Open AccessNew Antifolates: Pharmacology and Clinical Applications
Author(s) -
Takimoto Chris H.
Publication year - 1996
Publication title -
the oncologist
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.176
H-Index - 164
eISSN - 1549-490X
pISSN - 1083-7159
DOI - 10.1634/theoncologist.1-1-68
Subject(s) - antifolate , dihydrofolate reductase , thymidylate synthase , methotrexate , pharmacology , antimetabolite , ribonucleotide reductase , medicine , efflux , transporter , biochemistry , biology , chemotherapy , gene , fluorouracil , protein subunit
Many new antifolate compounds with unique clinical properties are currently in clinical development. Some of these agents have been rationally designed to circumvent known mechanisms of resistance to methotrexate, the most useful and extensively studied antifolate in clinical practice. Resistance to methotrexate can result from decreased active transport into cells, decreased polyglutamation resulting in enhanced drug efflux from cells, mutations in dihydrofolate reductase which reduce drug binding affinity, and increased expression of dihydrofolate reductase due to gene amplification or increased translational efficiency. As a consequence, the newer antifolates may differ from methotrexate because of increased lipid solubility, improved cellular uptake or increased ability to undergo polyglutamation. Several of these newer agents also uniquely target specific folate‐dependent enzymes such as thymidylate synthase or glycinamide ribonucleotide transformylase. Antifolates currently in clinical development include trimetrexate, edatrexate, piritrexim, ZD1694, lometrexol, AG337, LY231514 and 1843U89. This report summarizes the basic pharmacology and potential clinical applications of these promising new agents.