ABSTRACT
I. INTRODUCTION 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 An analog of both folic acid and the antecedent folic acid antagonist aminopterin (withdrawn because of toxicity), MTX competes with 5-methyltetrahydrofolate (the major folate in serum) and with folinic acid (5-formyltetrahydrofolate) for uptake into cells. Once inside the cell, MTX is polyglutamylated by folylpolyglutamate synthetase, and it is likely that this conversion, which impairs MTX egress from the cell, determines MTX’s cytotoxicity. Intracellularly, MTX inhibits tetrahydrofolate reductase leading to a reduced supply of tetrahydrofolates (especially folinic acid), which in turn impairs synthesis of thymidylate (a pyrimidine precursor) and purines and stops DNA biosynthesis, thereby causing cell death (1).
