A Novel Methionine Aminopeptidase-2 Inhibitor, PPI-2458, Inhibits Non–Hodgkin's Lymphoma Cell Proliferation In vitro and In vivo

• Published in: Clinical cancer research Vol. 12; no. 8; pp. 2583 - 2590
• Main Authors: Cooper, Andrew C, Karp, Russell M, Clark, Edward J, Taghizadeh, Nazbeh R, Hoyt, Jennifer G, Labenski, Matthew T, Murray, Michael J, Hannig, Gerhard, Westlin, William F, Thompson, Charles D
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 15.04.2006
• Subjects: Aminopeptidases - antagonists & inhibitors; Aminopeptidases - metabolism; Animals; B-Lymphocytes - drug effects; B-Lymphocytes - pathology; Blotting, Western; Cell Line, Tumor; Cell Proliferation - drug effects; Cynomolgus; Dose-Response Relationship, Drug; Epoxy Compounds - pharmacology; Epoxy Compounds - therapeutic use; Female; Germinal Center - drug effects; Germinal Center - pathology; Humans; Lymphocyte Count; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - metabolism; Lymphoma, B-Cell - pathology; Lymphoma, Non-Hodgkin - drug therapy; Lymphoma, Non-Hodgkin - metabolism; Lymphoma, Non-Hodgkin - pathology; Macaca fascicularis; Metalloendopeptidases - antagonists & inhibitors; Metalloendopeptidases - metabolism; MetAP-2; Mice; Mice, SCID; non–Hodgkin‘s; PPI-2458; Proto-Oncogene Proteins c-bcl-2 - metabolism; Time Factors; Valine - analogs & derivatives; Valine - pharmacology; Valine - therapeutic use; xenograft; Xenograft Model Antitumor Assays - methods
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0871

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.