Breaking the COX code
Using the team approach
Editor’s Note: This story, first published in 2004, has been updated.
Prostaglandins, which were first isolated from the prostate gland in 1936, are very rapidly metabolized, or broken down, making measurement in the blood difficult. Researchers at Vanderbilt led by John Oates, M.D., developed methods for measuring levels of prostaglandin metabolites (breakdown products) in the urine using mass spectrometry.
Using this technique, the research team—which by the late 1970s included L. Jackson Roberts, M.D.—identified prostaglandin D2 as a product of the human mast cell and demonstrated its release during allergic asthma.
With colleagues including Garret A. FitzGerald, M.D., now chair of Pharmacology at the University of Pennsylvania, Oates and Roberts showed that low doses of aspirin blocked the production of thromboxane, a prostaglandin made by platelets that causes blood clotting and constriction of blood vessels. Their findings supported the use of low dose aspirin to prevent heart attacks.
In the early 1990s, Vanderbilt researchers led by Ray DuBois, M.D., Ph.D., discovered a link between the COX-2 enzyme and colon cancer. That work helped lead to current tests of COX-2 inhibitors as a potential way to prevent cancer.
In 2004 another group led by the late Jason Morrow, M.D., and David H. Johnson, M.D., director of the Hematology-Oncology division at Vanderbilt, reported that urine levels of a prostaglandin metabolite called PGE-M could predict the effectiveness of a COX-2 inhibitor in patients with non-small cell lung cancer. This suggests, Morrow said in 2004, “that the measurement of these inflammatory ‘mediators’ and their suppression may be useful in the treatment of lung cancer.”
COX enzymes also may play a role in Alzheimer’s disease. In addition to prostaglandins, the COX pathway can lead to the production of highly reactive molecular compounds called levuglandins, which, in turn, can form “adducts,” or irreversible attachments to proteins that may be toxic to nerve cells.
Also in 2004, Oates and his colleagues at Vanderbilt and Johns Hopkins University reported that they found a 12-fold increase in the level of adducts in the brains of patients who had Alzheimer’s disease compared to age-matched control brains.
“These are the first clear data showing that COX products are elevated in the brains of patients with Alzheimer’s disease,” says Oates, Thomas F. Frist Professor of Medicine and professor of Pharmacology.
Vanderbilt currently is participating in a national trial to see if long-term use of COX inhibitors will reduce the incidence of the disease.