1. Anticancer
Antimetabolites
Dr. S. Parasuraman
Faculty of Pharmacy, AIMST.

2. Antimetabolites
Folate antagonist:
Methotrexate (Mtx).
Purine antagonist:
6-Mercaptopurine (6-MP),
6-Thioguanine (6-TG), Azathioprine,
Fludarabine.
Pyrimidine antagonist:
5-Fluorouracil (5-FU), Capecitabine
Cytarabine (cytosine arabinoside).

3. Antimetabolites
• Antimetabolites are structurally
compounds that exist within the cell.
related
to
normal
• Antimetabolites generally interfere with the availability of
normal purine or pyrimidine nucleotide precursors, either
by inhibiting their synthesis or by competing with them in
DNA or RNA synthesis.
• Their maximal cytotoxic effects are in S-phase (and are,
therefore, cell-cycle specific).

4. Folate antagonist

5. Folate antagonist: Methotrexate
Mechanism of action:
• Folic acid is an essential dietary factor. It is converted by
enzymatic reduction to a series of tetrahydrofolate cofactors
that provide carbon groups for the synthesis of precursors of
DNA (thymidylate and purines) and RNA (purines).
• Methotrexate inhibits the enzyme dihydrofolate reductase
(DHFR). Inhibition of DHFR leads to partial depletion of the
tetrahydrofolate cofactors (5, 10-methylene tetrahydrofolic
acid and N10-formyl tetrahydrofolic acid) required for the
respective synthesis of thymidylate and purines.
• In addition, methotrexate undergoes conversion to a series of
polyglutamates (MTX-PGs) in both normal and tumor cells and
inhibits the thymidylate synthase (TS).

6. Folate antagonist:
Methotrexate
• The inhibition of DHFR can only be
reversed by a thousand fold excess of
the natural substrate, dihydrofolate, or
by administration of leucovorin.
Folinic acid, Thymidine also counteracts
MTX toxicity.
Resistance
• Non-proliferating cells are resistant to
MTX. Resistance in neoplastic cells can
be due to amplification (production of
additional copies) of the gene that codes
for DHFR, resulting in increased levels of
this enzyme.

7. Folate antagonist: Methotrexate
Therapeutic uses:
• MTX, usually in combination with other drugs, is effective
against acute lymphocytic leukemia, choriocarcinoma, Burkitt
lymphoma in children, breast cancer, and head and neck
carcinomas. In addition, low-dose MTX is effective as a single
agent against certain inflammatory diseases, such as severe
psoriasis and rheumatoid arthritis as well as Crohn disease.

8. Folate antagonist: Methotrexate
Pharmacokinetics:
• Oral, intramuscular, intravenous
intrathecal routes of administration.
(IV),
and
• MTX is metabolized to polyglutamate derivatives.
High doses of MTX undergo hydroxylation at the
7 position and become 7-hyroxymethotrexate.
• It is less water soluble
• MTX is less water soluble and may lead to
crystalluria (Therefore, it is important to keep
the urine alkaline and the patient well hydrated
to avoid renal toxicity).
• Excretion of the parent drug and the 7-OH
metabolite occurs primarily via urine.

9. Folate antagonist: Methotrexate
Adverse effects:
• MTX causes stomatitis, myelosuppression, erythema, rash,
urticaria, and alopecia.
• Most frequent toxicities: nausea, vomiting, and diarrhea.
• Adverse effects can be prevented or reversed by administering
leucovorin.
• Hepatic function: Long-term use of MTX may lead to cirrhosis.
• Renal function: Variable
• Neurologic toxicities: subacute meningeal irritation, stiff neck,
headache, and fever. Rarely, seizures, encephalopathy or
paraplegia occur.
• Contraindications: Because MTX is teratogenic in experimental
animals and is an abortifacient, it should be avoided in pregnancy.

10. Purine antagonist

11. Purine antagonist: 6-Mercaptopurine
• These are highly effective antineoplastic drugs.
• 6-Mercaptopurine is the thiol analog of hypoxanthine. 6-MP and
6-thioguanine were the first purine analogs to prove beneficial
for
treating
neoplastic
disease
(Azathioprine,
an
immunosuppressant, exerts its cytotoxic effects after
conversion to 6-MP).
• Purine antagonist used for the treatment of malignant
diseases (mercaptopurine, thioguanine), but also for
immunosuppression
(azathioprine)
and
antiviral
chemotherapy (acyclovir, ganciclovir, vidarabine, and
zidovudine)

12. Purine antagonist: 6-Mercaptopurine
• Mechanism of action:
• 6-MP inhibit the conversion of inosine monophosphate to
adenine and guanine nucleotides that are building blocks for
RNA and DNA.
– Nucleotide formation: 6-MP converted to the nucleotide analog, 6-MPribose phosphate (6-thioinosinic acid, or TIMP)
– Inhibition of purine synthesis: TIMP can inhibit the first step of de novo
purine-ring biosynthesis
– Incorporation into nucleic acids: TIMP is converted to thioguanine
monophosphate (TGMP), which after phosphorylation to di- and
triphosphates can be incorporated into RNA. The deoxy-ribonucleotide
analogs that are also formed are incorporated into DNA. This results in
nonfunctional RNA and DNA.

13. Purine antagonist: 6-Mercaptopurine
Pharmacokinetics:
• Oral administration, well distributed except for
the cerebrospinal fluid.
• Metabolized in the liver, 6-MP is converted to
the 6-ethylmercaptopurine derivative or to
thiouric acid.
• The parent drug and its metabolites are
excreted by the kidney.
Adverse effects:
• Bone marrow depression is the principal
toxicity. Side effects also include anorexia,
nausea, vomiting, and diarrhea. Occurrence of
hepatotoxicity in the form of jaundice has been
reported in about one third of adult patients.
• Dose: 2.5 mg/kg/day

14. Purine antagonist: Azathioprine
• This antipurine acts by getting converted to 6-MP, and has
more immunosuppressant action.
• Inhibits the nucleic acid synthesis and suppresses cell mediated
immunity. Because of this effect azathiaprine is used mainly in
autoimmune disease (rheumatoid arthritis, ulcerative colitis)
and organ transplantation.
• Dose: 3-5 mg/kg/day
• The main toxic effect of antipurines is bone marrow
depression, which develops slowly.

15. Purine antagonist: 6-Thioguanine
• 6-Thioguanine is purine analog, is primarily used in the
treatment of acute nonlymphocytic leukemia in combination
with daunorubicin and cytarabine.
• MOA:
Like 6-MP, 6-TG is converted intracellularly to TGMP
(6-thioguanylic acid) by the enzyme Hypoxanthineguanine phosphoribosyltransferase (HGPRT)
TGMP is further converted to the di- and
triphosphates, thioguanosine diphosphate and
thioguanosine triphosphate
which inhibits the biosynthesis of purines and also
the phosphorylation of GMP to guanosine
diphosphate

16. Purine antagonist: 6-Thioguanine
• Pharmacokinetics: Similar to 6-MP.
• Adverse effects: Bone marrow depression is the dose-related
adverse effect. 6-TG is not recommended for maintenance
therapy or continuous long-term treatments due to the risk of
liver toxicity.

17. Purine antagonist: Fludarabine
• It is a prodrug, useful in the treatment of chronic lymphocytic
leukemia. Fludarabine is also effective against hairy cell
leukemia and indolent non-Hodgkin lymphoma.
• Phosphorylated intracellularly to the active triphosphate form
which inhibits DNA polymerase  dysfunctional DNA.
• Prominent adverse effects are chills, fever and vomiting after
injection, myelosuppression and opportunistic infections.

18. Pyrimidine antagonist

19. Pyrimidine antagonist: 5-Fluorouracil
• In system, 5-fluorouracil is converted in to 5-fluoro-2deoxyuridine monophosphate (5-FdUMP), which inhibits
thymidylate synthase (form covalent ternary complex with
methyl-THFA and thymidylate synthase  irreversible
inhibition of TS) and blocks the conversion of deoxyuridilic
acid to deoxythymidylic acid.
• 5-FU incorporated into RNA, interferes with RNA synthesis and
causing cytotoxic effect.
• 5-FU produces the anticancer effect in the S phase of the cell
cycle.
• 5-FU is employed primarily in the treatment of slowly growing
solid tumors (for example, colorectal, breast, ovarian,
pancreatic, and gastric carcinomas).

20. Pyrimidine antagonist: 5-Fluorouracil
• Pharmacokinetics: Because of its severe
toxicity to the GI tract, 5-FU is given IV or,
in the case of skin cancer, topically.
• Adverse effects: Nausea, vomiting,
diarrhea, and alopecia, severe ulceration
of the oral and GI mucosa, bone marrow
depression (with bolus injection), and
anorexia are frequently encountered.
• 5-FU causes “hand-foot syndrome” is
seen after extended infusions

21. Pyrimidine antagonist: Capecitabine
• It is a oral fluoropyrimidine carbamate, approved for the
treatment of resistant metastatic breast cancer (2nd line
treatment of metastatic breast cancer along with taxanes).
• It is a orally active prodrug of 5-FU.
• After absorption it will convert into the deoxy-5-fluorouridine
in the liver.
• Adverse effects: These are similar to those with 5-FU.

22. Pyrimidine antagonist: Cytarabine
• This is a cytidine (nucleoside molecule formed when cytosine
is attached to a ribose ring) analogue.
• It is phosphorylated in the body to the corresponding
nucleotide which inhibits DNA synthesis.
• The triphosphate of cytarabine is an inhibitor of DNA
polymerase and blocks generation of cytidilic acid.
• Cytarabine is cell cycle specific and act primarily during ‘S’
phase.
• Its main use is to induce remission in acute leukaemia in
children, also in adults. Other uses are-Hodgkin's disease and
non-Hodgkin lymphoma.

23. Pyrimidine antagonist: Cytarabine
• Pharmacokinetics: not effective
when given orally; IV
• Adverse effects: Nausea, vomiting,
diarrhea,
and
severe
myelosuppression
(primarily
granulocytopenia) are the major
toxicities
associated
with
cytarabine. Hepatic dysfunction is
also occasionally encountered.
• At high doses or with intrathecal
injection, cytarabine may cause
leukoencephalopathy or paralysis.

24. Thank you