Summary of Anti metabolites in Cancer Chemotherapy

1. By ORIBA DAN LANGOYA
MBchB

2. 1. ANTIFOLATES
Methotrexate
 Is a folic acid analog that
binds with high affinity
to the active catalytic site
of DHFR.
 This results in inhibition
of the synthesis of
tetrahydrofolate (THF).
 Inhibition of metabolic
processes interferes with
the formation of
DNA, RNA, and key
cellular proteins.

3. Resistance
1. Decreased drug tr’port
via the reduced folate
carrier or folate
receptor protein,
2. Decreased formation
of cytotoxic MTX
polyglutamates,.
3. Increased levels of the
target enzyme DHFR
through gene
amplification
4. Altered DHFR protein
with reduced affinity
for MTX.

4. PK
 administered by the
IV, intrathecal, or oral
route.
 Bioavailability is
saturable and erratic at
doses greater than 25
mg/m2
 Renal excretion is the
main route of
elimination
 Care must be taken when
MTX is used in the
presence of drugs such as
aspirin, nonsteroidal
anti-inflammatory
agents, penicillin, and
cephalosporins.
 These agents inhibit the
renal excretion of MTX.

5. Antimetabolites: Clinical activity
toxicities

6. Pemetrexed
 Is a pyrrolopyrimidine
antifolate analog.
Has activity in the S
phase of the cell cycle.
transported into the cell
via reduced folate carrier
Requires activation by
FPGS to yield higher
polyglutamate forms
MOA is inhibition of
thymidylate synthase.
 Approved for use in
comb with cisplatin in
the treatment of
mesothelioma,
 Mainly excreted in urine.
 Vit sup with folic acid
and vitamin B 12 appear
to reduce toxicities.

7. Pralatrexate
 A 10-deaza-aminopterin
antifolate analog.
 T’ported into the cell via
the reduced folate carrier
(RFC) and requires
activation by FPGS to
yield higher
polyglutamate forms.
 Excreted in the urine
MOA
1. Inhibits DHFR,
2. Inhibits enzymes in de
novo purine nucleotide
biosynthesis.
3. Inhibits thymidylate
synthase.
 Treatment of relapsed or
refractory peripheral T-
cell lymphoma.

8. 2. FLUOROPYRIMIDINES
5-Fluorouracil
 Inactive in its parent
form and requires
activation
 MOA: inhibition of DNA
synthesis through
“thymineless death.”
o Incorporat into cellular
DNA, resulting in
inhibition of DNA
synthesis and function
 Treatment of colorectal
cancer.
 Solid tumors, eg cancers
breast
cancer, stomach, pancrea
s, esophagus, liver, head
and neck, and anus.

9. Capecitabine
 Fluoropyrimidine
carbamate prodrug
 Undergoes extensive
metabolism in the liver.
 Converted to 5-FU
directly in the tumor
 Used in the treatment of
metastatic breast cancer.
 Approved for use in
adjuvant therapy of stage
III and high-risk stage II
colon cancer .
 For treatment of
metastatic colorectal
cancer as monotherapy.
 Main toxicities include
diarrhea and the hand-
foot syndrome.

10. 3. DEOXYCYTIDINE ANALOGS
Cytarabine
 An S phase-specific
antimetabolite that
 converted by
deoxycytidine kinase to
the 5'-mononucleotide
to di and tri.
 Ara-CTP triphosphate is
the cytotoxic metabolite.
MOA: competitively
inhibits DNA
polymerase-α &
β, resulting in blockade
of DNA synthesis and
DNA repair, respectively.
 Incorporation into DNA
leads to interference
with chain elongation
 Use for hematologic
malignancies

11. Gemcitabine
 A fluorine-substituted
deoxycytidine analog.
 Phosphorylated by the
enzyme deoxycytidine
kinase to the mono, di &
triphosphate nucleotide
forms.
 MOA
 Inhibition of DNA
polymerase-α &
β, resulting in blockade
of DNA synthesis &
repair.
 Incorporation of
triphosphate into
DNA, results in chain
termination.

12. 4. PURINE ANTAGONISTS
 6-Thiopurines
 6-Mercaptopurine (6-
MP) was the first of the
thiopurine analogs
 Used primarily in the
treatment of childhood
acute leukemia.
 6-MP is inactive in its
parent form.
 Inhibits several enzymes
of de novo purine
nucleotide synthesis.
 The monophosphate
form is metabolized to
the triphosphate
 Which can then be
incorporated into both
RNA and DNA.

13. MOA of 6-mercaptopurine and
6-thioguanine.

14. Fludarabine
 Phosphorylated
intracellularly by
deoxycytidine kinase to
the triphosphate.
 The triphosphate
metabolite interferes
with DNA syn & repair
thru’ inhibition of DNA
polymerase α & β.
 The diphosphate
metabolite inhibits
ribonucleotide reductase
 Induces apoptosis in
susceptible cells.
 Used mainly treatment
of low-grade non-
Hodgkin’s lymphoma &
chronic lymphocytic
leukemia

15. Cladribine
 Purine nucleoside analog with high specificity for
lymphoid cells.
 Inactive in parent form,
 Phosphorylated by deoxycytidine kinase to the mono
& metabolized to the triphosphate.
 The triphosphate metabolite interferes with DNA
synthesis & repair by inhibiting DNA polymerase-α& β
 indicated for treatment of hairy cell leukemia, CLL
and low-grade non-Hodgkin’s lymphoma.
 immunosuppressive effects.

17. THE END
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