374 Section 9/ ChemotherapyANTIMETABOLITESAntimetabolites are analogues of normal
DNA components or of coenzymes
involved in nucleic acid synthesis. They get
incorporated or competitively inhibit
utilization of normal substrate to form
dysfunctional nucleic acid molecules.
METHOTREXATE
It is a broad spectrum antineoplastic
drug which act as an antimetabolite of folic
acid.
It acts by inhibiting dihydrofolate
reductase. It inhibits conversion of
dihydrofolic acid to tetrahydrofolic which
is essential for purine synthesis and amino
acid interconversions. It primarily affects
DNA synthesis but also RNA and protein
synthesis. It has cell cycle specific action and
kills cells in S phase. It is readily absorbed
from gastrointestinal tract but larger doses
are absorbed incompletely, little drug is
metabolised and it is excreted largely
unchanged in urine.
Adverse effects include nausea,
vomiting, diarrhoea, anaphylaxis, hepatic
necrosis, fever, bone marrow depression,
osteoporosis, menstrual dysfunction,
cirrhosis, pulmonary infiltrates and fibrosis,
renal toxicity and depigmentation.
It is indicated in lymphoblastic leukemia
and choriocarcinoma, psoriasis, adjuvant
therapy of non-metastatic osteosarcoma and
to reduce corticosteroid requirement in
patients with severe steroid dependent asthma.
It is also used as ‘disease modifying
drug’ in rheumatoid arthritis as it reduces
lymphocyte proliferation, rheumatoid
factor production and interferes with the
release of inflammatory cytokines.6-MERCAPTOPURINE
It is an antimetabolite antineoplastic,
which being an analogue of hypoxanthine
and adenine inhibits purine metabolism.
After oral administration absorption is
incomplete and drug is metabolised in liver.
The active metabolites have longer half life
than parent drug.
Adverse effects include nausea,
vomiting, diarrhoea, cholestasis, bone
marrow depression, pancreatitis, oral and
intestinal ulcers. Rarely hepatic necrosis.
It is used in acute leukaemia,
choriocarcinoma and chronic granulocytic
leukaemia.FLUOROURACIL
It is fluorinated analogue of pyrimidine,
act by binding the enzyme thymidylate
synthetase and preventing the production
of basic component of DNA-thymine. It
is converted into 5-fluorouridine
triphosphate and is incorporated into RNA
where it interferes with RNA processing
and function.
It is used in the treatment of carcinoma
of breast, colon, urinary bladder, stomach
liver, rectum and ovaries.
The major toxicity includes myelosup-
pression and mucositis.CYTARABINE
Cytarabine or cytosine arabinoside
competitively inhibits DNA polymerase