title: Overview of phase I trials of multitargeted antifolate (MTA, LY231514).
abstract: Multitargeted antifolate (MTA, LY231514) is a novel antifolate antimetabolite, with antitumor activity via inhibition of thymidylate synthase, glycinamide formyl transferase, and dihydrofolate reductase. Three dosing schedules have been investigated in the phase I setting: daily x5 every 21 days, weekly x4 every 42 days, and once every 21 days. The maximum tolerated doses on these schedules were 4.0 mg/m2, 30 mg/m2, and 600 mg/m2, respectively. The major dose-limiting toxicity seen on all schedules was neutropenia, with a greater degree of reversible liver biochemistry disturbances observed on the daily x5 schedule. Given that toxicities were manageable and reversible, the antitumor activity exhibited, and the convenience of an every-21-day dosing schedule, this schedule was selected for phase II evaluation.
authors.affiliation: University of Texas Health Science Center, San Antonio, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Rinaldi
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005971:Glutamates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D000068437:Pemetrexed; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D013940:Thymidylate Synthase