Anti-Cancer Agents

a) Anti-metabolites

Cytotoxics

Anti-metabolites are structurally related to normal compounds present

within the cell that are involved in the biosynthesis of DNA and RNA.
They competitively block or subvert metabolic pathways. Two classes of
anti-metabolites are folate antagonists and nucleic acid synthesis
inhibitors.
Folates are essential for the synthesis of purine nucleotides and
thymidylate. Both of these are imperative for DNA synthesis and cell
division.
(FolateDHFTHFMethylene THFMethyl THFPurine)
Active
Ingredient

Clinical Use

MOA

Effects

Methotrexat
e

Cancer

Competitive
inhibitor of
DHFR

Inhibits the
metabolism
of folic acid.
THF is
converted to
a variety of
coenzymes
needed for
DNA/RNA
synthesis.

Folinic Acid
(Leucovorin)

Rescue bone
marrow and
GI mucosa
when using
methotrexat
e. It is also
used with 5FU.

Readily
converted to
other
reduced
folic acid
derivatives.
It has
vitamin
activity that
is equivalent
to that of
folic acid.

Allows for
some
purine/pyrimi
dine
synthesis to
occur so that
DNA
replication
and RNA
transcription
can proceed.

b) Nucleic Acid Synthesis Inhibitors

Side
Effects/Note
s
Max effect is
at the Sphase of the
cell cycle.
It binds to
methotrexat
e with an
affinity 1000
times more
than that of
folate.
With 5-FU, it
enhances 5FUs effects
by inhibiting
thymidylate
synthase.

They are analogues of purines/pyrimidines that inhibit enzymes by

forming false RNA or DNA which is unable or slower to replicate due to
extra binding groups.
Purine analogues6-thioguanine, 6-mercaptopurine
Pyrimidine analogues5-FU, Cytarabine

Active
Ingredient
5Fluorouracil

Clinical Use

MOA

Effects

Cancer,
particularly
colorectal
cancer

Inhibition of
thymidylate
synthase
(primary)
and
incorporatio
n of its
metabolites
into DNA
and RNA.

Prevents the
formation of
thymidine
monophosph
ate (dTMP)
which is
phosphoryla
ted to
thymidine
triphosphate
for use in
DNA
synthesis
and repair.

Side
Effects/Notes
It is
extensively
metabolized
in the gut
and liver by
dihydropyrim
idine
dehydrogena
se (DPD).
Three
metabolites
are made but
fluorodeoxyuridine
monophosph
ate (FdUMP)

There are two prodrugs for oral administration:

1- Capecitabine: activated by cascade of 3 enzymes into 5FU. Last
enzyme in cascade (thymidine phosphorylase) is expressed at
much higher concentrations in many solid tumours than in
corresponding normal tissue some tumour specificity.
2- UFT: Ftorafur + uracil in 1:4 molar ratio. Ftorafur is a pro-drug
converted to 5FU in the liver. Uracil is a competitive inhibitor of
DPD (inhibits degradation of 5FU).

Alkylating Agents
Alkylating agents contain a reactive alkyl group which have the
property of forming covalent bonds with nucleic acids. They form

irreversible bonds with guanine residues on the same or adjacent

strands (they can form both intra and inter-chain linking). Thus, they
inhibit DNA synthesis during the S-phase and interfere with
transcription. Max effectiveness occurs during replication when some
parts of the DNA are unpaired (G1 amd S).
Nitrogen Compounds
Cyclophospha
mide

Lymphomas,
some
leukemias,
and solid
tumors

Form
bifunctional
DNA adducts

Look above

Ifosfomide

Same

Same

Same

Prodrug,
metabolized
in liver by
CYP450 to
generate
phosphoram
ide mustard
Same but
generates
ifosforamide
mustard

Nitrosoureas
Carmustine

Brain
tumors,
myelomas,
Hodgkins
lymphoma

Causes
alkylation of
DNA and
forms
Carbamoyl
adducts with
proteins

Look above

Bisulphan

Chronic
leukemia

Selective
effect on
bone
marrow

Look above

Alkylating-like
Cisplatin

Testicular
cancer and
ovarian
cancer

Analogous
to alkylating
agents.
Platinum
complexes
react in vivo
by binding
to and
causing
cross-linking

Apoptosis of
cells.

Severely
nephrotoxic

Carboplatin
and
Oxaliplatin

Same

of DNA.
Same

Same

Much less
side-effects

Cytotoxic Anti-biotics
These are substances of microbial orgin which prevent mammalian
division. They are flat molecules which intercalate themselves into the
coils of DNA and inhibit macromolecular biosynthesis.
Anthracyclins
Doxorubicin

Bleomycin

Leukemias,
lymphomas,
solid tumors

Intercalate
DNA and
prevents
uncoiling
and
exposure of
DNA
topoisomera
se 2
complex.

Look above.

Metal
chelating
glycopeptide
s that
produces
fragmentati
on of DNA
molecules

Cumulative
cardiac
toxicity

Effective in
G2, mitosis,
and nondividing
cells

Plant Alkaloids
They affect microtubule functions and thus inhibit spindle formation
during mitosis.
Vinca Alkaloids
Vincristine

Inhibit
tubulin and
its
polymerizati

on into
microtubules
, preventing
spindle
formation
and causing
arrest at
metaphase
Same

Vinblastine

Taxanes
Paclitaxel
(Taxol)

Ovarian
cancer, drug
resistant
breast
cancer

Docetaxel

Same

Interferes
with mitosis
by
promoting
the
formation of
intracellular
mictrotubule
s and
preventing
disassembly
of formed
microtubules
during
anaphase
Same

Semisynthetic
analogue of
paclitaxel