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Study Probes How Aspirin Decreases Prostaglandin Levels

Study Probes How Aspirin Decreases Prostaglandin Levels

CHICAGO--Although 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 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."

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