The hallmark of rheumatoid arthritis (RA) is the progressive destruction of articular joints, characterized by invasive synovial hyperplasia and pathological neovascularization. Here we report that PPI-2458, a member of the fumagillin class of irreversible methionine aminopeptidase-2 (MetAP-2) inhibitors, potently inhibits the proliferation of human fibroblast-like synoviocytes (HFLS-RA), derived from RA patients, with a growth inhibitory concentration 50 (GI 50) of 0.04 nM and a maximum inhibition of >95% at 1 nM. Human umbilical vein endothelial cells (HUVEC) are similarly inhibited in proliferation by PPI-2458 (GI 50, 0.2 nM). We developed a method to measure the level of MetAP-2 enzyme inhibition after exposure to PPI-2458 and demonstrate that growth inhibition of PPI-2458-sensitive HFLS-RA and HUVEC is linked to MetAP-2 enzyme inhibition, in a dose-dependent fashion. The secretion of several inflammatory mediators such as IL-6 and vascular endothelial growth factor from activated HFLS-RA was not inhibited by PPI-2458. The CNS toxicity profile of PPI-2458, determined by the incidence of seizures, is significantly improved over that of the parental compound TNP-470. In the rat model of peptidoglycan-polysaccharide-induced arthritis, PPI-2458 significantly attenuated paw swelling when therapeutically administered after the onset of chronic disease. We suggest that the mechanism of PPI-2458 action, highly selective and potent antiproliferative activity on HFLS-RA and HUVEC in vitro, a significantly improved CNS toxicity profile, and marked attenuation of chronic disease in the rat peptidoglycan-polysaccharide arthritis model in vivo, positions this compound as a drug for the treatment of RA.

The important role that MetAP-2 has in the pathophysiological disease processes of PG-PS arthritis provides a strong rationale for evaluating PPI-2458 as a disease modifying antirheumatic treatment for rheumatoid arthritis.

Purpose: Fumagillin and related compounds have potent antiproliferative activity through inhibition of methionine aminopeptidase-2 (MetAP-2). It has recently been reported that MetAP-2 is highly expressed in germinal center B cells and germinal center^derived non^Hodgkin's lymphomas (NHL), suggesting an important role for MetAP-2 in proliferating B cells. Therefore, we determined the importance of MetAP-2 in normal and transformed germinal center B cells by evaluating the effects of MetAP-2 inhibition on the form and function of germinal centers and germinal center^derived NHL cells. Experimental Design: To examine the activity of PPI-2458 on germinal center morphology, spleen sections from cynomolgus monkeys treated with oral PPI-2458 were analyzed. Antiproliferative activity of PPI-2458 was assessed on germinal center^derived NHL lines in culture. A MetAP-2 pharmacodynamic assay was used to determine cellular MetAP-2 inhibition following PPI-2458 treatment. Finally, inhibition of MetAP-2 and proliferation by PPI-2458 was examined in the human SR NHL line in culture and in implanted xenografts. Results: Oral PPI-2458 caused a reduction in germinal center size and number in lymphoid tissues from treated animals. PPI-2458 potently inhibited growth (GI 50 = 0.2-1.9 nmol/L) of several NHL lines in a manner that correlated with MetAP-2 inhibition. Moreover, orally administered PPI-2458 significantly inhibited SR tumor growth, which correlated with inhibition of tumor MetAP-2 (>85% at 100 mg/kg) in mice. Conclusions: These results show the potent antiproliferative activity of PPI-2458 on NHL lines in vitro and oral antitumor activity in vivo and suggest the therapeutic potential of PPI-2458 as a novel agent for treatment of NHL should be evaluated in the clinical setting.Non-Hodgkin's lymphoma (NHL) is the sixth leading cause of cancer death in the United States and has increased in incidence by >80% since 1973 (1, 2). NHL can be divided into at least 29 different subtypes of malignancy of either T-or Blymphocyte origin. The vast majority of NHL malignancies are B cell derived. Moreover, a large number of these B-cell malignancies exhibit phenotypic characteristics consistent with a germinal center origin, the site where B cells undergo proliferation and somatic hypermutation.Germinal center -derived B-cell lymphomas can be divided into at least three groups. Follicular lymphoma is responsible for 22% of all NHLs, and almost always exhibits aberrant expression of the antiapoptotic gene 3,4). Follicular lymphoma typically follows an indolent course but often transforms into the more aggressive diffuse large B-cell lymphoma (DLBCL; ref. 5). Whereas at least half of all DLBCLs express germinal center markers (Bcl-6 + , CD10 + ), the remainder may more closely resemble activated B lymphocytes and potentially deserve a distinct classification (6, 7). Under the current classification, DLBCLs represent 40% of all NHLs (8). A third type of germinal center -derived B-cell neoplasm, Burkitt's lymphoma, is highly aggre...

Locating reliable health care information on the World Wide Web is difficult and confusing. Thus, Internet users must choose the appropriate resources to guide their health care decisions. This paper will describe the "typical" Internet user. Then, it will compare the three most "comprehensive" web site guidelines. Finally, it will summarize what criteria are necessary to create and maintain reliable health care web sites.

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