Aminopterin

• Aminopterin
• LN -(4 - (( (2,4- diamino-6- pteridinyl ) methyl ) amino) benzoyl) glutamic acid
• (S)- N-(4 - (( (2,4- diamino-6- pteridinyl ) methyl ) amino) benzoyl) glutamic acid

4' -deoxy -4'- aminofolsäure

Fixed

230 ° C ( decomposition)

Risk

3 mg · kg -1 ( LD50, mouse, oral)

Template: Infobox chemical / molecular formula search available

Aminopterin is an analog of folic acid (vitamin B9) and acts biologically as folic acid inhibitor. Chemically, it is a synthetic pterin derivative with antineoplastic ( anticancer ) and immunosuppressive properties.

Aminopterin was formerly used as a cytostatic agent, but is now mostly replaced by the structurally similar to methotrexate. Aminopterin in the cell culture is often used in the selection media, in particular in the production of monoclonal antibodies.

Had meaning the connection by a major recall of dog and cat food in 2007 in the United States, were in about a hundred ready-made food, even from reputable manufacturers, removed from the market. Contamination with aminopterin was discussed as a possible cause for evoked by feed kidney failure.

Application

The cytostatic effect of folic acid inhibitor aminopterin was first used in 1947 by Sidney Farber in children with leukemia, thereby enabling a temporary remission ( reduction, healing ) could be achieved of the cancer. In the years 1953-1964 was aminopterin in the United States by the company Lederle Laboratories, later taken over by the pharmaceutical company Wyeth, for the indication pediatric leukemia ' markets. At the same time structurally similar methotrexate was driven by the company already. Due to difficulties in the preparation of the substance presented Lederle Laboratories, the production of a later aminopterin in favor of methotrexate throughout.

In addition to its actual use as a cytostatic agent, the agent in the United States was established in the same period to more than 4,000 patients with great success in the treatment of psoriasis: obviously decreased the lesions without severe side effects were observed.

In the 1950s, aminopterin was replaced as cancer drug methotrexate, since the latter had a greater therapeutic index in a murine tumor model.

In the 1960s and before the substance was also tested as an abortifacient (abortion funding). After this, however, came to congenital malformations, this application was not pursued comparable teratogenic effects were also detected for methotrexate, so that the teratogenic effects of folic acid antagonists, the term ( fetal ) Aminopterinsyndrom are summarized. This is a complex syndrome with severe changes of the cranial bone and formation of clubfeet. Affected children are born alive rare and if they do, they usually do not survive the first year of life. Such severe developmental disorders of early embryo ( embryopathies ) may occur if folic acid inhibitors in the 4th be taken until the 12th week of pregnancy, the risk of damage to the embryo for aminopterin to 85 % and for methotrexate to 50 % estimated is.

Although it is often argued, for example, the Internet, aminopterin would as a rodenticide (eg rat poison ) are used, there is no evidence that it was ever actually used for such a purpose. Speaking against the one hand, that the preparation of the Substance is complex and expensive. On the other hand, is at aminopterin is an unstable molecule in the environment, which decays with light and heat exposure. Probably goes the erroneous assumption in aminopterin it were back to a means of controlling rodents, on a patent that was issued in 1951 by the American Cyanamid Company ( the parent company of Lederle Laboratories) and which is often quoted by various reference books and other sources.

Aminopterin today is mainly used in the production of monoclonal antibodies for the selection of hybridoma cells in the context of reasoned 1975 by Georges Kohler and Cesar Milstein hybridoma technology.

Pharmacology

A folate analog aminopterin blocked by the competitive inhibition of dihydrofolate reductase, an enzyme that reduces dihydrofolic acid. By blocking the synthesis of tetrahydrofolic acid, - it functions in the metabolism of all living creatures as a methyl group donor key - there is a lack of nucleotide precursors, whereby the cell division is necessary for synthesis of deoxyribonucleic acid ( DNA) and ribonucleic acid ( RNA) is inhibited. This in turn leads to a breakdown of the protein and thus the decline of the affected cells and tissues.

In addition, aminopterin is toxic, so it is no longer used in medicine. The lethal dose (LD) for mice orally as a single dose of 3 mg / kg.

Feed scandal

Aminopterin was demonstrated in 2007 by New York State Food Laboratory in amounts of at least 40 ppm in about a hundred dogs and cats finished feed. Since methotrexate crystallized at higher doses in the renal tubules, causing kidney damage, a similar mechanism is assumed for aminopterin. The direct relationship between aminopterin and the feed-borne diseases is not yet proven, under certain circumstances are also as yet unidentified toxins responsible.

Proof of aminopterin in living animals is not possible. Antioxidants and folinic acid can be used as a therapeutic trial, but its effect as an antidote after a long existing aminopterin exposure has not been established.