NEW YORKThe markedly improved safety profile of selective COX-2
inhibitors over conventional nonsteroidal anti-inflammatory drugs
(NSAIDs) has spurred a number of new studies aimed at demonstrating
their value as preventive agents among populations at high and
moderate risk for a variety of cancers, Andrew J. Dannenberg, MD,
said at a media briefing. Dr. Dannenberg is professor of medicine and
surgery, Weill Medical College of Cornell University.
Investigators at Cornell and Strang Cancer Prevention Center have
initiated a study of more than 2,000 patients worldwide to evaluate
whether COX-2 inhibitors will prevent sporadic colorectal adenomas.
Sporadic colorectal adenomas represent a very important target
for preventing colon cancer, Dr. Dannenberg said.
Were interested in identifying medications that prevent
recurrence of adenomas.
Another trial will evaluate the effectiveness of COX-2 inhibitors in
Barretts esophagus, a premalignancy that predisposes to
esophageal adenocarcinoma. Further studies of the preventive role of
COX-2 inhibitors are planned for bladder cancer and oral leukoplakia.
The therapeutic action of NSAIDs is thought to be due to inhibition
of COX-2, whereas their gastrointestinal toxicity is believed to be
due to inhibition of COX-1. NSAIDs, which inhibit both COX-1 and
COX-2, are responsible for an estimated 100,000 hospitalizations and
as many as 16,500 deaths a year in the United States alone, Dr.
With the development of selective COX-2 inhibitors, we can
expect dramatic improvement in these numbers and hence can begin to
consider using these agents for prevention of cancer, he said.
In the less than 2 years since celecoxib (Celebrex), the first
selective COX-2 inhibitor, was granted FDA approval, this new class
of drugs has revolutionized the treatment of osteoarthritis.
Rofecoxib (Vioxx) was the second selective COX-2 inhibitor to receive
In 1999, the FDA granted approval for the use of celecoxib for the
treatment of familial adenomatous polyposis (FAP). In preapproval
trials, celecoxib reduced overall tumor burden by an average of 31%,
over a 6-month course of treatment, with some FAP patients achieving
as much as an 80% reduction and some as little as 10%.
Theoretical Basis of Trials
Dr. Dannenberg, who is also director of cancer prevention at Weill,
is involved in an initiative with the American Association for Cancer
Research and the FDA to develop guidelines to expedite drug
development for premalignant lesions. At the press briefing, he
outlined the theoretical basis of the new COX-2 inhibitor cancer
Cyclooxygenase (COX) is an enzyme that catalyzes the synthesis of
prostaglandins from arachidonic acid, he said. Prostaglandins have
been implicated in carcinogenesis. In the early 1990s, it was
discovered that there are two isoforms of COX, each occupying a place
on a different chromosome.
COX-1, a constitutive gene, fulfills a homeostatic function in the GI
tract. COX-2, an inducible gene, is an immediate early response gene
that is induced by growth factors, proinflammatory cyto-kines,
carcinogens, oncogenes, and tumor promoters.
COX-2 can convert tobacco procar-cinogens into carcinogens. Further,
high levels of COX-2 promote angiogenesis, feeding tumor blood
supply, and inhibit apoptosis, leading to unregulated cell growth.
COX-2 is overexpressed in at least 85% of colorectal cancers and in
half of all premalignant adenomas, Dr. Dannenberg said. It is also
overexpressed in malignancies of the breast, lung, liver, pancreas,
skin, bladder, cervix, stomach, esophagus, and head and neck.