10.ANTICANCER DRUGS

BYBY
Dr.Dr. SAMINATHAN KAYAROHANAMSAMINATHAN KAYAROHANAM
M.PHARM, M.B.A, PhDM.PHARM, M.B.A, PhD
ANTICANCER DRUGS
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10

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NUM CONTENT SLIDE
1 INTRODUCTION/DIFINTION 4
2 EPIDEMIOLOGY OF CANCER 5
3 RISK FACTORS 6
4 CHARACTERISTIC OF CANCER 7
5 THE SEVEN WARNING SIGNS OF CANCER 8
6 CANCER TYPES 9
7 CELL CYCLE 10
8 CARCINOGENESIS 11
9 FORMATION OF MALIGNAT CELL BY MUTATION 12
10 TREATMENT OPTIONS OF CANCER 13
11 DIAGNOSIS OF CANCER 14
12 CELL CYCLE SPECIFIC /NON- SPECIFIC DUGS 15
13 ANTI CANCER DRUG CLASSIFICATION 16-19
14 CHEMOTHERAPEUTIC DRUGS AFFECTING RNA /DNA PRECURSORS 20
15 COMPARISON OF MYELOSUPPRESSIVE POTENTIAL OF
CHEMOTHERAPEUTIC DRUGS
21
16 MECHANISAM OF ANTICANCER DRUGS 22
17 TOXIC EFFECTS OF ANTI CANCER DRUGS 40
18 CONCLUSION. 42

3
LEARNING OUTCOME
1. Define cancer and Describe cell cycle.
2. Able to demonstrate the risk factor, character ,
diagnosis and treatment of cancer
3. Able to understand the warning signs of cancer.
4. List the anti cancer drug classification.
5. Abele to demonstrate the mechanism of cancer
drugs.
6. Describe the toxic effects of anti cancer drugs.

4
Cancer is the rapid creation of abnormal cells that grow beyond
their usual boundaries, and which can then invade adjoining parts
of the body and spread to other organs. This process is referred to
as metastasis. Metastases are the major cause of death from
cancer. (WHO)
Cancer known medically as a malignant neoplasm, is a broad
group of diseases involving unregulated cell growth. In
cancer, cellsdivide and grow uncontrollably, forming malignant
tumors, and invading nearby parts of the body. The cancer may
also spread to more distant parts of the body through
the lymphatic system or bloodstream. Not all tumors are
cancerous; benign tumors do not invade neighboring tissues and
do not spread throughout the body. There are over 200 different
known cancers that affect humans.
1. INTRODUCTION/DIFINTION
Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D

5
2. EPIDEMIOLOGY OF CANCER

6
3. RISK FACTORS
1.Tobacco
2.Sunlight
3.Ionizing radiation
4.Certain chemicals and other substances
5.Some viruses and bacteria
6.Certain hormones
7.Family history of cancer
8.Alcohol
9.Poor diet, lack of physical activity, or being overweight

7
Cancer arises as a result of a series of genetic and epigenetic changes,
the main genetic lesions being:
• inactivation of tumour suppressor genes
• the activation of oncogenes (mutation of the normal genes controlling
cell division and other processes).
Cancer cells have four characteristics that distinguish them from
normal cells:
• uncontrolled proliferation
• loss of function because of lack of capacity to differentiate
• invasiveness
• the ability to metastasise.
Cancer cells have uncontrolled proliferation because of changes in:
• growth factors and/or their receptors
• intracellular signalling pathways, particularly those controlling the cell
cycle and apoptosis
• telomerase expression
• tumour-related angiogenesis
4. CHARACTERISTIC OF CANCER

5. THE SEVEN WARNING SIGNS OF CANCER
The American Cancer Society uses the wordC-A-U-T-I-
O-N to help recognize the seven early signs of cancer:
1.Change in bowel or bladder habits
2.A sore that does not heal
3.Unusual bleeding or discharge
4.Thickening or lump in the breast, testicles, or
elsewhere
5.Indigestion or difficulty swallowing
6.Obvious change in the size, color, shape, or
thickness of a wart, mole, or mouth sore
7.Nagging cough or hoarseness
8

9
categorized based on the functions/locations of the cells from
which they originate:
Carcinoma: a tumor derived from epithelial cells, those cells that line the
surface of our skin and organs (80-90% of all cancer cases reported)
Sarcoma: a tumor derived from muscle, bone, cartilage, fat or connective
tissues.
Leukemia: a cancer derived from white blood cells or their precursors.
Lymphoma: a cancer of bone marrow derived cells that affects the
lymphatic system.
Myelomas: a cancer involving the white blood cells responsible for the
production of antibodies (B lymphocytes)
6. CANCER TYPES

Go – Resting phase
Restriction checkpoint
8hrs or more
6-8 hrs
2-5 hrs
7. CELL CYCLE
10 Dr.K.Saminathan.M.Pharm, M.B.A, Ph.D

Normal Cell
DNA Damage
Mutations in the genome
of somatic cells
Alteration of genes that
regulates apoptosis
Expression of altered gene products
Loss of regulatory gene product
MALIGNANT NEOPLASM
Activation of
growth promoting
oncogene
Inactivation of cancer
suppressor genes
Acquired
(environmental DNA
damaging agents)
Chemicals
Radiation
viruses
Successful DNA repair
Failure of DNA repair
8. CARCINOGENESIS
•Clonal expansion
•Additional mutations
•Heterogeneity
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12
9.FORMATION OF MALIGNAT CELL BY MUTATION

10. TREATMENT OPTIONS OF CANCER
13
1. Surgery:
before 1955
2.Radiotherapy:
1955~1965
3. Chemotherapy:
after 1965
4. Immunotherapy
5. Gene therapy

11. DIAGNOSIS OF CANCER
 Biopsy - involves histological examination by a pathologist of a piece of
tissue.
 Imaging techniques –
• CT scan,
• MRI,
• UTZ
 Laboratory test
 Tumor markers(produced by cancer)
Example:
CA15-3 - Breast cancer.
CA19-9 - Gastrointestinal tumours.
CA-125 - Ovarian cancers.
PSA - Prostate cancers.
14
14

12.CELL CYCLE SPECIFIC /NON- SPECIFIC DUGS
CON…
15

13.ANTI CANCER DRUG CLASSIFICATION
16

17
13.ANTI CANCER DRUG CLASSIFICATION WITH CLASS /TYPE
CON…

18
CON…

19

14.CHEMOTHERAPEUTIC DRUGS AFFECTING RNA /DNA PRECURSORS.
20

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15. COMPARISON OF
MYELOSUPPRESSIVE
POTENTIAL OF
CHEMOTHERAPEUTIC
DRUGS

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Methotrexate potently
inhibits Dihydrofolate
reductase (DHFR).
This leads to decreased
production of compounds
adenine, guanine and
thymidine and the amino acids
methionine and serine,
depletion of thymidine.
Finally depressed DNA,
RNA, and protein synthesis
and, ultimately, to cell death.
FH2 = dihydrofolate; FH4 = tetrahydrofolate; dTMP = deoxythymidine monophosphate;
dUMP = deoxyuridine mono phosphate.
16.1 MECHANISM OF ACTION OF METHOTREXATE

24
6-Mercaptopurine
penetrates target cells
and be converted to
the nucleotide analog.
This leads to inhibit
the first step of de novo
purine-ring
biosynthesis
This results in non-
functional RNA and
DNA.
16.2 MECHANISM OF ACTION OF 6-MERCAPTOPURINE

25
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.
16.3 MECHANISM OF ACTION OF 5-FLUOROURACIL
5-Fluorouracil
competes with
deoxyuridine
monophosphate for
thymidylate synthase
and reduce the
thymidine.
 DNA synthesis
decreases due to lack
of thymidine, leading to
imbalanced cell growth.

26
Gemcitabine inhibits
DNA synthesis by being
incorporated into sites in
the growing strand that
ordinarily would contain
cytosine.
 Gemcitabine
diphosphate inhibits
ribonucleotide reductase,
which is responsible for
the generation of
deoxynucleoside
triphosphates required for
DNA synthesis.
16.4 MECHANISM OF ACTION OF GEMCITABINE

27
Doxorubicin and
daunorubicin bind to the sugar-
phosphate backbone of DNA.
This causes local uncoiling.
Which leads to blocks DNA &
RNA synthesis and catalyzed
breakage supercoiled DNA
strands, causing irreparable
breaks.
 Catalyzes the reduction of free
radicals. These in turn reduce
molecular O2, producing
superoxide ions and hydrogen
peroxide, which mediate single-
strand scission of DNA.
16.5 MECHANISM OF ACTION OF DOXORUBICIN AND DAUNORUBICIN

28
A DNA-bleomycin-Fe2+
complex appears to
undergo oxidation to
bleomycin-Fe3+
.
The liberated electrons
react with oxygen to form
superoxide or hydroxyl
radicals, which in turn
attack the phosphodiester
bonds of DNA, resulting in
strand breakage and
chromosomal aberrations.
16. 6 MECHANISM OF ACTION OF BLEOMYCIN

29
Mechlorethamine is
alkylates the N7
nitrogen of
a guanine residue in one or
both strands of a DNA
molecule This alkylation
leads to cross-linkages
between guanine residues
in the DNA chains and/or
depurination, thus
facilitating DNA strand
breakage.
 Alkylation can also cause
miscoding mutations.
16. 7 MECHANISM OF ACTION OF MECHLORETHAMINE

16. 8 MECHANISM OF ACTION OF VINCA ALKALOIDS
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16. 9 MECHANISM OF ACTION OF PACLITAXEL

16. 10 MECHANISM OF ACTION OF ANTIESTROGEN
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Flutamide,nilutamide and
bicalutamide are synthetic,
nonsteroidal antiandrogens used in
the treatment of prostate cancer.
Estrogens, such as ethinyl estradiol
or diethylstilbestrol, had been used in
the treatment of prostatic cancer.
However, they have been largely
replaced by the GnRH analogs
because of fewer adverse effects.
Estrogens inhibit the growth of
prostatic tissue by blocking the
production of LH, thereby decreasing
the synthesis of androgens in the testis.
16. 11 MECHANISM OF ACTION OF ESTROGENS IN PROSTATIC
CANCER

34
Tamoxifen binds to the
estrogen receptor and the
complex fails to induce estrogen-
responsive genes, and RNA
synthesis does not ensue.
 The result is depletion (down-
regulation) of estrogen
receptors, and the growth-
promoting effects of the
natural hormone and other
growth factors are suppressed.
The action of tamoxifen is not
related to any specific phase of
the cell cycle.
16. 12 MECHANISM OF ACTION OF TAMOXIFEN

35
Normal unwinding of
double helix
Irinotecan and
topotecan are inhibit
the unwinding of
double helix
Con…
16. 13 MECHANISM OF ACTION OF IRINOTECAN &TOPOTECAN

36
Irinotecan and
topotecan are
semisynthetic
derivatives.These
drugs are S-phase
specific. They inhibit
topoisomerase I,
which is essential for
the replication of DNA
in human cells.
16. 13 MECHANISM OF ACTION OF IRINOTECAN &TOPOTECAN

37
16. 14 MECHANISM OF ACTION OF ETOPOSIDE &TENIPOSIDE
Normal catalytic cycle
of topoisonerase
which is inhibited by
the Etoposide and its
analog, teniposide
Con…

38
Etoposide and its analog,
teniposide are semisynthetic
derivatives of the plant
alkaloid, They block cells in
the late S to G2 phase of the
cell cycle.
Their major target is
topoisomerase II. Binding of
the drugs to the enzyme-DNA
complex results in persistence
of the transient, cleavable
form of the complex and, thus,
renders it susceptible to
irreversible double-strand
breaks
16. 14 MECHANISM OF ACTION OF ETOPOSIDE &TENIPOSIDE

39
16. 15 MECHANISM OF ACTION OF L-ASPARAGINASE

40
•Bone marrow toxicity (myelosuppression) with
decreased leucocyte production and thus decreased
resistance to infection
•Impaired wound healing
•Loss of hair (alopecia)
•Damage to gastrointestinal epithelium
•Depression of growth in children
•Sterility
•Teratogenicity.
17.TOXIC EFFECTS OF ANTI CANCER DRUGS

 Acute toxicity
 Vomiting
 Allergic reactions
 Arrhythmias
 Delayed effects
 Mucositis
 Alopecia
 Bone marrow suppression
 Chronic toxicities
 Heart
 Kidney
 Liver
 Lungs
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18.CONCLUSION
Every year, more than 1 million Americans and more than 10 million
people worldwide are expected to be diagnosed with cancer, a disease
commonly believed to be preventable.
Only 5–10% of all cancer cases can be attributed to genetic defects,
whereas the remaining 90–95% have their roots in the environment
and lifestyle.
The evidence indicates that of all cancer-related deaths, almost 25–
30% are due to tobacco, as many as 30–35% are linked to diet, about
15–20% are due to infections, and the remaining percentage are due
to other factors like radiation, stress, physical activity, environmental
pollutants etc.
Therefore, cancer prevention requires smoking cessation, increased
ingestion of fruits and vegetables, moderate use of alcohol, caloric
restriction, exercise, avoidance of direct exposure to sunlight, minimal
meat consumption, use of whole grains, use of vaccinations, and
regular check-ups.

10.ANTICANCER DRUGS

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