Novel antifolate drugs

Abstract

Antimetabolites are active chemotherapeutic agents for many solid tumor and hematologic malignancies. Folate antagonists, purine analogues, and pyrimidine analogues are the three main categories of antimetabolites. Methotrexate, the most studied folate antagonist, is effective in many malignancies. Methotrexate inhibits dihydrofolate reductase, which leads to accumulation of polyglutamated folates, causing further inhibition of thymidylate synthase and glycinamide ribonucleotide formyltransferase. Subsequently, the lack of reduced folate substrates impairs synthesis of purine nucleotides, thymidylate, and certain amino acids, which can lead to cell death. However, methotrexate resistance develops through several mechanisms, including decreased folate carrier-mediated membrane transport, dihydrofolate reductase gene amplification, specific transcription-translational modifications, and downregulation of intracellular methotrexate polyglutamation. Antifolate drug development has focused on agents designed to overcome different aspects of methotrexate resistance. This article reviews the enzymatic targets for antifolates, describes the known mechanisms of antifolate resistance, and summarizes the current development of novel antifolate agents. Discussed specifically are trimetrexate, edatrexate, raltitrexed, pemetrexed, ZD9331, lometrexol, LY309887, GW1843, OSI-7904(L), and nolatrexed, all of which have unique clinical pharmacology and are in various stages of development. The toxicity of antifolates has been sporadic and difficult to predict clinically. Supplementation with folic acid and vitamin B(12) has been shown to reduce the toxicity of pemetrexed without affecting efficacy and has increased the therapeutic index for this novel agent.