Cyclooxygenases (COXs) are enzymes that
catalyze the rate-limiting step in the conversion of arachidonic acid to
prostaglandins (Figure 1).[1-3] Prostaglandins, along with other arachidonic
acid products such as thromboxane and 15-hydroxy-eicosatetraenoic acids, belong
to the eicosanoid family of fatty acid molecules, which are known to regulate
many physiologic processes including the inflammatory response and other immune
response modulators,[4-6] ovulation,[7,8] and mitogenesis.[9,10] Paradoxically,
prostaglandins also have been shown to have anti-inflammatory and
immunosuppressive effects. Studies conducted by Gualde and colleagues
demonstrated that prostaglandins inhibited T-cell proliferation in vitro.
Furthermore, prostaglandins can block production of cytokines by T
Synthesis of prostaglandins can be regulated at several
different points in the pathway (Figure 1). In the first step, membrane
phospholipid is converted to arachidonic acid via phospholipase A2.
Subsequently, arachidonic acid is converted to prostaglandin H2 through a
two-step process that involves COX activity to convert arachidonic acid to
prostaglandin G2, followed by a peroxidase reaction that is also catalyzed by
COX to produce prostaglandin H2.[13-15]
The COX enzyme family comprises two known isoforms, COX-1 and
COX-2. Cyclooxygenase-1 is a membrane-bound hemoglycoprotein that is
constitutively expressed in the endoplasmic reticulum of cells in most healthy
tissues and is responsible for local prostaglandin synthesis. In contrast, COX-2
is primarily an inducible COX isoform, although low basal expression is apparent
in some tissues, including brain and kidney.[16,17] There are a number of
structural differences between the COX-1 and COX-2 genes, including differences
in the cis elements within the promoter regions and 3´-untranslated domains.
The structure of the COX-2 gene suggests that it is an
immediate, early gene product that can be switched on rapidly during the
inflammatory response.[18,19] Cyclooxygenase-2 synthesis is inducible by a
variety of stimuli, including proinflammatory cytokines such as interleukin-1
alpha and -1 beta,[20,21] growth factors such as platelet-derived growth
factor[22,23] and epidermal growth factor,[24,25] and lipopolysaccharide and
Most nonsteroidal anti-inflammatory drugs (NSAIDs) that are
commonly administered to patients inhibit both COX-1 and COX-2. However,
inhibition of the inducible isoform, COX-2, is the primary anti-inflammatory
mechanism.[5,28,29] Adverse effects associated with long-term use of NSAIDs,
including gastritis and gastrointestinal ulceration, in addition to reversible
liver and kidney dysfunction, are thought to be primarily due to inhibition of
the constitutively expressed COX-1 isoform.[30-32] In recent years, COX-2-specific
NSAIDs, including celecoxib (Celebrex) and rofecoxib (Vioxx), have become
available. Selective COX-2 inhibitors are advantageous because they may inhibit
pain and the inflammation process in arthritis and oncogenesis. However, they do
not inhibit COX-1 enzymes, the products of the "housekeeping genes"
required for the maintenance of the gastrointestinal tract and for normal renal
and hepatic function.
Rigas and colleagues have demonstrated that colorectal adenomas
and adenocarcinomas express elevated levels of prostaglandins. Furthermore,
accumulation of prostaglandins is associated with increased expression of COX-2,
but not of COX-1. It is also known that prostanoid levels increase during
the progression from adenoma to adenocarcinoma in patients with familial
adenomatous polyposis. In addition, elevated prostanoid expression is
associated with tumor growth, metastatic potential, disease stage,
recurrence, and survival in a broad spectrum of tumor types.
Furthermore, overexpression of COX-2 in humans has been documented in many
cancer types and neoplastic precursor lesions (Table
These data indicate that selective inhibition of COX-2 may be an
effective strategy for preventing colorectal cancer and also may have
application in other cancers. Furthermore, because COX-2 overexpression has been
observed in both preneoplastic lesions and cancers, chemoprevention intervention
is possible at multiple stages of carcinogenesis.
Overexpression of COX-2 may affect a broad range of mechanisms
implicated in the process of carcinogenesis, including angiogenesis, apoptosis,
and immune function. Cancer prevention offers more than one opportunity to
inhibit disease growth. Effective chemopreventive agents may reduce the risk of
cancer by preventing the initiation stage of carcinoma by inducing apoptosis or
DNA repair in cells harboring mutations, or they may act to prevent tumor growth
during the promotion and progression stages of carcinogenesis (Figure
Ongoing clinical trials evaluating COX-nonspecific and COX-2-specific
inhibitors as chemoprevention and therapeutic agents are shown in Table 2[82-84]
and are discussed in the following sections.
Colorectal cancer is a major national health problem. It is the
third leading cause of cancer death in the United States, with 2002 estimates of
148,300 new cases and 56,600 deaths. Some (approximately 15%) individuals
who develop colorectal carcinoma belong to clinically identifiable high-risk
groups due to familial adenomatous polyposis and hereditary nonpolyposis
syndromes. However, the majority of cases of colon carcinoma develop
sporadically in patients who have no known predisposition for the disease.
It is estimated that adherence to the current American Cancer Society and
Gastrointestinal Society colorectal cancer screening guidelines could lower the
annual mortality rate by at least 50% over the next decade.
COX-2: Expression and Preclinical Data
In humans, overexpression of COX-2 has been documented in
colorectal adenomas and cancers, but not in normal-appearing mucosa. For
example, Figure 3 shows immunohistochemical staining for COX-2 in colon adenoma
tissue. Similar overexpression of COX-2 has been documented in a wide range of
cancers and their precursors (Table 1).[40-81] The chemopreventive effects of
COX-2 inhibitors on the development of colorectal cancer are the subject of
intense study, and animal models have been useful in investigating colorectal
A mutation in the adenomatous polyposis coli (APC) gene results
in spontaneous adenoma formation in the small intestine of APC delta716 knockout
mice. Using this rodent model, Oshima and colleagues demonstrated that there is
a cause-effect relationship between COX-2 overexpression and gastrointestinal
tumor incidence. It was shown that suppression of one allele of the COX-2
gene reduced the number of intestinal polyps by 66%, and suppression of both
alleles resulted in a reduction of 86%. Furthermore, treatment of COX-2-expressing
azoxymethane-treated rats with oral celecoxib suppressed formation of colorectal
tumors by > 90%, compared with a suppression of 40% to 65% following
administration of a nonselective COX inhibitor.[91,92]
Reduced Incidence of Colorectal Neoplasia
In prospective cohort studies, long-term administration of
aspirin and other NSAIDs has been associated with a reduction in the incidence
of colorectal adenomas, cancer, and cancer mortality by 40% to 50%.[93-95] An
inverse relationship also has been demonstrated between the use of NSAIDs and
the incidence of colorectal cancer in several case studies.[96,97] Furthermore,
clinical trials showed that the administration of sulindac, a commonly
prescribed NSAID, prescribed to familial adenomatous polyposis patients was
associated with a reduction in the number and size of adenomas.[97-99]
The US Food and Drug Administration recently granted approval of
celecoxib for treatment of familial adenomatous polyposis. Celecoxib, which was
initially approved for the relief of signs and symptoms of osteoarthritis and
rheumatoid arthritis, is highly selective for COX-2 (375-fold greater
selectively compared with COX-1) and has a significantly reduced incidence of
common gastrointestinal toxicities, such as bleeding and upper gastrointestinal
ulcers, associated with NSAIDs.
The pivotal trials of celecoxib for the treatment of familial
adenomatous polyposis enrolled 77 patients who were randomized to receive either
placebo or celecoxib (100 or 400 mg twice daily) for 6 months. The primary
efficacy end point was the percent change in the number of colorectal adenomas
(> 2 mm in size) at 6 months. There was a 4.5% reduction in the
placebo-treated group, a 11.9% reduction in the 100-mg celecoxib-treated group,
and a 28.0% reduction in the 400-mg celecoxib-treated group. The decrease in
incidence between the 400-mg celecoxib twice-daily group and the placebo group
was statistically significant (P = .003). The prevalence of adverse events was similar among the treatment
groups and consisted primarily of diarrhea, dyspepsia, fatigue, upper
respiratory infection, and rash.
The results from the pivotal trial of celecoxib in familial
adenomatous polyposis support further investigation of COX-2 inhibitors for an
overall chemoprevention strategy for colorectal tumors in other populations at
risk, including patients with sporadic adenomatous polyps. As shown in Table
2,[82-84] there are several recently initiated clinical trials of celecoxib in
the prevention or recurrence of colorectal adenomas. Two are being conducted
under the sponsorship of the Division of Cancer Prevention at the National
One clinical trial is being led by Monica Bertagnolli, MD,
Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Boston. This trial
is investigating two dose levels of celecoxib compared with placebo with 1- and
3-year colonoscopy end points. A second phase III clinical trial (using a
factorial design) is studying celecoxib (400 mg/d) vs selenium (in the form of
baker’s yeast) vs the combination of celecoxib/selenium vs a double placebo.
This study is being conducted at the Arizona Cancer Center, Tucson, by Drs.
David Alberts and Peter Lance.
An additional randomized, phase III trial is evaluating the
potential for celecoxib to reduce the incidence of sporadic adenomas. Adenoma
recurrence rates will be evaluated at a 3-year colonoscopy end point. The
results of these trials will not be available for several years, but could
establish COX-2 inhibitors as important components of the management strategy
for colorectal adenomas and the prevention of colon cancer.
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