CHEMOTHERAPY

Presented by :- prn no 32

08/05/2025 JAJNURE MADHAV

 Cancer :-
 Cancer refers to the disease of cells which shows uncontrolled
proliferation, dedifferentiation i.e anaplasia, invasiveness and
the ability to metastasis i.e spread to distal parts of body.
 The appearance of abnormal characteristics refers to
chromosomal abnormality including an expression of
abnormal gene sequences called as oncogenes.
 When such cells proliferate excessively, they form local
tumors which can invade surrounding normal cellular
structure.
 Most cancer-causing DNA changes occur in sections
of DNA called genes. These changes are also called genetic
changes. A DNA change can cause genes involved in normal
cell growth to become oncogenes. Unlike normal genes,
oncogenes cannot be turned off, so they cause uncontrolled
cell growth.
 Types of cancer :-
1. Benign :- In this type the tumors are generally slow
growing, resemble normal cells, remain localized and
are usually not harmful. They do not spread to local
structures or to distant parts of the body. Benign
tumors tend to grow slowly and have distinct borders.
2. Malignant:- These are the solid tumors and
hematological malignances. Solid tumors can be
carcinomas, adenocarcinomas, sarcomas or myelomas.
Hematological malignances include lymphoma and
leukemia.
 Causes of Cancer
Signs and symptoms :-

■ Lump
■ Abnormal bleeding
■ Prolonged cough
■ Unexplained weight loss, and
■ Change in bowel movement.
■ While these symptoms may indicate cancer, they may have other
causes
Characteristics of cancer :-
[Link] Proliferation: The genetic changes in cancerous cells confer autonomy of
growth to them, so that their proliferation is subject to normal physiological processes.
[Link]: Normally, when daughter cells are matured, they differentiate and
behave like their parent cells; e.g. muscle cells will start contracting. However cancer cells
do not differentiate. As a result they grow in an uncontrolled manner with the same
morphology.
[Link]: Normal cells are not found outside their tissue of origil97 / 285c cells are
not found in brain. If any cell accidentally escapes, it would undergo apoptosis and die.
The cancer cells, due to mutations, have no such limitation and can slip into nearby organs.
[Link]: Cancer cells can disseminate to distal organs through blood and lymphatics,
e.g.. Bone cells can metastasize into lungs. It can lead to spread of cancer throughout the
body.
Site of action
Treatment of cancer :-

■ There are four main approaches to treat cancer :-

1. Surgical resection
2. Radio therapy
3. Chemotherapy
4. Immunotherapy
Surgical resection
Radiotherapy
Chemotherapy
Immunotherapy
  Chemotherapy
 Examples :
Chemotherapy : Use of chemical to destroy microorganisms. • Bacteria
• Fungi
Father of chemotherapy : Paul Ehrlich • virus
• Obtained from microorganisms • Protozoa
Antibiotics : • parasites
• Supress the growth or kill
Anti – Against
microorganisms
Biotics – Living organisms
• ex. Penicillin – P. Notatum
• Streptomycin – S. Griseus

 They are selective Penicillin : inhibit cell wall synthesis

Tetracyclines : inhibit protein synthesis

Antimicrobials : Those drugs which are obtained from naturally or synthetically and act
against microorganisms.
Ex. Quinine – Antimalarial
metronidazole- Antiamoebic
 All antibiotics act as antimicrobials but all antimicrobials are not antibiotics.
 Paul Ehrilch
■ Paul Ehrilch was a German
physician, serologist and
immunologist. Based on his
research, he is considered as the
founder of chemotherapy, since he
was the first scientist to develop
targeted pharmaceutical treatment
against syphilis using the organic
arsenic-based compound,
Salvarsan.
■ He is known as father of
chemotherapy.
 1)
Introduction
Definitions

4)
2)
Treatment Chemotherapy
Cancer
(MOA)

3)
Cell
division
  Malignancy :

Malignancy - Cancer

Cancer: Uncontrolled , abnormal growth of cells.

Cell cycle :-

■ The cells reproduce themselves through cell division. The division is of

two types: mitosis and meiosis.
■ During mitosis, each daughter cell gets the same number and kind of
chromosomes as that of parent cell.
■ During meiosis, the daughter cells contain half the number of
chromosomes. The normal cells are termed as diploid cells containing
2n number of chromosomes.
■ During mitosis the number 2n of chromosomes is retained. During
meiosis, dipoloid cells are converted to haploid cells, containing n
number of chromosomes. During meiosis, sperms and egg cells are
generated.
Go phase: Most cells do not divide constantly and spend a varying
amount of quiescent/calm state outside the cell cycle. This phase is
called as Go phase. The growth factors provide momentum for the
beginning of the cell cycle. The cell cycle consists of two major
activities:
■ The interphase i.e. G,→ S → G, phase; and the cell division ie mitosis,
M phase and cytokinesis.
• Helicase : cut the DNA

• Topoisomerase I &II

• Polymerase : form the leading and lagging strand and DNA repair
Interphase: When the cell is in between one mitosis and the next, it is said to be in
interphase. It is during interphase that the replication of chromosomes happens. In
addition, DNA, RNAs and protein, needed to produce structures which are required for
doubling all cellular components are manufactured in this phase. Interphase consists of
three distinct phases: Gy, S and Gz phase.
Gy, S and G, phases: It is a growth or gap phase during which cells are engaged in
metabolism and production of substances required for forthcoming cell division and
growth.
In S (synthesis) phase, DNA and chromosomes are replicated. S phase is followed by
another growth phase, G, phase. It is a gap period between S phase and mitosis.
During G, phase, the cell prepares itself for mitotic division into two daughter cells. In
G; and G, phase there are no events related to chromosomal or DNA replication, These
phases simply serve as preparatory ground or gaps in DNA synthesis.
Some cells like nerve cells, skeletal muscle cells are permanently arrested in G, phase;
but once a cell enters 5 phase it is bound to go through mitosis ie M phase. An entry of
the cell into the S phase or M phase is controlled at two check points in the cell cycle.
■ One check point starts at the beginning of $ phase and another check point starts
at the beginning of M phase. In the quiescent Go phase, a specialized protein called
Rb protein is not phosphorylated. Bare Rb protein serves as a break keeping the
cells in the G, phase by inhibiting the genes essential for passing into S phase
Mitosis (M phase): It can be divided further into four stages: prophase, metaphase, anaphase and
telophase.
1. Prophase (pro means before) PP: Till now, the chromosomes, although duplicated, are in a form
of tangled mass filled inside the nucleus. In prophase, they condense into visible chromosomes ie
two sister chromatids joined at centromere. Nuclear membrane now disintegrates and condensed
chromosomes are released in cytoplasm.
2. Metaphase (meta means after) MP: During metaphase, the chromatid pair, collectively a
chromosome and its copy, line up at the exact center or the mitotic spindle in an equatorial plane.
■ 3. Anaphase (ana means upward) AP: During anaphase, centromeres divide and identical sets
of chromosomes move to the opposite poles of the cell. The separated sister chromatids are
referred to as daughter chromosomes.
■ 4. Telophase (telo means at the end) TP: Telophase is the end stage of mitosis and is opposite
to that of prophase. During this stage, the identical sets of chromosomes at opposite poles of
the cell uncoil and revert to their thread-like chromatin form.
 • Synthesize protein and enzymes. Prophase • Chromosome start condense
G1
I • Replication of most of cell organelles. and become short and thick
• Cell size get increased • Centrosomes start forming
microtubules.
Check Point
Metaphase
S
DNA replication Microtubules extends and
attached to the chromatid

G2 • Protein Synthesis Anaphase

• Replication of remaining all organelles • Microtubules gets
• Fully grow pulls back .
• Cell elongate

M Telophase • Actin and Myosin

Mitosis

Daughter
 Cell Cycle Specific Drugs

G1 S
Methotrexate
Etoposide 6- Mercaptopurine
5- flurouracil

CCS
(Cell cycle specific)
M G2

Vincristin Etoposide
Vinblastin Topotecan
Paclitaxel Irinotecan
 Anticancer /antineoplastic/antitumor drugs:

 The drugs which are used in treatment of cancer is called anticancer drugs.
  Targets of Anticancer drugs (Cytotoxic drugs)

 DNA replication

 Pyrimidine and purine

Cell Division
 Microtubules

 Topoisomerase I&II
  MOA
Alkylating agent

they produce the carbonium ion (electron deficient)

Guanine has two extra electrons that’s why the carbonium

ions transfer with alkyl group and forms a covalent bond
with N7 guanine .

In this way they do the cross linking / abnormal base

pairing / DNA strand breakage

Results DNA proliferation

Moa of ifosfamide:-

■ Ifosfamide This congener of cyclophosphamide has a longer and dose-

dependent t½. It has found utility in bronchogenic, breast, testicular,
bladder, head and neck carcinomas, osteogenic sarcoma and some
lymphomas.
■ Ifosfamide produces greater neurotoxicity (mental changes,
hallucinations, seizures, coma) and haemorrhagic cystis than other
alkylating agents. To protect the bladder, MESNA, a SH compound is
mostly given with it.
■ Mesna is excreted in urine binds and inactivates the vasicotoxic
metabolites of ifosfamide and cyclophosphamide. Ifosfamide causes
less alopecia and is less emetogenic than cyclophosphamide.
 Topoisomerase Inhibitors
Moa of Irinotecan :-

■ Irinotecan It is a prodrug which is decarboxylated in liver to the active

metabolite SN-38. Cholinergic effects are produced in some patients
because it inhibits AChE. These effects can be suppressed by prior
atropinization.
■ Irinotecan is primarily indicated in metastatic/advanced. Colorectal
carcinoma, also in cancer lung/cervix/ ovary and stomach. It has been
combined with 5-FU and leucovorin.
■ Dose limiting toxicity is diarrhoea. Neutropenia, thrombocytopenia,
hemorrhage, bodyache and weakness are the other adverse effects
  Antimetabolites

dUMP Methylene THF

( deoxyuridine monophosphate)

5-Fliurouracil Thymidylase synthase

dTMP DHF
( deoxythymidine monophosphate) (Dihydrofolate)

Methotrexate DHFR (Dihydrofolate reductase)

Pyrimidine nucleotides:
( Thymidine , cytosine) THF
(Tetrahydrofolate)

Inhibits DNA
Purine nucleotide:
Synthesis
(Adenine , Guanine)
Moa of mitoxantrone :-

■ Mitoxantrone it is an anthracycline derivative related to doxorubicin

with lower cardiotoxicity, probably because it does not produce
quinone type free radicals. However, it does bind to DNA, inhibits
topoisomerase-2 causing strand.
■ Breaks and inhibiting DNA as well as RNA synthesis Clinical utility is
restricted mostly to acute myeloid lon- kaemia, advanced hormone-
refractory prostate cancer and occasionally in breast and hepatic
carcinoma, non-Hodgkin lymphoma.
■ It has been found useful in late stage multiple sclerosis as well.
Though cardiomyopathy can occur, major toxicity is marrow
depression and mucosal inflammation. Discoloration of nails and eye
may occur.
  Microtubule damaging agents

 The drugs bind to tubulin and inhibit its polymerisation into microtubules,
preventing spindle formation in dividing cells and causing arrest at metaphase.
Moa of vincristine :-

■ Vincristine (oncovin) It is a rapidly acting drug, very useful for

inducing remission in child- hood acute lymphoblastic leukaemia, but
is not good for maintenance therapy.
■ Other indications are acute myeloid leukaemia, Hodgkin’s disease,
Wilms tumour, Ewing’s sarcoma, neuroblastoma and carcinoma lung.
Prominent adverse effects are peripheral neuropathy and alopecia.
■ Vincristine also causes ataxia, nerve palsies, autonomic dysfunction
(postural hypotension, paralytic ileus, urinary retention) and seizures
Miscellaneous agents :-
Moa of L – Asparaginase :-

■ L-asparaginase (L-ASPase) This enzyme was introduced on the basis of a difference

observed between normal cells and those from childhood lymphoblastic leukaemia, viz.
the leukaemia cells were found to be deficient in L-asparagine synthase enzyme and
depended on the supply of L-asparagine from the medium.
■ The enzyme L-ASPase (from E. coli.) degrades L-asparagine to L-aspartic acid,
depriving the leukaemia cells of an essential metabolite, and causes cell death. L-
asparaginase is a component of regimen for inducing remission in acute lymphoblastic
leukaemia along with Mtx., prednisolone, vincristine, etc. However, resistance develops
to L-ASPase mostly by induction of L-asparagine synthase in the leukaemia cells.
■ Moreover, L-ASPase is antigenic, produces neutralizing antibodies which inactivate and
clear the enzyme rapidly, so that clinical response is lost. A polyethylene glycol
conjugated L-ASPase (Peg-asparaginase) has been produced which has very slow
clearance from the body, is injected every 2 weeks and is more effective. It is also less
antigenic
 Adverse effects

• Bone marrow toxicity (myelosuppression) with decreased leukocyte production

and thus decreased resistance to infection

• Impaired wound healing

• Loss of hair (alopecia)

• Damage to gastrointestinal epithelium (including oral mucous membranes)

• Depression of growth in children

• Teratogenicity
Thank
You