CHICAGO--Although aspirin(Drug information on aspirin)'s role in cancer prevention remains controversial, two recent studies (see "Long -term Aspirin Use Reduces Colon Cancer Risk, Study Shows" and "Regular Aspirin Use May Lower Breast Cancer Risk") show a reduced risk of colorectal and breast cancer with long-term aspirin use.
In neither of these cancers is the exact mechanism(s) of aspirin's preventive effects known. However, work from the University of Chicago Medical Center is providing insights into how aspirin blocks the production of prostaglandin. This research may allow development of new forms of aspirin, possibly with fewer side effects and targeted to specific needs.
A study led by Michael Garavito, PhD, associate professor of biochemistry and molecular biology, and published in Nature/Structural Biology (August, 1995), shows that the aspirin molecule splits into two parts; one part binds to prostaglandin H2 synthase (PGHS-1).
As shown in the illustration on page 1, the salicylic acid(Drug information on salicylic acid) portion of aspirin partially blocks, but does not covalently bond to, the tunnel through which prostaglandin precursors pass to reach the PGHS-1 core for conversion into prostaglandin. The acetyl group covalently bonds to a serine residue of the protein inside the tunnel, where it blocks precursors from reaching the enzyme core.
Four years ago, Dr. Garavito noted, several investigators reported that there are two types of PGHS. PGHS-1 is constantly present in nearly all cells, while PGHS-2 is made only as needed and just by those cells involved in inflammation and immune responses.
None of the currently available NSAIDs discriminates between the two enzyme forms, he said. Instead, current drugs block PGHS-1 in the stomach, leading to GI side effects. PGHS-2 is only partly blocked by aspirin, while PGHS-1 is completely knocked out, he said.
"Just 4 years ago the consensus in the pharmaceutical community was that you couldn't build a better aspirin," Dr. Garavito commented. "But understanding the differences between the two forms of PGHS may allow us to do exactly that."