ABSTRACT
Methotrexate (MTX) is a folate antagonist, first developed for the treatment of malignancies,1 and subsequently used in non-neoplastic diseases as an antiinflammatory and/or immunosuppressive drug. Biochemical pharmacologic studies of MTX in tumor cell lines have shown that MTX, like physiological folates, is converted to polyglutamate forms that are not readily transported across the cell membrane.2-4 Those polyglutamated derivatives not only inhibit dihydrofolate reductase (DHFR), the major MTX target, but also have markedly increased affinity for certain folate-dependent enzymes, such as thymidylate synthase (TS), 5-amino-imidazol-4-carboxamide ribonucleotide transformylase, and the triple complex of enzymes that interconvert various forms of reduced folate.4,5 Low dose MTX is currently the most commonly used treatment for rheumatoid arthritis,6,7 and other chronic inflammatory disorders. MTX is also effective in the prophylaxis of acute graft-versus-host disease either alone or in association with cyclosporin A and/or prednisone,8-10 or FK506.11 MTX has also been used as an adjunct therapy for persistent mild cardiac allograft rejection.12 Most pharmacologic studies have addressed the use of MTX in cancer chemotherapy, where doses could be escalated up to 30 g/m2 by administration of the antidote leucovorin (folinic acid, citrovorum factor). In autoimmune diseases and allografts, however, MTX dosage is usually given in a range of 7-15 mg per week, given orally or by intramuscular injections.
