| Infiltrated inflammatory cells in synovial fluids and tissue are main targets for therapeutic intervention for patients with rheumatoid arthritis (RA). Disease Modifying Anti-Rheumatic Drugs (DMARDs) represent a class of anti-rheumatic drugs with proven efficacy, although long-term treatment is often accompanied with gradual loss of efficacy. This project aims to identify possible determinants of drug resistance on infiltrated inflammatory cells in synovial tissues of RA with active disease and during the course of therapy. Preliminary results of immunohistochemical staining experiments from synovial biopsies revealed the expression of the multidrug resistance (MDR) related proteins MRP1, BCRP and LRP, The first two drug efflux proteins can mediate the cellular efflux, and thereby confer resistance, for the DMARDs methotrexate and sulfasalazine. The role of LRP (Lung Resistance Protein) is not clear yet. Furthermore, infiltrated inflammatory cells, notably macrophages in the synovial lining and sublining, displayed high expression of folate receptor isoform b (FR- b ). FR- b can transport methotrexate, but does this with a low affinity/efficiency. We identified folate antagonists with a high binding affinity, which may be more suitable for selective FR- b targeting (Van der Heijden et al, In Chemistry and Biology of Pteridines & Folates , 2007, in press). |
