Antineoplastic agents. Class : Antimetabolites

1. Antimetabolites
 Antimetabolites are a class of anticancer drugs which belong to cytotoxic drugs..
 These are analogues related to the normal components of DNA or of coenzymes involved in
nucleic acid synthesis. They competitively inhibit utilization of the normal substrate or get
themselves incorporated forming dysfunctional macromolecules.
There are three types of anti-metabolites
1. Folate antagonist e.g. Methotrexate (MTX), Pemetrexed
2. Purine antagonist e.g. 6-Mercaptopurine (6MP), 6-Thioguanine (6TG), Azathioprine,
Fludarabine
3. Pyrimidine antagonist e.g. 5-Flurouracil (5-FU) , Capecitabin, Cytarabine

2. 1. Folate antagonist
Methotrexate (MTX)
It is one of the oldest and most efficacious antineoplastic drug.
 Mode of action : It acts by inhibiting Dihydrofolate Reductase (DHFRase) which stops conversion
of DHFA to THFA. MTX kills cell in S phase .
It also inhibits enzyme thymidylate synthase which primarily causes inhibition of DNA
synthesis which also affects RNA and protein synthesis.
 Pharmacokinetics: Absorbed orally, 50% plasma protein bound, little metabolized and largely
excreted unchanged in urine.

3. Methotrexate (MTX)
 Dose: Methotrexate is apparently curative in choriocarcinoma: 15–30 mg/day for 5
days orally or 20–40 mg/m2 BSA i.m. or i.v. twice weekly.
 Drug interaction : Salicylates, sulfonamides displace it from protein binding sites.
Aspirin and sulfonamides enhance toxicity of Mtx by decreasing its renal tubular
secretion
 Uses: Mtx is widely used in non-Hodgkin lymphoma, breast, bladder, head and neck
cancers, osteogenic sarcoma, etc
 Adverse effect : It exerts major toxicity on bone marrow—low doses given repeatedly
cause megaloblastic anaemia, but high doses produce pancytopenia. Mucositis and
diarrhoea are common side effects. Desquamation and bleeding may occur in g.i.t.

4. 2. Purine Antagonist
Mercaptopurine (6-MP)
 Mode of action : They inhibit the conversion of inosine monophosphate to adenine and
guanine nucleotides.
There is also feedback inhibition of de novo purine synthesis. They also get
incorporated into RNA and DNA which are dysfunctional.
 Pharmacokinetics: All antipurines are absorbed orally (though incompletely).
Azathioprine and 6-MP are oxidized by xanthine oxidase; their metabolism is inhibited by
allopurinol.
 Dose: 2.5 mg/kg/day, half dose for maintenance
 Uses : childhood acute leukemia, choriocarcinoma and some solid tumors
 Adverse effect: bone marrow depression, nausea and vomiting, reversible jaundice,
hyperuricaemia

5. 3. Pyrimidine antagonist
Fluorouracil (5-FU)
 Mode of action : 5-FU converted to 5-fluoro-2-deoxyuridine monophosphate, which
forms complex with methyl-THFA and tymidylate synthase (TS) resulting in irreversible
inhibition of TS.
5-FU itself gets incorporated into RNA, interferes with RNA synthesis and
function contributing to its cytotoxicity
 Pharmacokinetics: It is primarily used by i.v. infusion. It is rapidly metabolized by
dihydropyrimidine dehydrogenase (DPD) resulting in t½ of 15–20 min
 Dose: Dose: 500 mg/m2 i.v. infusion over 1–3 hours weekly for 6–8weeks, or 12
mg/kg/day i.v. for 4 days followed by 6 mg/kg i.v. on alternate days, 3–4 doses
 Uses : solid malignancies, especially of colon, rectum, stomach, pancreas, liver, urinary
bladder, head and neck
 Toxicity : Bone marrow , g.i.t. causing myelosuppression, mucositis, diarrhea, nausea
and vomiting.

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