ANTINEOPLASTIC

AGENTS
 Contents
• Classification of antineoplastic
agents
• Mechanism of action
• Resistance to antineoplastic
agents
• Some treatment protocols
 Classification of
Antineoplastic agents
I. Cytotoxic drugs (directly act on
cells)
a) Alkylating agents
i. Nitrogen mustards
ii. Ethyleneimine
iii. Alkyl sulfonate
iv. Nitrosoureas
v. Triazine
b) Antimetabolites (act on metabolic pathway
involved in DNA synthesis)
i. Folate antagonist
ii. Purine antagonist
iii. Pyrimidine
antagonist
c) Plant
derivatives
i. Vinca alkaloids
ii. Taxanes
iii. Epipodophyll
otoxin
 d) Antibiotics
II. Hormones (mainly steroids which
suppress hormone secretion or
antagonize hormone action)
a) Glucocorticoids
b) Estrogen
c) Progestins
d) Antiandrogens
III. Miscellaneous (include
Hydroxyurea, Cisplatin, Monoclonal
antibodies and L.Asparginase)
 I. CYTOTOXIC
DRUGS
a) Alkylating Agents
• Contain chemical groups that can form
covalent bonds with particular
nucleophilic substances in the cell.
• Produce highly reactive
carbonium ion intermediates.
• Forms covalent bond with electron
donors like amine, hydroxyl and
sulfhydryl groups.
• Alkylating agents are bifunctional, i.e. they
• The nitrogen at position 7 (N7) of guanine,
being strongly nucleophilic, is probably
the main molecular target for alkylation in
DNA.
• N1 and N3 of adenine and N3 of cytosine
may also be affected.
• Being bifunctional they can cause intra-
or interchain cross-linking, abnormal
base pairing or chain scission.
• Interferes not only with transcription but
also with replication.
• Main impact is seen during replication (S
phase) when some zones of the DNA are
unpaired and more susceptible to
alkylation.
• Results in a block at G2 and
subsequent apoptotic cell death.
 Types of Alkylating agents

Category Drugs
Nitrogen mustards Cyclophosphamide
,
Meclorethamine
, Chlorambucil
Ethyleneimine Thiotepa
Alkyl sulfonate Busulfan
Nitrosoureas Carmustine, Lomustine
Triazine Dacarbazine
 Mechanism of activation: Cyclophosphamide

Metabolised in the 4-
Inactive
liver by P450 mixed hydroxycyclophos-
Cyclophosphamide function oxidases phamide

Converted to
phosphoramide Aldophosphamide (Reversibly) forms
mustard, the actual is conveyed to
other tissues aldophosphamide.
cytotoxic molecule
 b. ANTIMETABOLITES
i. Folate Antagonist: Methotrexate

• Folates are essential for the synthesis of

purine nucleotides and thymidylate
which in turn are essential for DNA
synthesis and cell division.
• The main action of the folate
antagonists is to interfere with
thymidylate synthesis.
MOA: Methotrexate

Folate
Dihydrofolate
reductase
Dihydrofolate (FH2)

Tetrahydrofolate
(FH4)
• FH4 functions as an essential cofactor
carrying the methyl groups necessary for
the transformation of 2´-deoxyuridylate
(DUMP) to the 2´-deoxythymidylate
(DTMP) required for the synthesis of DNA
and purines.
• During the formation of DTMP from
DUMP, FH4 is converted back to FH2,
enabling the cycle to repeat.
• Methotrexate has a higher affinity than
FH2 for dihydrofolate reductase.Thus
inhibits the enzyme, depleting
intracellular FH4.
ii. Purine antagonist: 6-mercaptopurine

Converted in
the cells to
6-
ribonucleotide
mercaptopurin of 6-
e mercaptopurin
e

Suppresses
denovo
No
biosynthesis
of purines DNAsynthesis
iii. Pyrimidine Antagonist: 5-Fluorouracil
(Analogue of uracil)

5-fluorouracil

Converted to 5-fluoro-2-
deoxy uridine
monophosphate

Inhibits thymidilate
synthesis

Blocks conversion of
deoxyuridilic acid to
deoxythymidilic acid
 c) PLANT DERIVATIVES
i. Vinca Alkaloids
• Vincristine, vinblastine and vindesine:
Main vinca alkaloids used in cancer
chemotherapy.
• Obtained from the plant Vinca rosea.
• Inhibit mitosis.
• Bind to tubulin and inhibit its
polymerisation into microtubules,
preventing spindle formation in dividing
cells and causing arrest at metaphase.
• Cell cycle specific and phase specific.
ii. Taxanes: Paclitaxel

• Obtained from western yew tree.

• Reversibly binds to tubulin and results in
the formation of stable non-functioning
microtubule by promoting polymerization
and stabilization of the microtubules.
• Thus, interferes with mitosis causing cell
death.
iii. Epipodophyllotoxins: Etoposide

• Semi-synthetic derivative of
podophyllotoxin obtained from
Podophyllum peltatum.
• Inhibits enzyme topoisomerase II,
leading to DNA damage.
• Blocks the cell in S-G2 phase of cell
cycle.
 d) ANTIBIOTICS
i. MOA: Dactinomycin
• Intercalates into the minor grooves of
double helix between G-C base pairs of
DNA ad interferes with the movement
of RNA polymerase along the gene
preventing transcription.
• May also cause strand breaks and stabilise
DNA topoisomerase II complex.
ii. MOA: Doxorubicin

• Bind to DNA and inhibit both DNA and

RNA synthesis.
• Produces breaks in DNA strands by
activating topoisomerase II and
produces semiquinone free radicals.
• Semiquinone radicals reduce molecular
oxygen to superoxide ions and H2O2 that
mediates single strand scission of DNA.
iii. MOA: Bleomycins

• Group of metal-chelating glycopeptide

antibiotics obtained from Streptomyces
verticullus.
• Produces chelation of copper or iron ions
which produces superoxide ions that
interacts with DNA.
• Degrade preformed DNA, causing
chain fragmentation and release of
free bases.
 PURINE S YNT1JESIS PYRIMIDINE SYNTHESIS
PENTOSTA1 IM
inhio‹ts adenosine iM hi0›ts DTNP 8ynthosis
deaminose
niaoNUCLE OTI
6-MERCAPTOPURINE DES
damegB DNA and
6•TIOGLIANINE
prevent repair
inhibit punne synthesis
DEOXYRIBCNUC LEOT IDE'2
innioit nucleotide
i nterconve rsions

METuOYf EXATE
inhibits purino synthesis
inhibits D \’MP synthesis

CYYAPIABTNE
rnhibil topoisomer6s TI
inhibits DNA p@ymerase
inhi.bit RNA synthesis
inhibits RNA function

H II5i ANTASPAi5R
intercalatos in DNA
4eaminsles aepaiagina
inh bits topo‹so rnerBse II
inhibits pmein syntheses

£NZYNIGS (etc.)
fdICFICrFUBULG$-
 II. HORMONES
a) Glucocorticoids
• Glucocorticoids such as prednisolone and
dexamethasone have marked inhibitory
effects on lymphocyte proliferation
• Used in the treatment of
leukaemias and lymphomas.
• Their ability to lower raised intracranial
pressure, and to mitigate some of the
side effects of anticancer drugs, makes
them useful as supportive therapy .
 b) Oestrogens
• Diethylstilbestrol and ethinyloestradiol
are two oestrogens used clinically in the
palliative treatment of androgen-
dependent prostatic tumours.
• The latter compound has fewer side
effects. These tumours are also treated
with gonadotrophin-releasing hormone
analogues
• Oestrogens can be used to recruit resting
mammary cancer cells into the
proliferating pool of cells, thus facilitating
killing by other cytotoxic drugs.
 b) Progestins
– Progestins such as megestrol and
medroxyprogesterone have been useful in
endometrial neoplasms and in renal
tumours to bring temporary remission.
c) Anti-Androgen
– Flutamide: androgen antagonist used in
prostate tumors since they increase
androgen levels.
III. MISCELLANEOUS DRUGS
a) Hydroxyureas
– Acts by blocking the conversion of
ribonucleotide to deoxyribonucleotide by
inhibing the enzyme ribonucleoside
diphoshate reductase.
b) Cisplatin

Cisplatin enters the cell

Cl- dissociates leaving a reactive

complex
that reacts with water

Interacts with DNA

Causes intrastrand cross-linking

probably between N7 and O6 of
adjacent guanine molecules

Results in local denaturation

of DNA
c) L-Asparaginase
– Enzyme prepared from E.coli.
– Deaminates asparagine to aspartic acid
and ammonia, and is active against tumour
cells, such as those of acute lymphoblastic
leukaemia.
d) Monoclonal Antibodies
– Ex: Rituximab
– Activate the host immune mechanism
and kills the cancer cells.
– Used for β-cell lymphoma.
RESISTANCE TO ANTICANCER DRUGS
• Decreased accumulation of cytotoxic
drugs in cells as a result of the
increased expression of cell
surface, energy- dependent drug
transport proteins.
• A decrease in the amount of drug taken
up by the cell (e.g. in the case of
methotrexate).
• Insufficient activation of the drug
(e.g. Mercaptopurine,
• Increase in inactivation (e.g.
mercaptopurine).
• Increased concentration of target enzyme
(methotrexate).
• Decreased requirement for substrate
(L- Asparaginase).
• Increased utilisation of alternative metabolic
pathways (antimetabolites).
• Rapid repair of drug-induced lesions
(alkylating agents).
• Altered activity of target, for example
modified topoisomerase II (doxorubicin).
• Mutations in various genes, giving rise
to resistant target molecules. (several
cytotoxic drugs).
 Treatment Protocols
• Combination is more effective than
monotherapy without increasing toxicity.
• Also decreases possibility of
development of resistance.
• Higher responsive rates due to both
additive cytotoxic effects and non-
overlapping host toxicities.
 Some combination regimens:
• POPM: Methotrexate + Oncovin
(vincristine) + Prednisone + Purinethol
(mercaptopurine) in lymphocytic
leukaemia
• VAMP: Vincristine +
Amethopterine (methotrexate)
+ 6-mercaptopurine +
Prednisolone in acute leukaemia