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AntifolatesIn useDerivative of an earlier drugNeeds review

Methotrexate

Also known as amethopterin, methotrexate sodium

A folate analogue first used against childhood leukaemia in the late 1940s. A 2026 US injection label lists leukaemia, lymphoma, osteosarcoma, breast, head and neck cancers and gestational trophoblastic neoplasia, as well as rheumatoid arthritis and psoriasis.

From discovery to approval

  1. c. 1949 · Earliest report found

    A 2012 account says Farber's 1949 follow-up of about 60 children included treatment with amethopterin, now known as methotrexate, alongside aminopterin; a 2013 paper says methotrexate followed aminopterin shortly after 1947. A 2023 review calls it a methyl derivative of aminopterin. The first report of its synthesis was not identified.[2][3][4][5]

  2. 1953-12-07 · FDA regular · 4 years after first description

    Methotrexate sodium tablets, NDA 008085, original approval, classed as a new molecular entity with priority review in the Drugs@FDA history (the product is now listed as discontinued). The original label and letter are not available there, so the indication at approval is not stated here. The type regular is an inference: no accelerated-approval wording was found. Current labels list several cancers and non-cancer indications.[6]

How it works

Inhibits dihydrofolic acid reductase, which cells need to make the folate forms used in building purine nucleotides and thymidylate, so DNA synthesis, repair and cell replication are disturbed. Dividing tissues, including malignant cells, are in general more sensitive.[1]

Where it came from and why

Farber's 1948 report showed that an antifolate, aminopterin, could produce temporary remissions in children with acute leukaemia. A 2012 account says methotrexate has comparable effectiveness but fewer adverse effects than aminopterin. A 2016 review says methotrexate was discovered for childhood leukaemia.

Cancers

  • Acute lymphoblastic and meningeal leukaemia

    The 2026 US injection label lists acute lymphoblastic leukaemia as part of combination chemotherapy, and prophylaxis and treatment of meningeal leukaemia.[1]

  • Gestational trophoblastic neoplasia

    A 1956 paper is titled 'Effect of methotrexate therapy upon choriocarcinoma and chorioadenoma'; the 2026 US label lists gestational trophoblastic neoplasia as part of combination chemotherapy.[7]

  • Lymphoma, osteosarcoma, breast cancer and head and neck cancer

    The 2026 US injection label lists non-Hodgkin lymphoma, osteosarcoma (combination regimen), breast cancer (combination regimen) and squamous cell carcinoma of the head and neck (single agent).[1]

Family and partners

Derived from: Aminopterin

Worth knowing

  • A 2016 review says methotrexate, discovered for childhood leukaemia, became the standard of care for rheumatoid arthritis, and distinguishes the high doses used for leukaemia from the low doses used in rheumatology.[4]
  • The 2026 US injection label also lists rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and severe psoriasis.[1]
  • A 2012 account says Farber's 1949 follow-up of about 60 children included treatment with amethopterin, now known as methotrexate.[2]
  • A 2022 commentary notes that folate, in the form of leucovorin, is the main rescue treatment after high-dose methotrexate.[8]
  • A 2003 review describes methotrexate as the most studied folate antagonist and lists reduced transport, gene amplification of the target enzyme and reduced polyglutamation among the ways resistance develops.[9]

On this site

References

  1. Accord Healthcare, Inc. Methotrexate injection: prescribing information. DailyMed, set ID dd035a9f-cd40-4314-b9d8-2294b8a924e2, published 7 September 2026. Read 26 October 2026. Source
  2. Spain PD, Kadan-Lottick N. Observations of unprecedented remissions following novel treatment for acute leukemia in children in 1948. J R Soc Med. 2012;105(4):177-81. PubMedDOI
  3. Jo DS, Lee SH. Distal Tibial Hemimelia in Fetal Methotrexate Syndrome: A Case Study and Literature Review. Children (Basel). 2023;10(2). PubMedDOI
  4. Malaviya AN. Landmark papers on the discovery of methotrexate for the treatment of rheumatoid arthritis and other systemic inflammatory rheumatic diseases: a fascinating story. Int J Rheum Dis. 2016;19(9):844-51. PubMedDOI
  5. Visentin M, Unal ES, Zhao R, Goldman ID. The membrane transport and polyglutamation of pralatrexate: a new-generation dihydrofolate reductase inhibitor. Cancer Chemother Pharmacol. 2013;72(3):597-606. PubMedDOI
  6. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, letters, labels, reviews for NDA 008085 (methotrexate sodium tablets). Page read 2026-10-26. Source
  7. Li MC, Hertz R, Spencer DB. Effect of methotrexate therapy upon choriocarcinoma and chorioadenoma. Proc Soc Exp Biol Med. 1956;93(2):361-6. PubMedDOI
  8. Izraeli S. The first achievement of complete remission in childhood leukemia by treatment with the folic acid antagonist aminopterin. Haematologica. 2022;107(4):782. PubMedDOI
  9. Purcell WT, Ettinger DS. Novel antifolate drugs. Curr Oncol Rep. 2003;5(2):114-25. PubMedDOI