Lay Summary
Proposal No. IBD-0013
Principal Investigator: Daniel S. Straus, Ph.D.
Applicant Organization: University of California, Riverside (U.S.A.)
Project Title: Trial of anti-inflammatory prostaglandins for treatment of inflammatory bowel disease in IL-10 knockout mice
Period of Award: August 1, 2002 - July 31, 2004
Ulcerative colitis (UC) and Crohn’s disease (CD) are inflammatory bowel diseases (IBDs) with a chronic debilitating course. Frontline drugs currently in use for treatment of IBD include derivatives of 5-aminosalicylic acid and glucocorticoids. These drugs have varying efficacy from patient to patient and the glucocorticoids have harmful side effects. A fraction of patients with UC ultimately require removal of the colon (colectomy), and most patients with CD require at least one or more operations. In addition, patients with UC who do not undergo colectomy are at increased risk for colon cancer. In view of the devastating nature of IBD and limited efficacy of drugs used for its treatment, it would be extremely helpful to have more potent anti-inflammatory drugs with fewer side effects.
The purpose of the proposed research will be to test the therapeutic activity of a new class of anti-inflammatory drugs, cyclopentenone prostaglandin 15d-PGJ2, in IBD in mice. This compound has been shown previously to have potent anti-inflammatory activity in cell culture model systems and to suppress adjuvant-induced arthritis in rats, providing a strong rationale for testing its activity in rodent models for IBD. Several analogs of 15d-PGJ2 predicted to have enhanced anti-inflammatory activity will be synthesized by my collaborator, Dr. Kay Brummond. Compounds exhibiting greater activity than 15d-PGJ2 in cell culture models will be tested further for therapeutic activity in mouse models of IBD. Positive results in these experiments would provide a rationale for further testing of 15d-PGJ2 or its analogs for treatment of humans with IBD. These prostaglandin analogs have the advantage of being potent anti-inflammatory drugs with minimal side effects. They could form a new, safer and more potent therapeutic approach to IBD.