A person taking Methotrexate after 3 weeks the effect of methotrexate decreases. This is most probably due to? (LQ)
|A||Mutation of DHFR gene|
|B||Def of thymidylate kinase|
|C||Def of thymidylate synthase|
|D||Over production of DHFR enzyme|
(Ref: BG Katzung, Basic & Clinical Pharmacology’ 11th Edition’ 2010; pp-946)
a. MTx belong to antimetabolite class and acts by inhibiting DHFRase enzyme which is required for the
conversion of dihydrofolate to tetrahydrofolate, which is eventually been required for DNA formation there are mainly 3 methods of methotrexate resistance described:
b. Mutation of gene: by mutation of DHFRase gene, cancer cell will start producing modified form of DHFRase,
which is not been acted upon by methotrexate and result in resistance. If this mutation is present, methotrexate wont be able to act from day 1 of therapy.
c. Over production of DHFRase: this type of resistance occurs after some days(approx 1 week) of mtx therapy.
Initially cancer is sensitive, but after few days they start producing large amount of NORMAL enzyme, which is not been fully inhibited by given dose of MTx, therefore resistance occurs.
d. P glycoprotein efflux pump expression.- this is responsible for MDR type of cancer
e. Side effects include nausea, ulcers in stomach, hepatic fibrosis, rarely pulmonary fibrosis and
leukoencephalopathy. Side effects can be reduced by folinic acid rescue.
f. Folic acid for the same reason is less effective. The drug should not be combined with potassium sparing
diuretics as they could reduce its renal clearance leading to potential toxicity.