Folic acid Antagonists
Much has been learned regarding pathways and coenzyme activity through the use of antagonists in animals and in microorganisms. One of the most potent inhibitors is aminopterin (4-amino PGA). The marked potency of the inhibitor aminopterin is attested to by the fact that when the compound was fed at a level of only 1 mg per kilogram of diet, mice died in a few days. It produces anemia and leukopenia in guinea pigs and in rats. This antagonist has been used successfully to bring about remissions (not a cure) of acute leukemia in children.
Amethopterin (4-amino-Nlo-methyl PGA) has also been used to produce experimental deficiency and in the treatment of leukemia. Goldin and co-authors have reviewed the clinical use of such antagonists. Amethopterin markedly inhibited nucleic acid synthesis in rats following partial bepatectomy to induce mitosis. This is probably explained on the basis that the 4-amino antagonist suppresses formylcoenzyme synthesis, resulting in inadequate purines and/or pyrimidine production, with the consequent inability of the organism to fabricate nucleic acids. Timmis has reviewed many antifolic acid compounds with real or potential value in cancer chemotherapy.
