There already is a strong body of evidence suggesting that long-term,
consistent use of nonsteroidal anti-inflammatory agents (NSAIDs)
reduces the relative risk of colon cancer. Questions recently
have been raised, however, concerning the way in which these drugs
exert their protective effect.
"The concepts regarding the way these drugs work have been
challenged and perhaps are wrong," said Dennis Ahnen, MD,
at the National Conference on Colorectal Cancer, sponsored by
the American Cancer Society.
The anti-inflammatory action of NSAIDs actually may not be critical
to the chemoprevention of colon cancer. Rather, NSAIDs may influence
colon cancer through the induction of apoptosis, or programmed
cell death, said Dr. Ahnen, associate director, Cancer Prevention
and Control, University of Colorado Cancer Center, Denver.
He predicted that breakthroughs in the investigation of colon
cancer chemo-prevention in the next few years will focus on the
mechanism of action of NSAIDs. "We need to know the mechanism
of action at both the biological and the biochemical levels so
we can design better chemopreventive agents," he said.
Studies of the biologic actions of sulindac suggest that the mechanism
of action of NSAIDs may be more complex than previously thought,
David S. Alberts, MD, said at the conference. Sulindac has properties
similar to those of aspirin and has been shown to reduce the number
and size of polyps in individuals with familial adenomatous polyposis.
The agent is metabolized into two principal compounds, said Dr.
Alberts, director, Cancer Prevention and Control, Arizona Cancer
Center, Tucson. One compound is the active drug sulindac sulfide,
which inhibits PGE2, a stable prostaglandin produced in the gastrointestinal
mucosa. The other is sulindac sulfone, an inactive metabolite.
While sulindac sulfone decreased the number of intestinal tumors
in a dose-responsive manner in an animal model, it did not inhibit
PGE2, as would be expected if the drug affected the arachidonic
acid pathway, Dr. Alberts said.
More recent data indicate that sulindac may operate through apoptosis.
"Our research group at the Universities of Colorado and Arizona
has used chromatin condensation, morphological or DNA fragmentation
studies, to show that sulindac and its sulfone metabolite induce
apoptosis, not necrosis, in colon tumor cells," Dr. Alberts
He believes that this is "very likely a common mechanism
through which chemopreventive agents are working. We know this
is the case with anticancer drugs at this point."