PMID: 9420019Jan 7, 1998Paper

Folate and antifolate pharmacology

Seminars in Oncology
B Kamen

Abstract

Folic acid is a water-soluble vitamin associated with the other B vitamins. In its fully reduced form (tetrahydrofolate), folate serves as a 1-carbon donor for synthesis of purines and thymidine as well as in the remethylation cycle of homocysteine to methionine. Folate is essential for normal cell growth and replication. It therefore is not surprising that folate analogues have served and continue to serve well as antibiotics and cytotoxic drugs in the treatment of cancer, autoimmune diseases, psoriasis, and bacterial and protozoal infections. During the past 50 years, many of the enzymes requiring folate as a co-factor (ie, thymidylate synthase), and molecules critical in folate homeostasis (ie, the reduced folate carrier, folylpolyglutamate synthase), have been purified and even crystallized. The genes have been cloned, sequenced, and mapped, providing detailed knowledge of their regulation and three-dimensional structure. This has, in part, led to the rational synthesis of a large number of folate analogues that differ from methotrexate, the "classical antifolate," in transport, metabolism, and intracellular targets. Currently, several new folate analogues with unique biochemical properties and clinical applications are bei...Continue Reading

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