Aminopterin

Aminopterin (or 4-aminopteroic acid), the 4-amino derivative of folic acid, is an antineoplastic drug with immunosuppressive properties often 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. Its binding affinity for dihydrofolate reductase effectively blocks tetrahydrofolate synthesis. This results in the depletion of nucleotide precursors and inhibition of DNA, RNA, and protein synthesis. Aminopterin (or 4-aminopteroic acid), the 4-amino derivative of folic acid, is an antineoplastic drug with immunosuppressive properties often 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. Its binding affinity for dihydrofolate reductase effectively blocks tetrahydrofolate synthesis. This results in the depletion of nucleotide precursors and inhibition of DNA, RNA, and protein synthesis. It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities. Discovered by Dr. Yellapragada Subbarow, the drug was first used by Sidney Farber in 1947 to induce remissions among children with leukemia. Aminopterin was later marketed by Lederle Laboratories (Pearl River, New York) in the United States from 1953 to 1964 for the indication of pediatric leukemia. The closely related antifolate methotrexate was simultaneously marketed by the company during the same period. Aminopterin was discontinued by Lederle Laboratories in favor of methotrexate due to manufacturing difficulties of the former. During the period Aminopterin was marketed, the agent was used off-label to safely treat over 4,000 patients with psoriasis in the United States, producing dramatic clearing of lesions. The use of aminopterin in cancer treatment was supplanted in the 1950s by methotrexate due to the latter's better therapeutic index in a rodent tumor model. Now in a more pure preparation and supported by laboratory evidence of superior tumor cell uptake in vitro, aminopterin is being investigated in clinical trials in leukemia as a potentially superior antifolate to methotrexate. The compound was explored as an abortifacient in the 1960s and earlier, but was associated with congenital malformations. Similar congenital abnormalities have been documented with methotrexate, and collectively their teratogenic effects have become known as the fetal aminopterin syndrome. When a similar cluster of abnormalies appears in the absence of exposure to antifolates it is referred to as aminopterin-like syndrome without aminopterin. Although the use of aminopterin as a rodenticide is widely asserted on the web and elsewhere, there is no evidence that it has ever been used for that purpose either in the United States or elsewhere in the world. The preparation of the molecule is complex and expensive. It is also unstable in the environment due to degradation by light and heat. The apparently mistaken association of aminopterin with its use as a rodenticide likely dates back to a 1951 patent issued to the American Cyanamid Company (then the holding company of Lederle Laboratories) that is commonly cited by a variety of reference textbooks. Aminopterin has a single-dose LDLo of 2.5 mg/kg when orally administered to rats. Aminopterin is widely used in selection media (such as HAT medium) for cell culture, particularly in the development of hybridomas, which secrete monoclonal antibodies. On March 23, 2007, ABC News reported that aminopterin was the chemical linked to the 2007 Menu Foods pet food contamination incident. The incident resulted in a massive recall of the affected foods. The link to aminopterin was confirmed by New York State Agriculture Commissioner Patrick Hooker and Dr. Donald Smith, Dean of Cornell University's College of Veterinary Medicine, in a statement released on the same day.