A phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic acid

Invest New Drugs. 1996;14(3):325-35. doi: 10.1007/BF00194536.


Lometrexol is an antifolate which inhibits glycinamide ribonucleotide formyltransferase (GARFT), an enzyme essential for de novo purine synthesis. Extensive experimental and limited clinical data have shown that lometrexol has activity against tumours which are refractory to other drugs, notably methotrexate. However, the initial clinical development of lometrexol was curtailed because of severe and cumulative antiproliferative toxicities. Preclinical murine studies demonstrated that the toxicity of lometrexol can be prevented by low dose folic acid administration, i.e. for 7 days prior to and 7 days following a single bolus dose. This observation prompted a Phase I clinical study of lometrexol given with folic acid supplementation which has confirmed that the toxicity of lometrexol can be markedly reduced by folic acid supplementation. Thrombocytopenia and mucositis were the major toxicities. There was no clear relationship between clinical toxicity and the extent of plasma folate elevation. Associated studies demonstrated that lometrexol plasma pharmacokinetics were not altered by folic acid administration indicating that supplementation is unlikely to reduce toxicity by enhancing lometrexol plasma clearance. The work described in this report has identified for the first time a clinically acceptable schedule for the administration of a GARFT inhibitor. This information will facilitate the future evaluation of this class of compounds in cancer therapy.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / antagonists & inhibitors
  • Administration, Oral
  • Adult
  • Aged
  • Antidotes / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bone Marrow Diseases / chemically induced
  • Bone Marrow Diseases / metabolism
  • Dose-Response Relationship, Drug
  • Drugs, Investigational / administration & dosage
  • Drugs, Investigational / adverse effects
  • Drugs, Investigational / pharmacokinetics
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / pharmacokinetics
  • Female
  • Folic Acid / administration & dosage
  • Folic Acid / blood
  • Folic Acid Antagonists / administration & dosage
  • Folic Acid Antagonists / adverse effects
  • Folic Acid Antagonists / pharmacokinetics
  • Gastrointestinal Diseases / chemically induced
  • Gastrointestinal Diseases / metabolism
  • Humans
  • Hydroxymethyl and Formyl Transferases*
  • Kidney Diseases / chemically induced
  • Kidney Diseases / metabolism
  • Leucovorin / therapeutic use
  • Male
  • Middle Aged
  • Phosphoribosylglycinamide Formyltransferase
  • Tetrahydrofolates / administration & dosage
  • Tetrahydrofolates / adverse effects
  • Tetrahydrofolates / pharmacokinetics


  • Antidotes
  • Drugs, Investigational
  • Enzyme Inhibitors
  • Folic Acid Antagonists
  • Tetrahydrofolates
  • lometrexol
  • Folic Acid
  • Hydroxymethyl and Formyl Transferases
  • Phosphoribosylglycinamide Formyltransferase
  • Acyltransferases
  • Leucovorin