprations: NEOTREXATE 2.5 rng tab, 50
rng/2 rnl inj; BIOTREXATE 2.5 rng tab, 5, 15, 50
rng/vial inj.
Pharmacy
10-01-17 142

Adverse effects:
• Commonly observed toxicities:
• Nausea, vomiting, and diarrhea, the most
frequent toxicities occur in tissues that are
constantly renewing.
• Thus, MTX causes stomatitis, myelosuppression,
rash, urticaria, and alopecia.
• Some of these adverse effects can be prevented
or reversed by administering leucovorin, which is
taken up more readily by normal cells than by
tumor cells.
Pharmacy
10-01-17 143

• Doses of leucovorin must be kept minimal to
avoid possible interference with the antitumor
action of MTX.
• B. Renal damage: Although uncommon during
conventional therapy.
• Renal damage is a complication of high-dose MTX
and its 7-OH metabolite, which can precipitate in
the tubules.
• Alkalinization of the urine and hydration help to
prevent this problem.
Pharmacy
10-01-17 144

• C. Hepatic function:
• Hepatic function should be monitored.
• Long-term use of MTX may lead to cirrhosis.
• D. Pulmonary toxicity:
• This is a rare complication.
• Children who are being maintained on MTX may
develop cough, dyspnea, fever, and cyanosis.
Pharmacy
10-01-17 145

• E. Neurologic toxicities:
• These are associated with intrathecal
administration of MTX and include subacute
meningeal irritation, stiff neck, headache, and
fever.
• Rarely, seizures, encephalopathy, or
paraplegia occur.
• Long-lasting effects, such as learning
disabilities, have been seen in children who
received the drug by this route.
Pharmacy
10-01-17 146

• Contraindications:
• Because MTX is teratogenic in experimental
animals and is an abortifacient, it should be
avoided in pregnancy.
• [Note: MTX is used with misoprostol to induce
abortion.]
10-01-17
Pharmacy
147

2. Purine antagonists
Mercaptopurine (6-MP)
• The drug 6-mercaptopurine (6-MP) is the thiol
analog of hypoxanthine.
• 6-MP is used principally in the maintenance of
remission in acute lymphoblastic leukemia.
• 6-MP and its analog, azathioprine, are also
beneficial in the treatment of Crohn's disease.
Pharmacy
10-01-17 148

1. Nucleotide formation:
• To exert its antileukemic effect, 6-MP must penetrate
target cells and be converted to the nucleotide analog, 6-
MP-ribose phosphate.
• The addition of the ribose phosphate is catalyzed by the
salvage pathway enzyme, hypoxanthine-guanine
phosphoribosyl transferase (HGPRT).
HGPRT
• 6-MP 6-MP-ribose phosphate
Pharmacy
10-01-17 149
Ribose phosphate

2. Inhibition of purine synthesis:
• A number of metabolic processes involving- purine
biosynthesis and interconversions, are affected by
thioinosine monophosphate (TIMP) (a nucleotide
analog).
• TIMP can inhibit the first step of de novo purine-
ring biosynthesis (catalyzed by glutamine
phosphoribosyl pyrophosphate amidotransferase).
• TIMP also blocks the formation of AMP and
xanthinuric acid from inosinic acid.
Pharmacy
10-01-17 150

3. Incorporation into nucleic acids:
• TIMP is converted to thioguanine
monophosphate (TGMP), which after
phosphorylation to di- and triphosphates can
be incorporated into RNA.
• The deoxyribonucleotide analog that are also
formed are incorporated into DNA.
• This results in nonfunctional RNA and DNA.
Pharmacy
10-01-17 151

Pharmacy
10-01-17 152

Resistance:
• Resistance is associated with
• 1) an inability to biotransform 6-MP to the
corresponding nucleotide because of
decreased levels of HGPRT (for example, in
Lesch-Nyhan syndrome, in which patients lack
this enzyme),
• 2) increased dephosphorylation, or
• 3) increased metabolism of the drug to thiouric
acid or other metabolites.
Pharmacy
10-01-17 153

Adverse effects:
• Bone marrow depression is the principal
toxicity.
• Side effects also include anorexia, nausea,
vomiting, and diarrhea.
• Occurrance of hepatotoxicity in the form of
jaundice has been reported in about one-third
of adult patients.
Pharmacy
10-01-17 154

Pyrimidine antagonist
5-Fluorouracil (5-FU)
• Is converted in the body to the corresponding
nucleotide 5-fluoro-2-deoxyuridine
monophosphate, which inhibits thymidylate
synthase and blocks the conversion of
deoxyuridilic acid to deoxythymidylic acid.
• Thus depriving the cell of thymidine, one of the
essential precursors for DNA synthesis.
• Fluorouracil itself gets incorporated into nucleic
acids and this may contribute to its toxicity.
Pharmacy
10-01-17 155

• Even resting cells are affected, though
rapidly multiplying ones are more
susceptible.
• Used in slowly growing solid tumors (for
example, colorectal, breast, ovarian,
pancreatic, and gastric carcinomas).
• When applied topically, 5-FU is also effective
for the treatment of superficial basal cell
carcinomas.
Pharmacy
10-01-17 156

Mechanism of the cytotoxic action of 5-FU.
5-FU is converted to 5-FdUMP, which competes with
deoxyuridine monophosphate (dUMP) for the
enzyme thymidylate synthetase.
5-FU = 5-fluorouracil;
5-FUR = 5-fluorouridine;
5-FUMP = 5-fluorouridine monophosphate;
5-FUDP = 5-fluorouridine diphosphate;
5-FUTP = 5-fluorouridine triphosphate;
dUMP = deoxyuridine monophosphate;
dTMP = deoxythymidine monophosphate.
5-FdUMP=5-fluorodeoxyuridine monophosphate.
•5-FU is converted to 5-fluorouridine-5′-
triphosphate (FUTP), which is then incorporated
into RNA, where it interferes with RNA
processing and mRNA translation.
•5-FU is also converted to 5-fluorodeoxyuridine-
5′-triphosphate (FdUTP), which can be
incorporated into cellular DNA, resulting in
inhibition of DNA synthesis and function.
•Thus, the cytotoxicity of 5-FU is thought to be
the result of combined effects on both DNA-
and RNA-mediated events.Dr. Bharat Mishra, Nirmala College of
Pharmacy
10-01-17 157

Resistance &Adverse effects:
• Resistance is encountered when the cells have
lost their ability to convert 5-FU into its active
form (5-FdUMP) or when they have altered or
increased thymidylate synthase levels.
• In addition to nausea, vomiting, diarrhea, and
alopecia, severe ulceration of the oral and GI
mucosa, bone marrow depression (with bolus
injection), and anorexia are frequently
encountered.
• An allopurinol mouthwash has been shown to
reduce oral toxicity.
• A dermopathy (erythematous desquamation of
the palms and soles) called the hand-foot
syndrome is seen after extended infusions.
Pharmacy
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NATURAL PRODUCT CANCER CHEMOTHERAPY DRUGS : Mitotic Inhibitors
VINCA ALKALOIDS
• Vincristine (VX) and vinblastine (VBL) are
structurally related compounds derived from
the periwinkle plant, Vinca rosea.
• New (and less toxic) agent is vinorelbine (VRB).
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Mechanism of Action
• They are cell cycle specific and act in the
mitotic phase.
• These are mitotic inhibitors, bind to
microtubular protein-'tubulin',
• prevent its polymerization and assembly of
microtubules, cause disruption of mitotic
spindle and interfere with cytoskeletal function.
• The chromosomes fail to move apart during
mitosis: metaphase arrest occurs.
• Although the vinca alkaloids are structurally
very similar to each other, their therapeutic
indications, anti tumour activity and toxicity are
different.
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Uses
• VX is used in the treatment of acute
lymphoblastic leukemia in children, Wilms‘
tumor, Ewing's soft-tissue sarcoma, Hodgkin's
and non-Hodgkin's lymphomas, as well as
some other rapidly proliferating neoplasms.
• VBL is administered with bleomycin and
cisplatin for the treatment of metastatic
testicular carcinoma.
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• It is also used in the treatment of systemic
Hodgkin's and non-Hodgkin's lymphomas.
• VRB is beneficial in the treatment of advanced
non small cell lung cancer, either as a single agent
or with cisplatin.
• Adverse effects
• Both VX and VBL have certain toxicities in
common.
• These include phlebitis or cellulitis during
injection, as well as nausea, vomiting, diarrhea,
and alopecia.
• Granulocytopenia is dose limiting for VRB.
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• VBL is a more potent myelosuppressant than VX,
whereas peripheralneuropathy (paresthesias, loss
of reflexes, foot drop, and ataxia) is associated with
VX.
• The anticonvulsants phenytoin, phenobarbital, and
carbamazepine can accelerate the metabolism of
VX, whereas the azole antifungal drugs can slow its
metabolism.
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EPIPODOPHYLLOTOXINS
Etoposide
• It is a semisynthetic derivative of
podophyllotoxin, a plant glycoside.
• It is not a mitotic inhibitor, but arrests cells in
the G2 phase and causes DNA breaks by
affecting DNA topoisomerase II function.
• While the cleaving of double stranded DNA is
not interfered, the subsequent resealing of the
strand is prevented.
• It has been primarily used in testicular tumours,
lung cancer, Hodgkin's and other lymphomas,
carcinoma bladder.
• Alopecia, leucopenia and g.i.t. disturbances are
the main toxicity.
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CAMPTOTHECIN ANALOGUES
• Topotecan and Irinotecan are two recently
introduced semisynthetic analogues of
camptothecin, an anti tumour principle obtained
from a Chinese tree (Camptotheca acuminata).
• They act in a manner similar to etoposide, but
interact with a different enzyme (DNA
topoisomerase 1).
• Their binding to this nuclear enzyme allows
single strand breaks in DNA, but not its resealing
after the strand has untwisted.
• They damage DNA during replication; act in the S
phase and arrest cell cycle at G2 phase.
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• Topotecan is used in metastatic carcinoma of
ovary and small cell lung cancer after
primary chemotherapy has failed.
• The major toxicity is bone marrow
depression, especially neutropenia.
• Other adverse effects are pain abdomen,
vomiting, anorexia and diarrhoea.
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• lrinotecan is a prodrug; is decarboxylated in
liver to the active metabolite.
• Cholinergic effects are produced in some patients
because it inhibits AChE.
• These effects can be suppressed by prior
atropinization.
• Irinotecan is indicated in metastatic/ advanced
colorectal carcinoma, cancer lung/cervix/ovary,
etc.
• Dose limiting toxicity is diarrhoea; neutropenia,
thrombocytopenia, haemorrhage, bodyache and
weakness are the other adverse effects.
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Miscellaneous Drugs
lmatinib
• It acts as a signal transduction inhibitor, inhibits
the tyrosine protein kinases in chronic myeloid
leukaemia (CML) cells and other tumers
activated by platelet derived growth factor
(PDGF) receptor, stem cell receptor and c-kit
receptor found in gastrointestinal stromal
tumour (GIST), a rare tumour.
• Stricking success has been obtained in chronic
phase of CML as well as in accelerated phase,
and in metastatic kit-positive GIST.
• Adverse effects are fluid retention, edema,
vomiting, abdominal pain, myalgia and liver
damage.
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References
• Robbins.; Basic Pathology. 7th edition, Elsevier, publication 2007;
641-655.
• Dipiro JT.; Pharmacotherapy, A Pathophysiologic Approach. 6th ed.
Mcgraw hill medical publishing division 2005; 1333-1368 .
• Rang HP, Dale MM.;Pharmacology ;6th ed. Elsevier publication
2007:97-409
• Harvey A. Richard ;Pharmacology. 4th edition.Lippincotts illusrative
review.
• Goodman & Gilman's the pharmacological basis of therapeutics -
11th ed. (2006).
• Kd tripathi ;essentials of medical pharmacology ,sixth edition.
jaypee brothers medical publishers (p) ltd.2008.
• Bertram Katzung, Susan Masters, Anthony Trevor Basic and Clinical
Pharmacology, 12E. 2011.
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Thank you for the patient listening .......
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