ABSTRACT
Methotrexate (MTX), a classic antimetabolite that inhibits folic acid metabolism, has been
licensed in the United States since 1953 and commercially available since 1955. An analog of
both folic acid and the antecedent folic acid antagonist aminopterin (1) that was withdrawn
because of toxicity, MTX competes with 5-methyltetrahydrofolate (found in food and the major
folate in serum) and with folinic acid (5-formyltetrahydrofolate or leucovorin) for uptake into
cells via the reduced folate carrier. Once inside the cell, MTX is polyglutamylated
by folylpolyglutamate synthetase (2), and it is likely that this conversion, which impairs
MTX egress from the cell (2), determines MTX’s activity and cytotoxicity (3,4). Intracellularly,
MTX inhibits dihydrofolate reductase leading to a reduced supply of tetrahydrofolates
(especially methylene-and methyl-tetrahydrofolate), and it also interferes with thymidylate
synthase, which together impair synthesis of thymidylate (a pyrimidine precursor). MTX
inhibition of glycinamide and aminoimidazoleoxamide ribonucleotide transformylases
depletes purines. DNA biosynthesis is stopped and cell death ensues (5,6).
