Current understanding of methotrexate pharmacology and efficacy in acute leukemias. Use of newer antifolates in clinical trials

Abstract

BACKGROUND AND OBJECTIVES: Methotrexate (MTX) is a key drug in the curative regimen of children with acute lymphocytic leukemia. This drug is widely used not only in the treatment of neoplastic diseases such as leukemia, lymphoma, choriocarcinoma, head and neck cancer and osteogenic sarcoma, but also for various autoimmune diseases, e.g., rheumatoid arthritis and psoriasis, and for the prevention of graft-versus-host disease after transplantation. The development of drug resistance is the limiting factor in the use of MTX. This review will outline the mechanisms of acquired and natural resistance to MTX that have been studied in patients affected by acute lymphocytic leukemia and acute myelocytic leukemia and the cell cycle genes involved in MTX resistance. This information may improve the use of MTX or could lead to the development of better drugs. Moreover a short description of newer antifolates with their mechanisms of action is presented. EVIDENCE AND INFORMATION SOURCES: The authors of this review have a long-standing interest in the mechanism of action of and resistance to MTX and other antifolates. Information from journal articles covered by the Science Citation Index and Medline has been reviewed together with work performed by the authors. PERSPECTIVES: Antifolates continue to be an extremely important class of drugs for the treatment of non-neoplastic as well as neoplastic diseases. New inhibitors that target dihydrofolate reductase as well as other folate-dependent enzymes are being evaluated in the clinic, and show promise.