tailieunhanh - Báo cáo y học: "Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic acidaminopterin conjugate"

Tuyển tập các báo cáo nghiên cứu về y học được đăng trên tạp chí y học General Psychiatry cung cấp cho các bạn kiến thức về ngành y đề tài: Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic acidaminopterin conjugate. | Lu et al. Arthritis Research Therapy 2011 13 R56 http content 13 2 R56 RESEARCH ARTICLE Open Access Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic acid-aminopterin conjugate 1 11111 Yingjuan Lu Torian W Stinnette Elaine Westrick Patrick J Klein Mark A Gehrke Vicky A Cross lontcho R Vlahov1 Philip S Low2 and Christopher P Leamon1 Abstract Introduction Folate receptor FR -expressing macrophages have been shown to accumulate at sites of inflammation where they promote development of inflammatory symptoms. To target such a macrophage population we designed and evaluated the biologic activity of EC0746 a novel folic acid conjugate of the highly potent antifolate aminopterin. Methods Using a FR-positive subclone of murine macrophage-derived cells and rat thioglycollate-elicited macrophages we studied the effect of EC0746 on dihydrofolate reductase activity cell proliferation and cellular response towards bacterial lipopolysaccharide as well as IFNg activation. The EC0746 anti-inflammatory activity pharmacokinetics and toxicity were also evaluated in normal rats or in rats with adjuvant-induced arthritis that is a FR-positive macrophage model that closely resembles rheumatoid arthritis in humans. Results EC0746 suppresses the proliferation of cells and prevents the ability of nonproliferating rat macrophages to respond to inflammatory stimuli. In the macrophage-rich rat arthritis model brief treatment with subcutaneously administered EC0746 is shown to mediate an FR-specific anti-inflammatory response that is more potent than either orally administered methotrexate or subcutaneously delivered etanercept. More importantly EC0746 therapy is also shown to be 40-fold less toxic than unmodified aminopterin with fewer bone marrow and gastrointestinal problems. Conclusions EC0746 is the first high FR-binding dihydrofolate reductase inhibitor that demonstrates FR-specific anti-inflammatory .