Methotrexate (MTX), formerly known as amethopterin, is a

chemotherapy agent Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

and immune-system suppressant. It is used to treat

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

autoimmune disease An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...

s, and ectopic pregnancies. Types of cancers it is used for include

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...

lung cancer Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. Lung carcinomas derive from transformed, mali ...

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include en ...

, gestational trophoblastic disease, and osteosarcoma. Types of autoimmune diseases it is used for include

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to comple ...

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are inv ...

, and Crohn's disease. It can be given by mouth or by injection. Common side effects include nausea, feeling tired, fever, increased risk of infection, low white blood cell counts, and breakdown of the skin inside the mouth. Other side effects may include liver disease, lung disease, lymphoma, and severe skin rashes. People on long-term treatment should be regularly checked for side effects. It is not safe during

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...

. In those with kidney problems, lower doses may be needed. It acts by blocking the body's use of

folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing a ...

. Methotrexate was first made in 1947 and initially was used to treat cancer, as it was less toxic than the then current treatments. In 1956 it provided the first cures of a metastatic cancer. It is on the World Health Organization's List of Essential Medicines. Methotrexate is available as a generic medication. In 2020, it was the 113th most commonly prescribed medication in the United States, with more than 5million prescriptions.

Medical uses

Chemotherapy

Methotrexate was originally developed and continues to be used for

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...

, either alone or in combination with other agents. It is effective for the treatment of a number of cancers, including breast, head and neck, leukemia, lymphoma, lung, osteosarcoma, bladder, and

trophoblastic neoplasm Gestational trophoblastic neoplasia (GTN) is group of rare diseases related to pregnancy and included in gestational trophoblastic disease (GTD) in which abnormal trophoblast cells grow in the uterus. GTN can be classified into benign and malign ...

Autoimmune disorders

Methotrexate is used as a disease-modifying treatment for some autoimmune diseases, including rheumatoid arthritis,

juvenile dermatomyositis Juvenile dermatomyositis (JDM) is an idiopathic inflammatory myopathy (IMM) of presumed autoimmune dysfunction resulting in muscle weakness among other complications. It manifests itself in children; it is the pediatric counterpart of dermatomyo ...

psoriatic arthritis Psoriatic arthritis is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. T ...

, lupus,

sarcoidosis Sarcoidosis (also known as ''Besnier-Boeck-Schaumann disease'') is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph nodes. Less commonly af ...

, Crohn's disease,

eczema Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved c ...

and many forms of

vasculitis Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily caused ...

. Although originally designed as a chemotherapy drug (using high doses), in low doses methotrexate is a generally safe and well-tolerated drug in the treatment of certain autoimmune diseases. Because of its effectiveness, low-dose methotrexate is first-line therapy for the treatment of rheumatoid arthritis. Weekly doses are beneficial for 12 to 52 weeks duration therapy, although discontinuation rates are as high as 16% due to adverse effects. Although methotrexate for autoimmune diseases is taken in lower doses than it is for cancer, side effects such as hair loss, nausea, headaches, and skin pigmentation are still common. Use of low doses of methotrexate together with NSAIDs such as

aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...

or analgesics such as paracetamol is relatively safe in people being treated for rheumatoid arthritis, if adequate monitoring is done. Studies and reviews have found that most rheumatoid arthritis patients treated with methotrexate for up to one year had less pain, functioned better, had fewer swollen and tender joints, and had less disease activity overall as reported by themselves and their doctors. X-rays also showed that the progress of the disease slowed or stopped in many people receiving methotrexate, with the progression being completely halted in about 30% of those receiving the drug. Those individuals with rheumatoid arthritis treated with methotrexate have been found to have a lower risk of cardiovascular events such as myocardial infarctions (heart attacks) and strokes. Results of a systematic review exploring the comparative effectiveness of treatments of early

can be improved with combination therapy of tumor necrosis factor (TNF) or non-TNF

biologics A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, th ...

with methotrexate alone. Likewise, a 2016 study found the use of methotrexate, in combination with anti-TNF agents, has been shown to be effective for the treatment of ulcerative colitis. Methotrexate has also been used for multiple sclerosis and is used occasionally in systemic lupus erythematosus, with tentative evidence to support such use.

During pregnancy

Methotrexate is an abortifacient and it is used to treat ectopic pregnancies, provided the fallopian tube has not ruptured. Methotrexate with

dilation and curettage Dilation (or dilatation) and curettage (D&C) refers to the dilation (widening/opening) of the cervix and surgical removal of part of the lining of the uterus and/or contents of the uterus by scraping and scooping ( curettage). It is a gynecologi ...

is used to treat molar pregnancy. Rarely, it is used in combination with mifepristone to abort uterine pregnancies.

Administration

Methotrexate can be given by mouth or by injection (

intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles ha ...

, intravenous, subcutaneous, or intrathecal). Doses are usually taken weekly, not daily, to limit toxicity. Routine monitoring of the

complete blood count A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cells and ...

liver function tests Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin ti ...

, and creatinine are recommended. Measurements of creatinine are recommended at least every two months.

Adverse effects

The most common adverse effects include: hepatotoxicity (liver damage), ulcerative stomatitis,

leukopenia Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of ...

and thus predisposition to infection, nausea, abdominal pain, fatigue, fever, dizziness, acute pneumonitis, rarely pulmonary fibrosis, and

kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

. Methotrexate is

teratogenic Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related ...

and hence is not advised for either the prospective father to take it before or for the mother to take it before or during pregnancy ( pregnancy category X) and for a period after birth. Methotrexate can also cause mucositis. Central nervous system reactions to methotrexate have been reported, especially when given via the intrathecal route (directly into the

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...

), which include myelopathies and leukoencephalopathies. It has a variety of cutaneous side effects, particularly when administered in high doses. Another little understood but serious possible adverse effect of methotrexate is neurological damage and memory loss. Neurotoxicity may result from the drug crossing the blood–brain barrier and damaging neurons in the cerebral cortex. People with cancer who receive the medication often nickname these effects " chemo brain" or "chemo fog".

Drug interactions

Penicillins may decrease the elimination of methotrexate, so increase the risk of toxicity. While they may be used together, increased monitoring is recommended. The aminoglycosides, neomycin and

paromomycin Paromomycin is an antimicrobial used to treat a number of parasitic infections including amebiasis, giardiasis, leishmaniasis, and tapeworm infection. It is a first-line treatment for amebiasis or giardiasis during pregnancy. Otherwise it is gen ...

, have been found to reduce gastrointestinal (GI) absorption of methotrexate. Probenecid inhibits methotrexate excretion, which increases the risk of methotrexate toxicity. Likewise, retinoids and trimethoprim have been known to interact with methotrexate to produce additive hepatotoxicity and haematotoxicity, respectively. Other immunosuppressants like

cyclosporins The cyclosporins are a group of macrolides isolated from fungi and used as immunosuppresant drugs, for example after transplant surgery. They are nonribosomal peptide synthesized by cyclosporin synthetase. *Cyclosporin A Ciclosporin, als ...

may potentiate methotrexate's haematologic effects, hence potentially leading to toxicity. NSAIDs have also been found to fatally interact with methotrexate in numerous case reports.

Nitrous oxide Nitrous oxide (dinitrogen oxide or dinitrogen monoxide), commonly known as laughing gas, nitrous, or nos, is a chemical compound, an oxide of nitrogen with the formula . At room temperature, it is a colourless non-flammable gas, and ha ...

potentiating the haematological toxicity of methotrexate has also been documented. Proton-pump inhibitors such as omeprazole and the anticonvulsant valproate have been found to increase the plasma concentrations of methotrexate, as have nephrotoxic agents such as cisplatin, the GI drug

colestyramine Colestyramine (INN) or cholestyramine (USAN) (trade names Questran, Questran Light, Cholybar, Olestyr) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, whic ...

, and dantrolene.

Mechanism of action

Methotrexate is an antimetabolite of the antifolate type. It is thought to affect cancer and rheumatoid arthritis by two different pathways. For cancer, methotrexate competitively inhibits

dihydrofolate reductase Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry ...

(DHFR), an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

that participates in the tetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about 1000-fold that of folate. DHFR catalyses the conversion of

dihydrofolate Dihydrofolic acid (conjugate base dihydrofolate) (DHF) is a folic acid ( vitamin B9) derivative which is converted to tetrahydrofolic acid by dihydrofolate reductase. Since tetrahydrofolate is needed to make both purines and pyrimidines, which a ...

to the active tetrahydrofolate. Tetrahydrofolate is needed for the ''de novo'' synthesis of the nucleoside thymidine, required for DNA synthesis. Also, folate is essential for

purine Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines ...

and pyrimidine base biosynthesis, so synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s. For the treatment of rheumatoid arthritis, inhibition of DHFR is not thought to be the main mechanism, but rather multiple mechanisms appear to be involved, including the inhibition of enzymes involved in

purine metabolism Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms. Biosynthesis Purines are biologically synthesized as nucleotides and in particular as ribotides, i.e. bases attached to ...

, leading to accumulation of adenosine; inhibition of

T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

activation and suppression of intercellular adhesion molecule expression by T cells; selective down-regulation of B cells; increasing CD95 sensitivity of activated T cells; and inhibition of methyltransferase activity, leading to deactivation of enzyme activity relevant to immune system function. Another mechanism of MTX is the inhibition of the binding of interleukin 1-beta to its cell surface receptor.

History

In 1947, a team of researchers led by Sidney Farber showed aminopterin, a chemical analogue of

developed by Yellapragada Subbarao of Lederle, could induce

remission Remission often refers to: *Forgiveness Remission may also refer to: Healthcare and science *Remission (medicine), the state of absence of disease activity in patients with a chronic illness, with the possibility of return of disease activity *R ...

in children with acute lymphoblastic leukemia. The development of folic acid analogues had been prompted by the discovery that the administration of folic acid worsened leukemia, and that a diet deficient in folic acid could, conversely, produce improvement; the mechanism of action behind these effects was still unknown at the time. Other analogues of folic acid were in development, and by 1950, methotrexate (then known as amethopterin) was being proposed as a treatment for leukemia. Animal studies published in 1956 showed the therapeutic index of methotrexate was better than that of aminopterin, and clinical use of aminopterin was thus abandoned in favor of methotrexate. In 1951, Jane C. Wright demonstrated the use of methotrexate in solid tumors, showing remission in breast cancer. Wright's group was the first to demonstrate use of the drug in solid tumors, as opposed to leukemias, which are a cancer of the marrow.

Min Chiu Li Min Chiu Li (; 1919–1980) was a Chinese-American oncologist and cancer researcher. Li was the first scientist to use chemotherapy to cure widely metastatic, malignant cancer. Early life and education Born in China, Li studied at Mukden Med ...

and his collaborators then demonstrated complete remission in women with

choriocarcinoma Choriocarcinoma is a malignant, trophoblastic cancer, usually of the placenta. It is characterized by early hematogenous spread to the lungs. It belongs to the malignant end of the spectrum in gestational trophoblastic disease (GTD). It is also c ...

and chorioadenoma in 1956, and in 1960 Wright et al. produced remissions in

mycosis fungoides Mycosis fungoides, also known as Alibert-Bazin syndrome or granuloma fungoides, is the most common form of cutaneous T-cell lymphoma. It generally affects the skin, but may progress internally over time. Symptoms include rash, tumors, skin lesions ...

Research

In 2018, a photoactivated version of methotrexate (

phototrexate Phototrexate is a photochromic antifolate drug developed at the Institute for Bioengineering of Catalonia (IBEC, The Barcelona Institute of Science and Technology). In particular, it is a photopharmacological agent that behaves as light-regulat ...

) has been developed and proposed to be useful in localized, target-specific chemotherapy of psoriasis and cancer.

References

External links

*
National Rheumatoid Arthritis Society (NRAS)
article on Methotrexate

MedlinePlus article from NIH {{Authority control Antifolates Antineoplastic and immunomodulating drugs Benzamides Chemotherapy Disease-modifying antirheumatic drugs Folates Hepatotoxins IARC Group 3 carcinogens Immunosuppressants Mammalian dihydrofolate reductase inhibitors Nephrotoxins Orphan drugs Wikipedia medicine articles ready to translate World Health Organization essential medicines