Study Probes How Aspirin Decreases Prostaglandin Levels

CHICAGO--Although aspirin's role in cancer prevention remainscontroversial, two recent studies (see "Long -term AspirinUse Reduces Colon Cancer Risk, Study Shows" and "RegularAspirin Use May Lower Breast Cancer Risk") show a reducedrisk of colorectal and breast cancer with long-term aspirin use.

In neither of these cancers is the exact mechanism(s) of aspirin'spreventive effects known. However, work from the University ofChicago Medical Center is providing insights into how aspirinblocks the production of prostaglandin. This research may allowdevelopment of new forms of aspirin, possibly with fewer sideeffects and targeted to specific needs.

A study led by Michael Garavito, PhD, associate professor of biochemistryand molecular biology, and published in Nature/Structural Biology(August, 1995), shows that the aspirin molecule splits into twoparts; one part binds to prostaglandin H2 synthase (PGHS-1).

As shown in the illustration on page 1, the salicylic acid portionof aspirin partially blocks, but does not covalently bond to,the tunnel through which prostaglandin precursors pass to reachthe PGHS-1 core for conversion into prostaglandin. The acetylgroup covalently bonds to a serine residue of the protein insidethe tunnel, where it blocks precursors from reaching the enzymecore.

Four years ago, Dr. Garavito noted, several investigators reportedthat there are two types of PGHS. PGHS-1 is constantly presentin nearly all cells, while PGHS-2 is made only as needed and justby those cells involved in inflammation and immune responses.

None of the currently available NSAIDs discriminates between thetwo enzyme forms, he said. Instead, current drugs block PGHS-1in the stomach, leading to GI side effects. PGHS-2 is only partlyblocked by aspirin, while PGHS-1 is completely knocked out, hesaid.

"Just 4 years ago the consensus in the pharmaceutical communitywas that you couldn't build a better aspirin," Dr. Garavitocommented. "But understanding the differences between thetwo forms of PGHS may allow us to do exactly that."

He said that drug developers are most interested in targetingPGHS-2 to develop better anti-inflammatory agents, and his laboratoryis attempting to grow crystals of that form of the enzyme largeenough to x-ray, as they did with PGHS-1. He noted that aspirin'sbeneficial effects in preventing vascular disease and heart attacksare thought to be a PGHS-1 phenomenon, and improved antiplateletdrugs may derive directly from this research into the PGHS-1 mechanism.