Looking at an alternative to aspirin.

First synthesized 100 years ago, aspirin is a mainstay of the well-stocked medicine cabinet. A new compound, created by researchers at Vanderbilt University School of Medicine in Nashville, Tenn., and tested at Searle in Saint Louis, Mo., may someday provide the benefits of aspirin while avoiding the drug's unpleasant side effects.

Most people know aspirin to be a fever reducer and pain reliever, but scientists have discovered recently that it combats other conditions too. For example, aspirin cuts the risk of heart disease and of colon and breast cancers, says Charles N. Serhan of Harvard Medical School and Brigham and Women's Hospital in Boston (SN: 6/14/97, p. 374). It acts by inactivating an enzyme called cyclooxygenase-2 (COX-2), which plays a role in inflammation.

The drawback, however, is that aspirin also inactivates cyclooxygenase-1 (COX-1), a related enzyme that produces prostaglandins, substances necessary for normal tissue function. Therefore, people who take aspirin regularly for long periods of time often develop stomach ulcers or kidney disturbances.

The Vanderbilt team's compound, an acetoxyphenyl alkylsulfide known as APHS, skirts these problems by selectively targeting COX-2, with which it reacts 15 times more readily than with COX-1. Aspirin, in contrast, reacts with COX-1 up to 100 times more readily than with COX-2.

Several aspirinlike compounds, including celecoxib, manufactured by Searle, are already being tested on people. Unlike those drugs, APHS causes irreversible changes in COX-2, permanently knocking out the enzyme. Irreversibility is good, says Serhan, because the action of the compound could be long-lasting, thus reducing the dosage needed.

Lawrence J. Marnett and his colleagues at Vanderbilt synthesized a series of aspirinlike molecules and found APHS to be 60 times more potent than aspirin in reacting with COX-2. The compound effectively blocked the action of the enzyme in both inflammatory cells grown in the lab and in rats. APHS also hindered the growth of colon cancer cells in culture.

To determine how APHS works, the researchers created mutant COX-2 enzymes and measured the compound's ability to block their action. APHS appears to inactivate COX-2 in a different way than other inhibitors do, they report in the May 22 Science.

After a century of aspirin use, "its beneficial aspects are still being appreciated," says Serhan. Considering that "14 billion aspirin tablets are consumed each year, more selective inhibitors could have a huge impact on major health concerns," he adds.