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Methotrexate |
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Methotrexate (abbreviated MTX; formerly
known as amethopterin) is an antimetabolite drug used in
treatment of cancer and autoimmune disease. It acts by
inhibiting the metabolism of folic acid.
Uses
Methotrexate was originally used, as part of combination
chemotherapy regimens, to treat many kinds of cancers. It is
still the mainstay for the treatment of many neoplastic
disorders including acute lymphoblastic leukemia.
More recently it has come into use as a treatment for some
autoimmune diseases, including psoriasis, rheumatoid arthritis,
and crohn's disease. In the case of rheumatoid arthritis,
parallel use with infliximab or etanercept has been shown to
markedly improve symptoms.
Although not licensed for this indication, methotrexate is also
sometimes used (generally in combination with misoprostol) to
terminate early pregnancies, particularly ectopic pregnancies.
It can be taken orally or administered by injection
(intramuscular, intravenous or intrathecal). Although daily
preparations are occasionally used, most patients take weekly
doses, which decreases the risk of certain side-effects.
Adverse effects
Possible side effects can include anemia, neutropenia, increased
risk of bruising, and nausea. A small percentage of patients
develop hepatitis, while there is an increased risk of pulmonary
fibrosis.
The higher doses of methotrexate often used in cancer
chemotherapy can cause toxic effects to the rapidly-dividing
cells of bone marrow and gastrointestinal mucosa. The resulting
myelosuppression and mucositis are often prevented (termed
methotrexate "rescue") by using folinic acid supplements (not to
be confused with folic acid).
Mode of action
Methotrexate inhibits dihydrofolate reductase, an enzyme that is
part of the folate synthesis metabolic pathway. Dihydrofolate
reductase catalyses the conversion of dihydrofolate to the
active tetrahydrofolate. Folic acid is needed for the de novo
synthesis of the nucleoside thymidine, required for DNA
synthesis). Methotrexate, therefore, inhibits the synthesis of
DNA, RNA, thymidylates, and proteins.
Methotrexate is cell cycle S-phase selective, and has a greater
negative effect on rapidly dividing cells (such as malignant and
myeloid cells), which are replicating their DNA, and thus
inhibits the growth and proliferation of these cells. |
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