In an effort to dissect the underlying mechanisms ofintracellular signaling processes, particularly those triggered byinterleukin-2, researchers at Cell Therapeutics Inc. havedeveloped a number of synthetic small-molecule compoundsthat interfere with the process.

According to experimental data reported this week at theannual meeting of the American Society of Hematology (ASH)in St. Louis, one of those compounds acts by means of amechanism that is different from other immunosuppressiveagents such as rapamycin, FK-506 and cyclosporin A.

CT-2526 apparently does not affect the pathways generallybelieved to be associated with IL-2 signaling, but it does seemto affect a pathway that involves signaling by phospholipids.

Researchers at Cell Therapeutics of Seattle have found that thephospholipid inositol phosphate-glycan (gly-PI) may be thatupstream signaling molecule. Glenn Rice, director of cell biologyat Cell Therapeutics, presented in vitro data at the ASH meetingon the ability of CT-2576 to block the breakdown of gly-PI andthe subsequent formation of a unique myristylatedphosphatidic acid (mPA) species (which could act as a secondmessenger) in IL-2-induced mouse cytotoxic T cells. Moreover,Rice presented data indicating that CT-2576 inhibits IL-2induced proliferation in those cells.

Cell Therapeutics scientists have designed the CT-2576compound by "modeling it off the enzyme that hydrolyzes gly-PI to phosphatidic acid," explained James Bianco, president andchief executive officer of the privately held company.

"We believe this phospholipid signaling pathway divergedevolutionarily (from the other signaling pathways)" and is notinvolved in the normal cellular response, Bianco told BioWorld.In fact, Cell Therapeutics said that the phospholipid signalingpathway is part of the Bursten pathway, a unique second-messenger pathway that apparently responds to noxious andstress-related stimuli such as chemotherapy, radiation, severebacterial infection and viral replication.

According to Bianco, the compound CT-2576 may also prove tobe effective in inhibiting cell activation and abnormal immuneresponse. "In in vitro models of immune and antigenicchallenge, CT-2576 potently inhibits T cell activation at lowconcentrations yet was not toxic to a variety of cell types atconcentrations 1,000 to 10,000 fold higher," he said. "It's notinterfering with the normal cellular mechanisms."

-- Jennifer Van Brunt Senior Editor

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