New Folate Antagonist Drugs Portend Specific Treatment for Rheumatoid Arthritis

Researchers have compared the efficacy of a group of folate antagonist drugs to methotrexate (MTX) the drug widely used for treatment of rheumatoid arthritis (RA).

Investigators at VU University Medical Center (Amsterdam, The Netherlands) were particularly interested in drugs that could enter cells by binding to the folate receptor FR-beta, which is primarily located on synovial cells. Methotrexate, on the other hand, enters cells through the reduced folate carrier (RFC) pathway, which is found on most cells in the body. The widespread distribution of RFC limits the usefulness of MTX because of adverse side effects and development of resistance to the drug.

In the current study, the investigators screened candidate drugs for their ability to bind to FR-beta. They employed immunohistochemistry and computer-assisted digital imaging analyses to detect FR-beta protein expression on immunocompetent cells in synovial biopsy samples from RA patients with active disease and in noninflammatory control synovial tissues. FR-beta messenger RNA (mRNA) levels were determined by reverse transcription-polymerase chain reaction (PCR) analysis.

Results published in the January 2009 issue of the journal Arthritis & Rheumatism revealed that immunohistochemical staining of RA synovial tissue indicated high expression of FR-beta on macrophages in the intimal lining layer and synovial sublining, whereas no staining was observed in T-cell areas or in control synovial tissue. Levels FR-beta mRNA were highest in synovial tissue extracts and RA monocyte-derived macrophages, but low in peripheral blood T-cells and monocytes. Screening of 10 new-generation folate antagonists revealed four compounds for which FR-beta had a high binding affinity (20-77-fold higher than for MTX). One of these, the thymidylate synthase inhibitor BCG 945, displayed selective targeting against FR-beta-transfected cells. BCG 945 was not taken up by through the FRC pathway.

The authors concluded that their results suggested, "Further evaluation of folate antagonists with properties of high binding affinity for FR-beta and low affinity for the RFC may pave the road for a more selective targeted therapy of activated synovial macrophages.”

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