title: Antifolates in clinical development.
abstract: Many novel antifolate compounds with unique pharmacologic properties are currently in clinical development. These newer antifolates differ from methotrexate, the most widely used and studied drug in this class, in terms of their lipid solubility and cellular transport affinity, their level of polyglutamation, and their specificity for inhibiting folate-dependent enzymes, such as dihydrofolate reductase, thymidylate synthase, or glycinamide ribonucleotide formyltransferase. The current status (ie, mechanism of action, clinical response rates, and toxicity) of some of the newer antifolate compounds presently in clinical testing, including edatrexate, piritrexim, raltritrexed, LY 231514, AG337, AG331, 1843U89, ZD 9331, and lometrexol, is reviewed.
authors.affiliation: Developmental Therapeutics Department, National Cancer Institute, Bethesda Naval Hospital, MD 20889-5105, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Takimoto
mesh_terms: D000630:Aminopterin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005493:Folic Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005971:Glutamates / Q000494:pharmacology / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D054833:Isoindoles; D000068437:Pemetrexed; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D013763:Tetrahydrofolates / Q000494:pharmacology / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D005971:Glutamates; D007211:Indoles; D054833:Isoindoles; D011743:Pyrimidines; D011799:Quinazolines; D013763:Tetrahydrofolates; D013876:Thiophenes; C094299:ZD 9331; D000068437:Pemetrexed; C079601:1843U89; D006147:Guanine; C045894:lometrexol; D013940:Thymidylate Synthase; C068874:raltitrexed; C040210:edatrexate; D000630:Aminopterin; C099178:nolatrexed; C024530:piritrexim