Methotrexate
Encyclopedia
Methotrexate (icon), abbreviated MTX and formerly known as amethopterin, is an antimetabolite
and antifolate drug. It is used in treatment of cancer
, autoimmune disease
s, ectopic pregnancy
, and for the induction of medical abortion
s. It acts by inhibiting the metabolism of folic acid
. Methotrexate began to replace the more toxic antifolate aminopterin
starting in the 1950s. The drug was developed by Yellapragada Subbarao
.
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 neoplasms.
, psoriasis
, psoriatic arthritis
, lupus
and Crohn's disease
, to name a few. Although methotrexate was originally designed as a chemotherapy drug (in high doses), in low-doses methotrexate is a safe and well tolerated drug in the treatment of certain autoimmune diseases. Because of its efficacy and safety, low-dose methotrexate is now first-line therapy for the treatment of rheumatoid arthritis. Indeed, multiple studies and reviews showed that patients receiving methotrexate for up to 1 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 patients receiving methotrexate.
It has also been used for multiple sclerosis
but is not approved by the Food and Drug Administration
.
) to terminate pregnancies
during the early stages (i.e., as an abortifacient
). It is also used to treat ectopic pregnancies
.
). Oral doses are taken weekly not daily. Routine monitoring of the complete blood count
, liver function tests
, and creatine
are recommended. Measurements of creatinine are recommended at least every 2 months.
and thus predisposition to infection, nausea, abdominal pain, fatigue, fever, dizziness and rarely pulmonary fibrosis.
Methotrexate is a highly teratogenic drug and categorized in pregnancy category X
by the FDA. Women must not take the drug during pregnancy, if there is a risk of becoming pregnant, or if they are breastfeeding. Men who are trying to get their partner pregnant must also not take the drug. To engage in any of these activities (after discontinuing the drug), women must wait until the end of a full ovulation cycle and men must wait three months.
Central nervous system reactions to methotrexate have been reported, especially when given via the intrathecal route which include myelopathies and leucoencephalopathies. It has a variety of cutaneous side effects, particularly when administered in high doses.
Generally, the more "nonspecific" action a pharmacological substance has, the more possible side effects can be expected. Methotrexate has, like all "cell toxic" substances, a broad array of possible adverse effects. Care should always be taken to read the manufacturer's original instructions for the preparation in question.
Probenicid inhibits methotrexate excretion, which increases the risk of methotrexate toxicity.
(DHFR), an enzyme
that participates in the tetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about one thousand-fold that of folate. DHFR 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
. Also, folate is needed for purine base synthesis, so all purine synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA
, RNA
, thymidylates, and protein
s.
Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle
. Logically, it therefore has a greater toxic effect on rapidly dividing cells (such as malignant
and myeloid
cells, and gastrointestinal and oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and proliferation of these noncancerous cells, as well as causing the side effects listed below. Facing a scarcity of dTMP, rapidly dividing cancerous cells undergo cell death via thymineless death
.
For the treatment of rheumatoid arthritis, patients should supplement their diets with folate. In these cases, inhibition of DHFR is not thought to be the main mechanism, but rather the inhibition of enzyme
s involved in purine metabolism
, leading to accumulation of adenosine, or the inhibition of T cell
activation and suppression of intercellular adhesion molecule
expression by T cell
s.
4.8 and 5.5, and thus it is mostly ionized
at physiologic pH. Oral absorption is saturatable and thus dose-dependent, with doses less than 40 mg/m2 having 42% bioavailability and doses greater than 40 mg/m2 only 18%. Mean oral bioavailability is 33% (13-76% range), and there is no clear benefit to subdividing an oral dose. Mean intramuscular bioavailability is 76%.
Methotrexate is metabolized by intestinal bacteria to the inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid (DAMPA), which accounts for less than 5% loss of the oral dose.
Factors that decrease absorption include food, oral nonabsorbable antibiotics (e.g. vancomycin
, neomycin
, and bacitracin
), and more rapid transit through the gastrointestinal tract
(GI) tract, such as diarrhea
, while slower transit time in the GI tract from constipation
will increase absorption. Methotrexate is also administered in the placenta accreta
, inhibiting the blood circulation to the target site.
showed aminopterin
, a chemical analogue
of folic acid
developed by Yellapragada Subbarao Lederle, could induce remission 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 that same year, methotrexate was found to be a curative treatment for choriocarcinoma
—a solid tumor
, unlike leukemia, which is a cancer of the marrow
. The drug was then investigated as a treatment for many other cancers, alone or in combination with other drugs, and was studied for other, noncancer indications in the 1970s. In 1988, it was approved by the U.S. Food and Drug Administration (FDA) to treat rheumatoid arthritis
. In 2002, the FDA approved methotrexate to treat Crohn's disease
.
Antimetabolite
An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid...
and antifolate drug. It is used in treatment of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s, ectopic pregnancy
Ectopic pregnancy
An ectopic pregnancy, or eccysis , is a complication of pregnancy in which the embryo implants outside the uterine cavity. With rare exceptions, ectopic pregnancies are not viable. Furthermore, they are dangerous for the parent, since internal haemorrhage is a life threatening complication...
, and for the induction of medical abortion
Abortion
Abortion is defined as the termination of pregnancy by the removal or expulsion from the uterus of a fetus or embryo prior to viability. An abortion can occur spontaneously, in which case it is usually called a miscarriage, or it can be purposely induced...
s. It acts by inhibiting the metabolism of folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
. Methotrexate began to replace the more toxic antifolate aminopterin
Aminopterin
Aminopterin , a 4-amino analog of folic acid, is an antineoplastic drug with immunosuppressive properties used in chemotherapy. Aminopterin is a synthetic derivative of pterin. Aminopterin works as an enzyme inhibitor by competing for the folate binding site of the enzyme dihydrofolate reductase...
starting in the 1950s. The drug was developed by Yellapragada Subbarao
Yellapragada Subbarao
Yellapragada Subbarao was an Indian biochemist who discovered the function of Adenosine Triphosphate as a energy source in the cell, and made important contributions to the treatment of cancer. Most of his career was spent in the United States...
.
Chemotherapy
Methotrexate was originally developed and continues to be used for chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
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
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
, lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
, lung, osteosarcoma
Osteosarcoma
Osteosarcoma is an aggressive cancerous neoplasm arising from primitive transformed cells of mesenchymal origin that exhibit osteoblastic differentiation and produce malignant osteoid...
, bladder, and trophoblastic neoplasms.
Autoimmune disorders
It is used as a treatment for some autoimmune diseases including: rheumatoid arthritisRheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
, psoriatic arthritis
Psoriatic arthritis
Psoriatic arthritis is a type of inflammatory arthritis that, according to the National Psoriasis Foundation, will develop in up to 30 percent of people who have the chronic skin condition psoriasis...
, lupus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
and Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
, to name a few. Although methotrexate was originally designed as a chemotherapy drug (in high doses), in low-doses methotrexate is a safe and well tolerated drug in the treatment of certain autoimmune diseases. Because of its efficacy and safety, low-dose methotrexate is now first-line therapy for the treatment of rheumatoid arthritis. Indeed, multiple studies and reviews showed that patients receiving methotrexate for up to 1 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 patients receiving methotrexate.
It has also been used for multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
but is not approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
.
Pregnancy termination
Methotrexate is commonly used (generally in combination with misoprostolMisoprostol
Misoprostol is a drug that is used for the prevention of non steroidal anti inflammatory drug induced gastric ulcers, for early abortion, to treat missed miscarriage, and to induce labor. The latter use is controversial in the United States. Misoprostol was invented and marketed by G.D...
) to terminate pregnancies
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
during the early stages (i.e., as an abortifacient
Abortifacient
An abortifacient is a substance that induces abortion. Abortifacients for animals that have mated undesirably are known as mismating shots....
). It is also used to treat ectopic pregnancies
Ectopic pregnancy
An ectopic pregnancy, or eccysis , is a complication of pregnancy in which the embryo implants outside the uterine cavity. With rare exceptions, ectopic pregnancies are not viable. Furthermore, they are dangerous for the parent, since internal haemorrhage is a life threatening complication...
.
Administration
It can be taken orally or administered by injection (intramuscular, intravenous, subcutaneous, or intrathecalIntrathecal
Intrathecal is an adjective that refers to something introduced into or occurring in the space under the arachnoid membrane of the brain or spinal cord...
). Oral doses are taken weekly not daily. Routine monitoring of the complete blood count
Complete blood count
A complete blood count , also known as full blood count or full blood exam or blood panel, is a test panel requested by a doctor or other medical professional that gives information about the cells in a patient's blood...
, liver function tests
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
, and creatine
Creatine
Creatine is a nitrogenous organic acid that occurs naturally in vertebrates and helps to supply energy to all cells in the body, primarily muscle. This is achieved by increasing the formation of Adenosine triphosphate...
are recommended. Measurements of creatinine are recommended at least every 2 months.
Adverse effects
The most common adverse effects include: ulcerative stomatitis, low white blood cell countLeukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
and thus predisposition to infection, nausea, abdominal pain, fatigue, fever, dizziness and rarely pulmonary fibrosis.
Methotrexate is a highly teratogenic drug and categorized in pregnancy category X
Pregnancy category
The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does not include any risks conferred by pharmaceutical agents or their metabolites that are present in breast...
by the FDA. Women must not take the drug during pregnancy, if there is a risk of becoming pregnant, or if they are breastfeeding. Men who are trying to get their partner pregnant must also not take the drug. To engage in any of these activities (after discontinuing the drug), women must wait until the end of a full ovulation cycle and men must wait three months.
Central nervous system reactions to methotrexate have been reported, especially when given via the intrathecal route which include myelopathies and leucoencephalopathies. It has a variety of cutaneous side effects, particularly when administered in high doses.
Generally, the more "nonspecific" action a pharmacological substance has, the more possible side effects can be expected. Methotrexate has, like all "cell toxic" substances, a broad array of possible adverse effects. Care should always be taken to read the manufacturer's original instructions for the preparation in question.
Drug interactions
Penicillins may decrease the elimination of methotrexate and thus increase the risk of toxicity. While they may be used together increased monitoring is recommended.Probenicid inhibits methotrexate excretion, which increases the risk of methotrexate toxicity.
Mechanism of action
Methotrexate competitively inhibits dihydrofolate reductaseDihydrofolate reductase
- Function :Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids...
(DHFR), an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that participates in the tetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about one thousand-fold that of folate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Folic acid is needed for the de novo synthesis of the nucleoside
Nucleoside
Nucleosides are glycosylamines consisting of a nucleobase bound to a ribose or deoxyribose sugar via a beta-glycosidic linkage...
thymidine
Thymidine
Thymidine is a chemical compound, more precisely a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine in double-stranded DNA...
, required for DNA synthesis
DNA synthesis
DNA synthesis commonly refers to:*DNA replication - DNA biosynthesis *Polymerase chain reaction - enzymatic DNA synthesis *Oligonucleotide synthesis - chemical synthesis of nucleic acids...
. Also, folate is needed for purine base synthesis, so all purine synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
, thymidylates, and protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s.
Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
. Logically, it therefore has a greater toxic effect on rapidly dividing cells (such as malignant
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
and myeloid
Myeloid
The term myeloid suggests an origin in the bone marrow or spinal cord, or a resemblance to the marrow or spinal cord.In hematopoiesis, the term "myeloid cell" is used to describe any leukocyte that is not a lymphocyte...
cells, and gastrointestinal and oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and proliferation of these noncancerous cells, as well as causing the side effects listed below. Facing a scarcity of dTMP, rapidly dividing cancerous cells undergo cell death via thymineless death
Thymineless death
Thymineless death is the phenomenon by which bacteria, yeasts and mammalian cells undergo irreversible cell death when they are starved of thymidine triphosphate , an essential precursor for DNA replication...
.
For the treatment of rheumatoid arthritis, patients should supplement their diets with folate. In these cases, inhibition of DHFR is not thought to be the main mechanism, but rather the inhibition of enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s involved in purine metabolism
Purine metabolism
-Biosynthesis:Purines are biologically synthesized as nucleotides and in particular as ribotides, i.e. bases attached to ribose 5-phosphate. A key regulatory step is the production of 5-phospho-α-D-ribosyl 1-pyrophosphate by PRPP synthetase, which is activated by inorganic phosphate and...
, leading to accumulation of adenosine, or the inhibition of T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
activation and suppression of intercellular adhesion molecule
Intercellular adhesion molecule
Intercellular adhesion molecules are members of the family of cell adhesion molecules. They include the following:* ICAM-1 * ICAM2* ICAM3* ICAM4* ICAM5...
expression by T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s.
Pharmacokinetics
Methotrexate is a weak dicarboxylic acid with pKaAcid dissociation constant
An acid dissociation constant, Ka, is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid-base reactions...
4.8 and 5.5, and thus it is mostly ionized
Ionization
Ionization is the process of converting an atom or molecule into an ion by adding or removing charged particles such as electrons or other ions. This is often confused with dissociation. A substance may dissociate without necessarily producing ions. As an example, the molecules of table sugar...
at physiologic pH. Oral absorption is saturatable and thus dose-dependent, with doses less than 40 mg/m2 having 42% bioavailability and doses greater than 40 mg/m2 only 18%. Mean oral bioavailability is 33% (13-76% range), and there is no clear benefit to subdividing an oral dose. Mean intramuscular bioavailability is 76%.
Methotrexate is metabolized by intestinal bacteria to the inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid (DAMPA), which accounts for less than 5% loss of the oral dose.
Factors that decrease absorption include food, oral nonabsorbable antibiotics (e.g. vancomycin
Vancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
, neomycin
Neomycin
Neomycin is an aminoglycoside antibiotic that is found in many topical medications such as creams, ointments, and eyedrops. The discovery of Neomycin dates back to 1949. It was discovered in the lab of Selman Waksman, who was later awarded the Nobel Prize in Physiology and medicine in 1951...
, and bacitracin
Bacitracin
Bacitracin is a mixture of related cyclic polypeptides produced by organisms of the licheniformis group of Bacillus subtilis var Tracy, isolation of which was first reported in 1945....
), and more rapid transit through the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
(GI) tract, such as diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, while slower transit time in the GI tract from constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
will increase absorption. Methotrexate is also administered in the placenta accreta
Placenta accreta
Placenta accreta is a severe obstetric complication involving an abnormally deep attachment of the placenta, through the endometrium and into the myometrium...
, inhibiting the blood circulation to the target site.
History
In 1947, a team of researchers led by Sidney FarberSidney Farber
Sidney Farber was a pediatric pathologist. He was born in 1903 in Buffalo, New York, the third oldest of a family of 14 children. He was a graduate of the University of Buffalo in 1923. He took his first year of medical school at the Universities of Heidelberg and Freiburg in Germany. He entered...
showed aminopterin
Aminopterin
Aminopterin , a 4-amino analog of folic acid, is an antineoplastic drug with immunosuppressive properties used in chemotherapy. Aminopterin is a synthetic derivative of pterin. Aminopterin works as an enzyme inhibitor by competing for the folate binding site of the enzyme dihydrofolate reductase...
, a chemical analogue
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
developed by Yellapragada Subbarao Lederle, could induce remission in children with acute lymphoblastic leukemia
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...
. 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
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
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
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
of methotrexate was better than that of aminopterin, and clinical use of aminopterin was thus abandoned in favor of methotrexate. In that same year, methotrexate was found to be a curative treatment for choriocarcinoma
Choriocarcinoma
Choriocarcinoma is a malignant, trophoblastic and aggressive cancer, usually of the placenta. It is characterized by early hematogenous spread to the lungs...
—a solid tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
, unlike leukemia, which is a cancer of the marrow
Hematological malignancy
Hematological malignancies are the types of cancer that affect blood, bone marrow, and lymph nodes. As the three are intimately connected through the immune system, a disease affecting one of the three will often affect the others as well: although lymphoma is technically a disease of the lymph...
. The drug was then investigated as a treatment for many other cancers, alone or in combination with other drugs, and was studied for other, noncancer indications in the 1970s. In 1988, it was approved by the U.S. Food and Drug Administration (FDA) to treat rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
. In 2002, the FDA approved methotrexate to treat Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
.
External links
- National Rheumatoid Arthritis Society (NRAS) article on Methotrexate
- Chembank entry on methotrexate
- Methotrexate general article from NIH
- Methotrexate Injection MedlinePlus article from NIH
- Patient Education - Methotrexate from American College of Rheumatology
- U.S. National Library of Medicine: Drug Information Portal - Methotrexate