Inhibition of glycinamide ribonucleotide formyltransferase results in selective inhibition of macrophage cytokine secretion in vitro and in vivo efficacy in rat adjuvant arthritis

Subba Chintalacharuvu, Glenn F. Evans, Chuan Shih, Henry U. Bryant, George E. Sandusky, Steven H. Zuckerman

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Objective: To determine the effects of a glycinamide ribonucleotide formyltransfei-ase (GARFT) inhibitor on macrophage inflammatory processes and in vivo in rat adjuvant arthritis. Methods: GARFT inhibitors, LY309886 (6S-2′,5′-thienyl-5,10-dideazatetrahydrofolic acid) and LY329201 (R)-N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3- d]pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamatic acid disodium salt, were investigated in vitro and ex vivo on primary murine peritoneal macrophages and in the RAW macrophage cell line for both purine depletion and inhibition of LPS induced monokine secretion. In vivo efficacy following GARFT inhibition was evaluated in modified rat adjuvant arthritis. Results: LY309886 inhibited purine biosynthesis in the RAW cell line with an EC50 of 90 nM, an effect readily reversible with exogenous hypoxanthine. LY309886 and LY329201 also inhibited LPS induced TNF alpha and MIP1 alpha in these cells and in primary macrophages. A similar effect could be demonstrated ex vivo with mice dosed for two days with 3 mg/kg of LY329201. LY329201 as well as methotrexate demonstrated a dose dependent reduction in both paw and spleen weight and improved joint histology following 2 weeks of dosing in a rat adjuvant arthritis study. Conclusion: These results suggest that GARFT inhibitors should be tested in the treatment of rheumatoid arthritis by considering their mechanism of action, here successfully tested on activated macrophages.

Original languageEnglish (US)
Pages (from-to)438-446
Number of pages9
JournalClinical and Experimental Rheumatology
Volume23
Issue number4
StatePublished - Jul 1 2005
Externally publishedYes

Keywords

  • Anti-folates
  • Inflammation
  • Macrophage inflammatory protein 1
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology

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