# Methotrexate

Source: https://onco.cc/drugs/methotrexate/  
OnCo record `methotrexate` (Treatment). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The 1948 antifolate that produced the first chemotherapy remissions in childhood leukaemia and the first cure of a solid tumour; still essential in ALL, lymphoma, osteosarcoma and CNS lymphoma.

## Summary

Farber (1948) with aminopterin; methotrexate cured choriocarcinoma (1956). Roles: ALL maintenance and CNS prophylaxis (intrathecal), high-dose regimens in osteosarcoma (MAP), PCNSL and Burkitt/DLBCL CNS prophylaxis, GTN, head and neck and bladder (MVAC). Toxicities: mucositis, nephrotoxicity (high dose; glucarpidase rescue), hepatotoxicity, pneumonitis. Also the standard DMARD in rheumatoid arthritis and used in ectopic pregnancy.

## Fields

- Kind: Treatment
- Status: approved
- Last checked: 2026-09-08
- Tags: gap-fill; generic; who-essential
- Brand: Trexall / Otrexup / Xatmep
- Modality: Antifolate (DHFR inhibitor)
- Mechanism: Inhibits dihydrofolate reductase, depleting tetrahydrofolate needed for thymidylate and purine synthesis; high doses with leucovorin rescue cross the blood-brain barrier.
- Approvals: US 1953: ALL, choriocarcinoma, and later osteosarcoma, breast, head and neck, lung, lymphoma, mycosis fungoides

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Methotrexate
- Label (DailyMed): https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=methotrexate%20injection

## Connected records

- drugs: [Aminopterin](https://onco.cc/drugs/aminopterin/), [Celecoxib](https://onco.cc/drugs/celecoxib/), [Glucarpidase](https://onco.cc/drugs/glucarpidase/), [Leucovorin (folinic acid)](https://onco.cc/drugs/leucovorin/), [Mercaptopurine](https://onco.cc/drugs/mercaptopurine/)
- cancers: [Acute lymphoblastic leukaemia](https://onco.cc/cancers/all-leukemia/), [Adolescent and young adult cancers (ages 15 to 39)](https://onco.cc/cancers/aya-cancers/), [Atypical teratoid/rhabdoid tumour (ATRT)](https://onco.cc/cancers/atrt/), [Bladder & urothelial cancer](https://onco.cc/cancers/urothelial/), [Buccal mucosa and gingivobuccal cancer (oral cancer in India)](https://onco.cc/cancers/buccal-mucosa-cancer/), [Burkitt leukaemia](https://onco.cc/cancers/burkitt-leukaemia/), [Burkitt lymphoma](https://onco.cc/cancers/burkitt-lymphoma/), [Childhood cancers (all types)](https://onco.cc/cancers/childhood-cancers/), [Choriocarcinoma of the testis](https://onco.cc/cancers/testicular-choriocarcinoma/), [Cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome)](https://onco.cc/cancers/cutaneous-t-cell-lymphoma/), [Desmoid tumour](https://onco.cc/cancers/desmoid-tumour/), [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Enteropathy-associated T-cell lymphoma](https://onco.cc/cancers/enteropathy-associated-t-cell-lymphoma/), [Erdheim-Chester disease](https://onco.cc/cancers/erdheim-chester-disease/), [Extranodal NK/T-cell lymphoma](https://onco.cc/cancers/extranodal-nk-t-cell-lymphoma/), [Gestational trophoblastic neoplasia](https://onco.cc/cancers/gestational-trophoblastic/), [Group 3 and group 4 medulloblastoma (non-WNT/non-SHH)](https://onco.cc/cancers/medulloblastoma-group-3-4/), [Head and neck squamous cell carcinoma](https://onco.cc/cancers/head-and-neck/), [High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL)](https://onco.cc/cancers/all-paediatric-high-risk/), [High-risk gestational trophoblastic neoplasia (FIGO score 7 or more, including ultra-high-risk)](https://onco.cc/cancers/high-risk-gtn/), [HIV-associated (AIDS-related) lymphomas](https://onco.cc/cancers/hiv-associated-lymphoma/), [HPV-negative head and neck squamous cell carcinoma (including HPV-negative oropharyngeal cancer)](https://onco.cc/cancers/hpv-negative-head-and-neck-cancer/), [Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year)](https://onco.cc/cancers/all-infant/), [Intravascular large B-cell lymphoma](https://onco.cc/cancers/intravascular-large-b-cell-lymphoma/), [Low-risk gestational trophoblastic neoplasia (FIGO score 0 to 6)](https://onco.cc/cancers/low-risk-gtn/), [Lymphomatoid papulosis](https://onco.cc/cancers/lymphomatoid-papulosis/), [Medulloblastoma](https://onco.cc/cancers/medulloblastoma/), [Monomorphic epitheliotropic intestinal T-cell lymphoma](https://onco.cc/cancers/monomorphic-epitheliotropic-intestinal-t-cell-lymphoma/), [Mycosis fungoides](https://onco.cc/cancers/mycosis-fungoides/), [Oral cavity cancer (mouth and tongue)](https://onco.cc/cancers/oral-cavity-cancer/), [Oral tongue and floor of mouth cancer](https://onco.cc/cancers/oral-tongue-cancer/), [Osteosarcoma](https://onco.cc/cancers/osteosarcoma/), [Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL)](https://onco.cc/cancers/all-paediatric-ph-positive/), [Placental-site trophoblastic tumour and epithelioid trophoblastic tumour](https://onco.cc/cancers/placental-site-trophoblastic-tumour/), [Primary CNS lymphoma](https://onco.cc/cancers/primary-cns-lymphoma/), [Primary cutaneous anaplastic large cell lymphoma](https://onco.cc/cancers/primary-cutaneous-anaplastic-large-cell-lymphoma/), [Primary large B-cell lymphoma of the testis](https://onco.cc/cancers/primary-testicular-lymphoma/), [Recurrent or metastatic head and neck squamous cell carcinoma](https://onco.cc/cancers/recurrent-metastatic-hnscc/), [Relapsed and refractory acute lymphoblastic leukaemia in children](https://onco.cc/cancers/all-paediatric-relapsed/), [Rosai-Dorfman-Destombes disease](https://onco.cc/cancers/rosai-dorfman-disease/), [Sezary syndrome](https://onco.cc/cancers/sezary-syndrome/), [SHH-activated medulloblastoma](https://onco.cc/cancers/medulloblastoma-shh/), [Standard-risk B-cell acute lymphoblastic leukaemia in children](https://onco.cc/cancers/all-paediatric-standard-risk/), [T-cell large granular lymphocytic leukaemia](https://onco.cc/cancers/t-large-granular-lymphocytic-leukaemia/), [Testicular germ cell tumours](https://onco.cc/cancers/testicular/)
- technologies: [Bone after childhood cancer: peak bone mass, osteonecrosis and what rebuilds](https://onco.cc/technologies/rejuv-paed-bone/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [Education, work and the years that were interrupted](https://onco.cc/technologies/rejuv-ayac-education-and-work/), [Generic sterile injectables (the 2023 platinum shortage)](https://onco.cc/technologies/sterile-injectable-generics-manufacturing/), [Memory, attention and learning after treatment of a childhood cancer](https://onco.cc/technologies/rejuv-paed-neurocognitive/), [Pharmacokinetic and pharmacodynamic modelling](https://onco.cc/technologies/pkpd-modelling/), [Preventing graft-versus-host disease, and what prevention costs](https://onco.cc/technologies/gvhd-prophylaxis/), [Small-molecule API synthesis](https://onco.cc/technologies/small-molecule-api-synthesis/), [TPMT and NUDT15 genotyping before thiopurines](https://onco.cc/technologies/tpmt-nudt15-genotyping/)
- terms: [Alkylating agents and antimetabolites](https://onco.cc/terms/alkylating-agent/), [Blood-brain barrier (BBB)](https://onco.cc/terms/blood-brain-barrier/), [CNS prophylaxis in aggressive B-cell lymphoma, and the evidence against it](https://onco.cc/terms/lymphoma-tx-cns-prophylaxis/), [Histological response to induction chemotherapy (osteosarcoma and Ewing sarcoma)](https://onco.cc/terms/histological-response-induction/), [The lymphoma regimen alphabet: R-CHOP, pola-R-CHP, DA-EPOCH-R, ABVD, BEACOPP and the rest](https://onco.cc/terms/lymphoma-tx-regimen-alphabet/)
- trials: [A Study of the Efficacy and Safety of Lisocabtagene Maraleucel (Liso-cel) as First-Line Therapy in Adults With Transplant-Ineligible Primary Central Nervous System Lymphoma](https://onco.cc/trials/nct07015242/), [A Study to Compare Standard Chemotherapy to Therapy With CPX-351 and/or Gilteritinib for Patients With Newly Diagnosed AML With or Without FLT3 Mutations](https://onco.cc/trials/nct04293562/), [AALL0232](https://onco.cc/trials/aall0232/), [ACNS0333](https://onco.cc/trials/acns0333/), [ALCANZA](https://onco.cc/trials/alcanza/), [ALL R3 (UKALLR3)](https://onco.cc/trials/ukallr3/), [COG AALL0434](https://onco.cc/trials/aall0434/), [Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk B Acute Lymphoblastic Leukemia and Ph-Like TKI Sensitive Mutations](https://onco.cc/trials/nct02883049/), [Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Children With Acute Myeloid Leukemia](https://onco.cc/trials/nct00003436/), [Combination Chemotherapy With or Without Lestaurtinib in Treating Younger Patients With Newly Diagnosed Acute Lymphoblastic Leukemia](https://onco.cc/trials/nct00557193/), [DBCG 82b and 82c](https://onco.cc/trials/dbcg-82bc/), [EURAMOS-1](https://onco.cc/trials/euramos-1/), [IELSG32](https://onco.cc/trials/ielsg32/), [Inotuzumab Ozogamicin and Frontline Chemotherapy in Treating Young Adults With Newly Diagnosed B Acute Lymphoblastic Leukemia](https://onco.cc/trials/nct03150693/), [Inter-B-NHL Ritux 2010](https://onco.cc/trials/inter-b-nhl-ritux-2010/), [International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia](https://onco.cc/trials/nct01117441/), [LCH-III](https://onco.cc/trials/lch-iii/), [LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis](https://onco.cc/trials/nct02205762/), [Low-dose nivolumab plus metronomic chemotherapy (Tata Memorial)](https://onco.cc/trials/low-dose-nivolumab-tmh/), [MATRix/IELSG43](https://onco.cc/trials/ielsg43/), [Methotrexate or Pentostatin for Graft-versus-host Disease Prophylaxis in Risk-adapted Allogeneic Bone Marrow Transplantation for Hematologic Malignancies](https://onco.cc/trials/nct01188798/), [METRO PLUS (Tata Memorial Centre, Varanasi)](https://onco.cc/trials/metro-plus-varanasi/), [Oral metronomic chemotherapy vs intravenous cisplatin (Tata Memorial)](https://onco.cc/trials/metronomic-vs-cisplatin-tmh/), [Perioperative Durvalumab With Neoadjuvant ddMVAC or Gemcitabine/Cisplatin in Patients With Muscle-invasive Bladder Cancer (NIAGARA-2)](https://onco.cc/trials/nct06960577/), [Premedication to Reduce Amivantamab Associated Infusion Related Reactions](https://onco.cc/trials/nct05663866/), [PRIMA-CNS](https://onco.cc/trials/prima-cns/), [Rituximab, Rasburicase, and Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Advanced B-Cell Leukemia or Lymphoma](https://onco.cc/trials/nct00057811/), [Safety and Efficacy of Asciminib in Pediatrics and Young Adults With Relapse/Refractory (r/r) Philadelphia Positive (Ph+) or ABL-class Ph-like Acute Lymphoblastic Leukemia (ALL)](https://onco.cc/trials/nct07387926/), [SMILE](https://onco.cc/trials/smile-enktl/), [Study to Investigate Outcome of Individualized Treatment in Patients With Metastatic Colorectal Cancer](https://onco.cc/trials/nct05725200/), [Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma](https://onco.cc/trials/nct01700946/), [Treatment Protocol of the NHL-BFM and the NOPHO Study Groups for Mature Aggressive B-cell Lymphoma and Leukemia in Children and Adolescents](https://onco.cc/trials/nct03206671/), [Will Glucarpidase After Methotrexate Treatment for Bone Sarcoma Lead to Fewer Side Effects and Reduce Chemotherapy Delays?](https://onco.cc/trials/nct02022358/)
- key papers: [AALL0232: dexamethasone and high-dose methotrexate improve outcome in high-risk B-cell acute lymphoblastic leukaemia in children and young adults](https://onco.cc/key-papers/paper-aall0232-larsen-jco-2016/), [EMA/CO for high-risk gestational trophoblastic tumours: results from a cohort of 272 patients](https://onco.cc/key-papers/paper-bower-ema-co-high-risk-gtn-charing-cross-jco-1997/), [FIGO Cancer Report 2021: diagnosis and management of gestational trophoblastic disease](https://onco.cc/key-papers/paper-figo-cancer-report-gestational-trophoblastic-disease-ijgo-2021/), [GOG 174: weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia](https://onco.cc/key-papers/paper-gog-174-methotrexate-vs-dactinomycin-low-risk-gtn-jco-2011/), [IELSG32 first randomisation: the MATRix regimen (methotrexate, cytarabine, thiotepa, rituximab) in primary CNS lymphoma](https://onco.cc/key-papers/paper-ielsg32-matrix-induction-ferreri-lancet-haematol-2016/), [Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study](https://onco.cc/key-papers/paper-smile-chemotherapy-nk-t-cell-lymphoma-jco-2011/)
- targets: [Dihydrofolate reductase (DHFR)](https://onco.cc/targets/dhfr/)
- people: [Akhil Kapoor](https://onco.cc/people/kapoor-akhil/), [Donald Pinkel](https://onco.cc/people/donald-pinkel/), [Emil J Freireich](https://onco.cc/people/emil-freireich/), [Jane Cooke Wright](https://onco.cc/people/jane-cooke-wright/), [Robert Sandler](https://onco.cc/people/robert-sandler/), [Sidney Farber](https://onco.cc/people/sidney-farber/)
- pathways: [DNA replication & origin licensing](https://onco.cc/pathways/dna-replication-licensing/)
- roadmaps: [Chemotherapy roadmap: mustard gas → curative combinations → the warhead inside smarter drugs](https://onco.cc/roadmaps/chemotherapy-roadmap/), [Paediatric oncology roadmap: cooperative-group cures → engineered immunity → drugs developed for children first](https://onco.cc/roadmaps/paediatric-oncology-roadmap/)

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