the history of Methotrexate

In 1947, a team of researchers led by Sidney Farber showed that 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 that 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 blood. The drug was then investigated as a treatment for many other cancers, alone or in combination with other drugs, and was studied for other, non-cancer indications in the 1970s. In 1988, it was approved by the U.S. Food and Drug Administration (FDA) to treat rheumatoid arthritis.