PMID: 8958188Jan 1, 1996Paper

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

Investigational New Drugs
S LaohavinijA H Calvert

Abstract

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 describ...Continue Reading

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Citations

Jan 1, 1996·Investigational New Drugs·T J BoritzkiE F Howland
Mar 22, 2002·The Lancet Oncology·N J Curtin, A N Hughes
May 12, 2006·Journal of Medicinal Chemistry·Jessica K DeMartinoDale L Boger
Jul 24, 2004·Expert Review of Anticancer Therapy·Victoria KutAthanassios Argiris
Sep 7, 2005·Advances in Enzyme Regulation·Homer L Pearce, Mary Alice Miller
Sep 18, 2016·Critical Reviews in Oncology/hematology·Peter V DanenbergNicholas Petrelli
Oct 7, 2005·Nutrition in Clinical Practice : Official Publication of the American Society for Parenteral and Enteral Nutrition·Kim Robien
Oct 1, 2003·The Journal of Biological Chemistry·Julie L Bronder, Richard G Moran
Mar 8, 2008·The Oncologist·Thomas E Stinchcombe, Mark A Socinski
Aug 23, 2020·Cells·Nefertiti MuhammadJiyeon Kim
Mar 22, 2002·Autoimmunity·T Abe, T Takeuchi
Nov 17, 2019·Cancer Letters·Alyncia D RobinsonSooryanarayana Varambally

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