"Now that we've characterized the iNOS-COX-2 inflammatory system and how to manipulate it, we have a road map for developing new drugs to treat inflammation and pain that permits simultaneous use of reduced dose levels of COX-2 inhibitors," Snyder says. "Our research suggests that the synergism between these two drugs would represent a highly effective and safer form of therapy.
"Blocking iNOS-COX-2 binding might salvage the value of COX-2 inhibitors by permitting the use of lower doses of these drugs, which have been shown to have troublesome potential side effects when used at their originally prescribed levels," Snyder added.
Researchers already knew that COX-2 can produce prostaglandins independently of iNOS. But the Hopkins study showed that iNOS is responsible for about half the total amount of prostaglandins that COX-2 produces in response to stimuli that trigger inflammation. This demonstrated the close connection between these two systems, Snyder says. Therefore, drugs that block iNOS activity could significantly reduce the amount of prostaglandins produced by COX-2 enzymes, he adds.
The Hopkins scientists showed the connection between the iNOS and COX-2 systems in both immune system cells and human embryonic kidney cells by adding substances known to activate these enzymes -- for example, LPS-IFN-gamma, a combination of a component of some infectious bacteria membranes and an immune system protein that targets viruses and tumors. When the investigators broke apart these cells and added antibodies that specifically bind to COX-2, tiny clumps formed that consisted of COX-2 enzymes bound to iNOS. Antibodies that bind specifically to iNOS al
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Contact: Joanna Downer
jdowner1@jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions
22-Dec-2005