Methotrexate (rINN) (pronounced /mɛθɵˈtrɛkseɪt/), abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug used in treatment of cancer and autoimmune diseases. It acts by inhibiting the metabolism of folic acid. Methotrexate replaced the more powerful and toxic antifolate aminopterin, and the two should not be confused with each other.

Methotrexate originated in the 1940s when Dr. Sidney Farber at Children's Hospital Boston was testing the effects of folic acid on acute leukemic (severe blood cancer) children. Inspired, he asked Dr. Y.

Subbarao, then Director of the Research Division of Lederle Labs (part of American Cyanamid), to synthesize the anti-folate (methotrexate). Dr. Subbarao, who also happened to be the head of the team which had earlier synthesized folic acid (1946) readily synthesized this anti-folate and handed it over to Dr.

Farber, who in turn administered it to a small group of very ill leukemic children. The remarkable clinical improvement that was observed in these patients heralded the era of cancer chemotherapy in modern medicine. This was reported by Dr. S.

Farber in the June 3rd, 1948 issue of NEJM. In 1950 Dr. Farber founded in Boston the world's first Cancer Research Center.

Methotrexate gained Food and Drug Administration (FDA) approval as an oncology drug in 1953. Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about one thousand-fold that of folate for DHFR.

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. 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 proteins.

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