Current Pharmaceutical Design, 2003, 9, 2177-2190 2177

Cyclooxygenase-2 Biology

Joan Clària*

DNA Unit, Institut d´Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de
Barcelona, Barcelona 08036, Spain

Abstract: In mammalian cells, eicosanoid biosynthesis is usually initiated by the activation of phospholipase A 2
and the release of arachidonic acid from membrane phospholipids in response to the interaction of a stimulus with a
receptor on the cell surface. Arachidonic acid is subsequently transformed by the enzyme cyclooxygenase (COX) to
prostaglandins (PGs) and thromboxane (TX). The COX pathway is of particular clinical relevance because it is the
major target for non-steroidal anti-inflammatory drugs, which are commonly used for relieving inflammation, pain
and fever. In 1991, it was disclosed that COX exists in two distinct isozymes (COX-1 and COX-2), one of which,
COX-2, is primarily responsible for inflammation but apparently not for gastrointestinal integrity or platelet
aggregation. For this reason, in recent years, novel compounds that are selective for this isozyme, the so-called
selective COX-2 inhibitors or COXIBs, which retain anti-inflammatory activity but minimize the risk of
gastrointestinal toxicity and bleeding, have been developed. This review article provides an overview and an
update on the progress achieved in the area of COX-2 and PG biosynthesis and describes the role of COX-2 in health
and disease. It also discusses some unresolved issues related to the use of selective COX-2 inhibitors as a safe and
promising therapeutic option not only for the treatment of inflammatory states but also for cancer.
Key Words: Eicosanoids, prostaglandins, cyclooxygenase-2, non-steroidal anti-inflammatory drugs, cyclooxygenase-2
inhibitors, gastrointestinal tract.

PROSTAGLANDINS aggregatory and vasoconstrictor molecule, thromboxane (TX)

The history of prostaglandins (PGs) date back in the early
1930´s when Goldblatt and Von Euler who independently
discovered a fatty acid in human seminal fluid with potent
vasoactive properties in rabbits and guinea pigs [1, 2]. von
Euler named this compound prostaglandin because he
assumed it was originated in the prostate gland (it is now
known to be originated in the seminal vesicles) and suggested
that prostaglandins played a role in sperm transport [2].
Thirty years later, Bergstrom and Samuelsson established the
structure of the first two PGs which were termed PGE and
PGF because of their respective partitions into ether and
phosphate buffer (fosfat in Swedish) and demonstrated that
they were produced from the essential fatty acid arachidonic
acid [3]. Today the nomenclature of PGs describes ten
specific molecular groups, designated by the letters A
through J, that are unique by their variation in the functional
groups attached to positions 9 and 11 of the cyclopentane
ring [4]. Each group of PGs consists of three series design-
ated by the subscript numbers 1, 2 and 3, depending on the
substrate originated: di-homo-γ -linoleic acid, arachidonic
acid, and eicosapentaenoic acid, respectively. Among the
PGs, the most widely distributed and best characterized are
those derived from arachidonic acid (i.e., PGE2, PGD 2, PGI 2
and PGF 2α). For PGF, the additional subscript α or β
denotes the spatial configuration of the carbon 9 hydroxyl
group. Special mention should be given to the platelet pro-
*Address correspondence to this author at the DNA Unit, Hospital Clínic,
Villarroel 170, Barcelona 08036, Spain; Tel: 34-93-2275400 ext. 2814;
Fax: 34-93-2275454; E-mail: jclaria@clinic.ub.es
A2, whose structure and biosynthesis was elucidated soon
after the discovery of PGs [4].
PROSTAGLANDIN BIOSYNTHESIS
In 1971, Vane [5], Ferreira et al. [6] and Smith et al. [7]
published their seminal observations proposing that the
ability of aspirin-like drugs to suppress inflammation rests
primarily on their ability to inhibit the production of PGs.
This work fostered further research with focus on the
elucidation of the pathway leading to the biosynthesis of
PGs in animal cells, which concluded that the synthesis of
PGs from arachidonic acid is initiated by the enzyme
cyclooxygenase (COX). Although in human cells there are at
least two different COX isozymes designated COX-1 and
COX-2 (as discussed below a third COX isoform termed
COX-3 has recently been identified), the basic catalytic
activities of these isozymes are similar enough to treat them
as if they were biochemically identical. Accordingly, the
biochemistry of these COX isozymes is herewith discussed
as one. Moreover, although other names for COX are PG
endoperoxide synthase, PG G/H synthase and PGH synthase,
in this review article this enzyme is referred to as COX.
COX is a membrane-bound byfunctional enzyme that
catalyzes the first two committed steps in the pathway
leading to the formation of PGs and TX, namely
cyclooxygenation and peroxidation. In the first step, COX
cyclizes and adds two molecules of O2 to arachidonic acid to
form the cyclic hydroperoxide PGG2. Subsequently, COX
reduces PGG2 to PGH 2 [8, 9]. PGH 2 is a highly unstable
endoperoxide, which functions as an intermediate substrate

1381-6128/03 $41.00+.00 © 2003 Bentham Science Publishers Ltd.

2178 Current Pharmaceutical Design, 2003, Vol. 9, No. 27
for the biosynthesis, by specific synthases and isomerases, of
PGs of the E2, F 2 and D2 series and also of PGI2
(prostacyclin) and TXA2 [4]. Interestingly, the coupling of
PGH2 synthesis to its transformation to PGs and TX by
downstream enzymes is intricately orchestrated in a cell-
specific fashion. That is, any given prostanoid-forming cell
tends to form only one of these compounds as its major
product. Thus, for example, in brain and mast cells, PGH2 is
converted to PGD2 by cytosolic enzyme PGD synthase.
PGH2 can alternatively be converted to PGF 2α by PGF
synthase, which is mainly expressed in the uterus. Vascular
endothelial cells produce PGI2 or prostacyclin from PGH2 by
means of the PGI or prostacyclin synthase, and platelets
release TXA2 from the same precursor (PGH 2) as the PGs
through the action of the enzyme TX synthase. Both PGI2
and TXA2, have a very short half-life (30 seconds and 3
minutes, respectively) and are rapidly hydrolyzed to the
inactive compounds TXB2 and 6-keto-PGF1α, respectively.
Finally, PGE2 is formed in many cell types by the enzyme
PGE synthase. A schematic representation of these pathways
is shown in Fig. (1). It is important to note that PGE
synthase is also present in an inducible form (mPGE
synthase), which is membrane-bound, glutathione-dependent
and whose expression is induced by proinflammatory
compounds, such as interleukin-1β [10, 11]. The coordinate
induction of multiple enzymes of the prostanoid pathway,
such as COX-2 and mPGE synthase, during the inflam-
matory response is a concept that is currently evolving.
Both cyclooxygenase and peroxidase activities of COX
are associated with a single protein molecule and use a single
heme moiety within the enzyme [9]. However, the active
sites for the cyclooxygenase and peroxidase activities of
COX have been shown to be distinct and independent in
pharmacological and in vitro mutagenesis studies [9]. Hence,
the two active sites for cyclooxygenase and peroxidase
probably overlap [9]. The cyclooxygenase active site is
proposed to be a long hydrophobic channel, which extends
from the membrane binding domain to near the heme group.
This hydrophobic channel has been shown to bind
arachidonate and also other fatty acids as substrates. Thus, in
addition to the 20-carbon arachidonate (20:4 ω 6), COX also
uses di-homo-γ -linolenate (20:3 ω 6), 5,8,11,14,17-eicosa-
pentanoic acid (EPA), γ -linolenic acid, α-linolenic acid and
linolenic acid. EPA is subsequently converted to PGH3
whereas the 18-carbon fatty acids are converted into mono-
hydroxy acids. Although COX-1 and COX-2 oxygenate
arachidonate with almost identical kinetics, in general, COX-
2 is much more efficient with alternative substrates. For
instance, COX-2 utilizes both fatty acids and endocanna-
binoids, including 2-archidonylglycerol and anandamide, as
substrates. COX-2 action on 2-archidonylglycerol and
anandamide generates endocannabinoid-derived prostanoids,
among them PG glycerol esters and ethanolamides [12]. In
addition, aspirin-acetylated COX-2 converts arachidonic acid
to 15R-hydroxyeicosatetraenoic acid (15R-HETE), which is
further transformed into 15-epi-lipoxins [13]. Moreover,
when exposed to aspirin, COX-2-expressing cells enzymati-
cally transform omega-3 docosaexaenoic acid (DHA) to
previously unrecognized compounds, i.e., a novel 17R series
of hydroxy-DHAs [14]. Both 15-epi-lipoxins and hydroxy-
DHAs bear potent anti-inflammatory properties and play a
key role in the resolution of inflammation.
Joan Clària
COX is an integral membrane protein found mainly in
microsomal membranes. Though confocal fluorescence imag-
ing microscopy and histofluorescence staining techniques
reveal that COX-1 and COX-2 are located in the endoplas-
mic reticulum and nuclear envelope, COX-2 is more highly
concentrated in the nuclear envelope [15]. It is unclear why
COX is associated with several different membrane systems
but one possibility may be that PG synthesis at different
subcellular sites is elicited by different stimuli. In any case,
the aspirin acetylation site, the site of trypsin cleavage and
the major antigenic determinants of COX are on the cyto-
plasmic side of the endoplasmic reticulum indicating that
PGH2 is generated intracellularly rather than extracellularly.
Most of the synthases, which further metabolize PGH2 also
appear to be localized on the endoplasmic reticulum.
PROSTAGLANDIN RECEPTORS
Similar to what occurs with the PGH2 downstream
metabolizing enzymes (i.e., PG synthases and isomerases),
prostanoid receptors are also cell and/or tissue specific. There
are at least 9 known PG receptors as well as several of their
splice variants that belong to a subfamily of the G protein-
coupled receptor (GPCR) superfamily of seven transmem-
brane spanning proteins [16]. Four of the receptor subtypes
bind PGE 2 (EP 1-EP4), two bind PGD2 (DP 1 and DP 2) and the
rest are single receptors for PGF2α, PGI 2 and TXA2 (FP, IP
and TP, respectively) [16-18]. IP, DP1, EP2 and EP 4
receptors are coupled with the activation of Gs proteins and
linked to increases in intracellular cAMP, whereas EP1, FP
and TP signal through Gq-mediated increases in intracellular
calcium concentration. Exceptionally, the EP 3 receptor is
coupled to Gi and decreases cAMP formation. Interestingly,
in addition to signaling through G-protein linked receptors,
PGs generated from COX-2 located in the nuclear envelope
may mediate signals preferentially through a nuclear
pathway, whereas COX-1 derived PGs may mediate signals
solely through cell surface receptors [16]. This emphasizes
the importance of COX-2 and nuclear receptors (i.e.,
peroxisome proliferator-activating receptors, PPARs) in cell
growth and survival.
COX ISOZYMES: COX-1, COX-2 AND NOW COX-3
The understanding that NSAIDs block prostanoid
formation via inhibition of COX explained the anti-
inflammatory effects of these drugs. Similarly, prostanoids,
such as PGE2 and prostacyclin, were found to be protective
to the stomach and, therefore, inhibition of their formation
provided an explanation for the gastrointestinal toxicity
associated with prolonged use of NSAIDs (see later in this
review). On the other hand, inhibition of COX in platelets
explained the ability of aspirin to reduce platelet aggregation
and blood clotting. But still a number of questions remained
unanswered; such as why the toxicity of NSAIDs differs in
the gastrointestinal tract when used at similar anti-
inflammatory doses? The answer was provided in the early
1990´s when it was established that there are at least two
COX isozymes present in human cells: COX-1, which is
constitutively expressed; and COX-2, which is inducible
[19-21].
COX-1 and COX-2 are the products of two distinct
genes, which in humans are localized on chromosomes 9 and
Cyclooxygenase-2 Biology Current Pharmaceutical Design, 2003, Vol. 9, No. 27 2179

Phospholipids

COOH

Arachidonic Acid

O COOH
O

COX-1 OOH
PGG2
COX-2

COX-3

O COOH
O

OH
ynth ase PGH2
TX S PGI S
yntha
se
O
COOH
O
O
PGD

OH
TXA2 HO
Syn

OH
e
has

thas

PGI2
ynt

OH
e

COOH
ES

PGF Synthase

O
PG

COOH
HO
HO O
OH
TXB2 HO
HO OH
O COOH 6-Keto-PGF1α
COOH

HO OH O OH
PGE2
PGD2
HO

COOH

HO OH
PGF2α
Fig. (1). Enzymatic pathway of prostaglandin (PG) formation from arachidonic acid. Cyclooxygenase (COX), which is present in three
different isozymes COX-1, 2 and 3, oxygenates arachidonic acid to form PGG 2 which is further reduced to PGH 2. PGH2 is a highly
unstable endoperoxide that is rapidly converted by specific synthases to PGs of the E2, F2 and D2 series and also to PGI2
(prostacyclin) and thromboxane (TX) A2. Both PGI 2 and TXA2 have a very short half-life (30 seconds and 3 minutes, respectively) and
are rapidly hydrolyzed to the inactive compounds 6-keto-PGF1α and TXB2, respectively.

1, respectively [22, 23]. The COX-1 gene is about 22 kb in
length with 11 exons and is transcribed as a 2.8 kb mRNA
[22, 24]. The COX-2 gene is about 8 kb long with 10 exons
and it is transcribed as 4.6, 4.0 and 2.8 kb mRNAs variants
[25-27]. Sequence analysis of the COX-2 5´-flanking region
has revealed several potential transcription regulatory
elements, including a TATA box, a NF-IL-6 motif, two AP-
2 sites, three Sp1 sites, two NF-kB sites a CRE motif and
an E-box [28].
2180 Current Pharmaceutical Design, 2003, Vol. 9, No. 27 Joan Clària

The amino acid sequences of COX-1 and COX-2 from a
single species are about 60% identical. COX-1 is a
glycoprotein that in its native, processed form has 576
amino acids with an apparent molecular mass of 70 kDa [22,
24]. The cDNA for COX-2 encodes a polypeptide that,
before cleavage of the signal sequence, contains 604 amino
acids with an apparent molecular mass of 70 kDa [25, 26].
The main difference is that the COX-1 protein contains a 17
amino acid sequence near its amino terminus that is not
present in COX-2. In contrast, COX-2 contains a 18 amino
acid sequence near its carboxyl terminus that is not present
in COX-1 [22, 24-26]. However, and as already mentioned,
the two COX isoforms catalyze identical reactions and
exhibit the same kinetic constants for the conversion of
arachidonic acid to prostanoids.
The most striking distinctions between COX-1 and
COX-2 are the differential regulation of their expression and
their tissue distribution (Fig. 2). COX-1 is ubiquitous and is
constitutively expressed throughout the gastrointestinal
system, the kidneys, the vascular smooth muscle and
platelets [28]. COX-1 is presumably involved in the
housekeeping functions of PGs, such as the cytoprotective
effects in the gastric mucosa, the integrity of platelet
function and the maintenance of renal perfusion. Conversely,
COX-2 is undetectable in most tissues, but its expression
can be induced by a variety of stimuli related to
inflammatory response. COX-2 is, therefore, commonly
referred to as the inducible COX isoform because, like other
immediate-early genes, it can be rapidly upregulated in
response to growth factors and cytokines [28]. This has led
to the supposition that the inducible COX-2 isoform is
responsible for the synthesis of PGs involved in
inflammatory response, whereas COX-1-derived PGs are
involved in preserving the physiological functions of these
prostanoids. However, this distinction is not entirely
accurate, since COX-1 can be induced or upregulated under
certain conditions and COX-2 has been consistently shown
to be constitutively expressed in organs, such as the brain
and the kidneys (see later in this review).
Although the discovery of COX-2 was a great
advancement in our understanding of COX biology, it did
not appear to explain everything. In particular, the
mechanism of action of acetaminophen remained a mystery.
Hugely popular and with a history almost as venerable as
that of aspirin, this drug exerts antipyretic and analgesic
effects without displaying anti-inflammatory activity.
Moreover, at therapeutic concentrations, acetaminophen only
weakly inhibits COX-1 and COX-2. Willoughby first
suggested that this is because of the presence of another
COX isozyme, COX-3 [29]. In fact, Dan Simmons´s group
has recently demonstrated the existence of a new COX that is
especially sensitive to acetaminophen and related compounds
(Fig. 2) [30]. This novel COX, termed COX-3, is a splice
variant of COX-1 and in human tissues its mRNA is
expressed as an 5.2-kb transcript, which is most abundant in
cerebral cortex and heart [30].

Fig. (2). Proposed separate functions for prostaglandins (PGs) derived from cyclooxygenase (COX)-1, -2 and -3. While COX-1 is
found in most tissues and is believed to participate in physiologic homeostasis in the stomach, kidneys and platelets, COX-2 is
preferentially expressed in cells that mediate inflammation and in the central nervous system. Therefore, inhibition of COX-2 is
supposed to be responsible for the beneficial actions of non-steroidal anti-inflammatory drugs (NSAIDs), whereas inhibition of COX-
1 accounts for the unwanted side-effects of these drugs. A splice variant of COX-1, termed COX-3, that is especially sensitive to
acetaminophen and may explain the antipyretic and analgesic effects of this drug, has been recently identified.
Cyclooxygenase-2 Biology Current Pharmaceutical Design, 2003, Vol. 9, No. 27 2181

INHIBITION OF THE COX PATHWAY: NSAIDS
AND COXIBS
COX is the main pharmacological target for NSAIDs.
The observation that NSAIDs reduce or prevent the
production of PGs by direct inhibition of COX enzymes was
first reported by Vane, Ferreira et al. and Smith et al. in
1971 [5-7]. At present, NSAIDs are among the most widely
prescribed class of pharmaceutical agents worldwide, having
broad clinical utility in treating pain, fever and inflammation
[31, 32]. The most popular NSAID, aspirin, is also sought
as a potentially viable option in the prevention of sporadic
colon cancer and neurodegenerative disorders [33, 34].
Unfortunately and apart from the beneficial anti-
inflammatory, antipyretic and analgesic effects of NSAIDs,
COX inhibition also results in unwanted side effects,
particularly in the gastrointestinal tract [35]. Gastroduodenal
ulceration is the best-characterized serious adverse event of
NSAID therapy and is the consequence of inhibiting PGs,
which are the most important gastric cytoprotective agents
[36]. On the other hand although the incidence of renal side
effects in healthy subjects is not significant, adverse renal
events are frequent in those patients with impaired effective
arterial blood volume in which renal function is critically
dependent on PGs, such as decompensated liver cirrhosis
[37]. Since COX-1-derived PGs are presumably involved in
housekeeping functions, such as gastrointestinal cytoprotec-
tion, and COX-2-derived PGs are implicated in inflammation,
NSAID gastrotoxicity is considered to be the consequence of
the inhibition of both COX-1 and COX-2 isozymes by
traditional NSAIDs (i.e., aspirin, indomethacin, ibuprofen,
meclofenamate, …). That is, at the concentrations required to
inhibit PG biosynthesis at sites of inflammation (COX-2
activity), they also elicit a marked suppression of PG
production in the gastrointestinal and renal systems (COX-1
activity) jeopardizing the integrity of the gastric mucosa and
renal and platelet function.
The discovery of the COX-2 isozyme and the
characterization of its role in inflammation fostered the
development of a new class of compounds that selectively
inhibit COX-2, without affecting the COX-1-dependent PG
biosynthesis necessary for physiological functions [38-41].
This new generation of anti-inflammatory drugs has been
proven in vitro to selectively inhibit COX-2 activity and to be
as efficacious as standard NSAIDs in a number of in vivo
models of inflammation (rat carrageenan-induced foot pad
edema and rat adjuvant-induced arthritis) and hyperalgesia (rat
carrageenan-induced hyperalgesia) [40, 41]. Two COXIBS
(selective COX-2 inhibitors), celecoxib (Celebrex) and
rofecoxib (Vioxx) have been marketed in the past three years,
and in clinical trials have proven to provide significant relief of
the signs and symptoms of osteoarthritis and rheumatoid
arthritis and in alleviating pain following dental extraction,
while reducing the incidence of gastrointestinal ulcers and
erosions seen with standard NSAID therapy [42-47].
Moreover, these eagerly awaited highly selective COX-2
inhibitors are of great interest because they may represent an
alternative therapeutic option for the treatment of inflamma-
tion in diseases, such as in cirrhosis with ascites, in which
renal function is critically dependent on PGs [48, 49]. A
second-generation of selective COX-2 inhibitors (i.e.,
valdecoxib and etoricoxib) with a higher COX-1 to COX-2
selectivity ratio than celecoxib and rofecoxib is currently
under evaluation in patients with osteoarthritis and rheumatoid
arthritis. Furthermore, the analgesic efficacy and tolerability of
parecoxib, an injectable prodrug of valdecoxib, is currently
being tested in postoperative laparotomy and orthopedic knee
surgery patients [50, 51]. A list of currently available
NSAIDs and COXIBs is provided in Table 1.
COX-2 IN HEALTH AND DISEASE
Activation of prostanoid receptors triggers an astonishing
array of biological effects (Table 2). The most important
targets of PGs include the gastrointestinal tract, the

Table 1. Classification of Non-Steroidal Anti-Inflammatory Drugs According to their Selectivity Towards COX-2. Brand
Names are Given in Brackets

Traditional NSAIDs Preferential COX-2 inhibitors Selective COX-2 inhibitors

Aspirin Etodolac ( Lodine) Celecoxib ( Celebrex)

Diclofenac (Arthrotec, Cataflam, Voltaren) Meloxicam ( Mobic) Etoricoxib (Arcoxia)

Flurbiprofen (Ansaid) Nabumetone (6-MNA) (Relafen) Parecoxib (Dynastat)

Ibuprofen (Advil, Motrin, Nuprin, Others) Nimesulide (Mesulid, Nexen) Rofecoxib (Vioxx)

Indomethacin (Indocin, Inacid, Others) Valdecoxib (Bextra)

Ketoprofen (Orudis, Oruvail)

Ketorolac (Acular, Toradol)

Naproxen (Aleve, Naprelan, Naprosyn )

Piroxicam (Feldene)

Sulindac (Clinoril)

Tolmetin (Tolectin)
2182 Current Pharmaceutical Design, 2003, Vol. 9, No. 27
Table 2. Biological Effects of Cyclooxygenase Products
Tissue/Organ Mediators
Female Reproductive Organs PGE2 , PGF2 α
Male Reproductive Organs PGE2 , PGF2 α
Cardiovascular System TXA 2 , PGI2
TXA 2
PGE2 , PGI2
TXA 2 , PGF2 α
PGE2 , PGI2
Respiratory System PGE2
PGF2 α , TXA 2
Renal System PGE2 , PGI2
PGE2 , PGI2
PGE2
Gastrointestinal System PGE2 , PGI2
Immune System PGE2 , PGI2
Central Nervous System PGE2
PGD2
PGE2 , PGI2
cardiovascular system, the central and peripheral nervous
systems, the renal system and the reproductive organs. A
detailed discussion of PG actions and the role of COX-2
under physiologic and pathologic conditions is herewith
provided.
COX-2 and the Gastrointestinal Tract
Gastric Secretion
In human gastric mucosa, PGE 2 and PGF 2α have been
reported as the most abundant COX-derived products, with
low production of PGD 2 and PGI2 [52]. In 1967, initial
observations reported PGE2 to be anti-secretory and anti-
ulcerogenic [53]. Subsequently, it was demonstrated that
intravenous administration of PGE1 or PGE 2 inhibits acid
and pepsin secretion induced by secretagogues, such as
pentagrastin and histamine [54]. Moreover, PGE2 has been
shown to inhibit gastric parietal cells and to increase
bicarbonate secretion, resulting in decreased acidity of gastric
juice [55]. It must be taken into account that these
observations on gastric acid secretion were obtained by
administering PGs at pharmacological doses and that
establishing the role of endogenously produced PGs in
gastric acid secretion has proven to be more challenging. In
this regard, blockade of PG biosynthesis with COX
inhibitors has yielded disparate and non-conclusive results
[56]. Moreover, although studies in experimental models
have shown that animals actively or passively immunized
with PG-protein conjugates develop gastrointestinal tract
erosions and ulcerations primarily in the stomach and
occasionally in the small bowel, in these experiments basal
and stimulated acid secretion did not differ in the treated
versus non-treated animals [57]. Therefore, the role of
endogenous COX-derived products in gastric secretory
physiology still remains controversial.
Joan Clària
Effects
Uterine Contraction, Oxytocic Action
Fertility
Thrombosis, Platelet Aggregation
Vascular Permeability
Arterial Vasodilation
Venous vasoconstriction
Patency of the Fetal Ductus Arteriosus
Bronchodilation
Bronchoconstriction
Regulation Renal Blood Flow and Glomerular Filtration Rate
Renin Release
Inhibition Hydroosmotic Effect of ADH
Cytoprotection
Inhibition T and B lymphocyte activation and proliferation
Fever
Sleep
Pain
Recently, COX-2 has been reported to be induced in
human gastric mucosa infected with Helicobacter pylori [58,
59]. Moreover, the production of PGE2 in gastric mucosa is
increased in patients with gastritis and infection with H.
pylori stimulates synthesis of PGE2 in gastric mucosal cells
in vitro [58, 60]. While H. pylori infection is considered to
increase acid secretion in duodenal ulcer patients, in severe
gastritis, acid secretion is generally decreased and basal
gastrin levels are assumed to be stimulated. In particular,
acid secretion was significantly reduced in an experimental
group of mice with H. pylori infection, an effect that was
restored to the same level as in the control mice following
COX-2 inhibition [61].
Gastrointestinal Motility
Essential to digestion, gastrointestinal motility is a
complex process regulated by both neural and humoral
components. Paracrine modulation of normal intestinal
motility by eicosanoids such as PGs is still a matter of
debate, but pharmacological doses of certain prostanoids
have been shown to alter motility both in vivo and in vitro
[62]. Vascular reactivity studies in isolated intestinal muscle
show that PGE2 induces contraction of longitudinal muscle
and relaxation of circular muscle, whereas PGF 2α induces
contraction of both muscles [63]. Isolated colonic
longitudinal and circular muscle layers respond to PGE2 and
PGF 2α in the same manner as the small intestine, although
the results obtained preclude any generalization. For
example, low doses of PGE2 can induce activity in the distal
colon and be inhibitory in the proximal colon [64]. On the
other hand, in most animal studies, PGs of the E series relax
the lower esophageal sphincter whereas PGF2α constricts it
[55]. In any case, when administered in vivo both PGs
decrease transit time and produce diarrhea through increased
Cyclooxygenase-2 Biology
fluid and electrolyte secretion and/or altered gastrointestinal
motility [65, 66].
Little is known about the roles that COX-1 and COX-2
may play in the regulation of gastrointestinal motility.
Although several studies have shown that the non-selective
NSAIDs indomethacin and aspirin impair intestinal
peristalsis, which is the most relevant clinical motor pattern
of the gut, recent findings suggest that this effect is unrelated
to COX inhibition and have different targets, such as nuclear
factor-κ B and/or peroxisome proliferator-activated receptors
γ [67]. In fact, the selective COX-2 inhibitor NS-398 has
been shown not to affect gastric motility in rats with
gastroduodenal ulcerogenic responses induced by
hypothermic stress [68]. Nevertheless, a role for prostanoids
derived from COX-2 in postoperative bowel motility has
been proposed. In this regard, selective inhibition of COX-2
significantly increases postoperative small bowel transit in
experimental rodent models of postoperative ileus [69, 70].
Gastrointestinal Inflammation
Eicosanoids along with many other soluble factors, such
as cytokines, reactive oxygen species, bacterial products and
lipid mediators, play a critical role in gastrointestinal
inflammation. Several eicosanoids, including products from
COX (PGE2 and TXB 2) and lipoxygenase (leukotriene (LT)
B 4 and HETEs), are increased in inflamed tissues compared
with normal mucosa [71]. A positive correlation exists
between the increase in these eicosanoids and the activity of
the disease, returning the levels during remission to values
similar to those from normal colorectal mucosa [55]. An
increasing body of evidence, especially in animal models of
inflammatory bowel disease (IBD), indicate that PGs
counteract the pro-inflammatory activity of LTB4. Indeed,
the administration of NSAIDs to either patients or animal
models with IBD does not have a salutary effect but rather is
associated with flare-ups and colitis [72, 73]. This
phenomenon is interpreted as NSAIDs suppressing PGE2
formation thus allowing LTB4 synthesis to proceed toward
pro-inflammation.
In experiments using animal models of inflammation,
such as carrageenan injection into the footpad and the murine
air pouch model, COX-2 expression and activity is markedly
upregulated [38, 74]. In these experimental models of acute
inflammation, selective COX-2 inhibition by inhibiting
edema at the inflammatory site and being analgesic is
beneficial [38, 74, 75]. Therefore, because there is increased
expression of COX-2 in both animal models of colitis and in
human IBD [76, 77], in theory, selective COX-2 inhibition
would also likely be beneficial in this disease. Although
preliminary results suggest that COX-2 inhibitors may be
safe and beneficial in most patients with IBD [78], other
investigators do not agree because they have enough evidence
to support that PGs derived from COX-2 are important in
promoting the healing of mucosal injury, in protecting
against bacterial invasion, and in down-regulating the
mucosal immune system [79]. Indeed, in experimental
models, suppression of COX-2 in a setting of
gastrointestinal inflammation and ulceration has been shown
to result in the impairment of healing and exacerbation on
inflammation-mediated injury [76, 79]. In humans, clear
cases of exacerbation of IBD have been reported with the use
Current Pharmaceutical Design, 2003, Vol. 9, No. 27 2183
of a selective COX-2 inhibitor [80]. Therefore, the use of
COX-2 selective inhibitors in patients with IBD should be
viewed with the same caution as the use of traditional
NSAIDs.
COX-2 and Colon Cancer
The most solid, unequivocal and well-established role of
COX-2 in the gastrointestinal system is its participation in
colon cancer [81-84].
Early observations in this field were obtained in studies
comparing the levels of PGs in colon tumors with those of
normal colon tissue. The concentration of PGs, in particular
of PGE 2, was found increased in human colorectal cancer
tissue when compared with normal colonic mucosa [85-87].
Similar findings were reported in experimental models of
colonic carcinogenesis [88]. These early investigations also
established which PG series is involved in colon cancer.
Rigas et al. compared the levels of different PGs in colon
tumors with those of normal colon tissue and found that
PGE2 was elevated about two-fold in the cancer samples [86].
In contrast, no significant changes were found in the levels
of PGF 2α and TXA 2, and, even, PGI2 was reduced about
three-fold in tumors [86]. Therefore, because both human and
experimental colonic tumors produce increased amounts of
this particular PG, PGE2 appears to be the eicosanoid
involved in colon carcinogenesis.
Since PGE2 levels are increased in tumors, COX is
suspected to play a key role in the progression of colon
cancer. The relative levels of COX-1 and COX-2 expression
in colorectal cancers were evaluated by a number of
independent laboratories. All the investigations reported
increased expression of COX-2, but not COX-1, in colorectal
carcinomas [89-91]. Published reports indicate that roughly
85% of adenocarcinomas exhibit a two- to fifty-fold increase
in COX-2 expression at both mRNA and protein levels
compared with matched, macroscopically normal, colonic
mucosa from the same patient [89-92]. Both carcinogen-
induced (azoxymethane-induced colonic tumors in rats) and
genetic (Min mice with multiple intestinal neoplasia) animal
models of colon cancer have confirmed the existence of an
increased expression of COX-2 in tumors [92-94].
Nevertheless, although COX-2 is differentially expressed in
various regions of the colon in human colorectal cancer, with
the COX-2 protein being greatly over-expressed in tumors
located in the rectum [89-92], at present its cellular origin is
still debated. Cancer cells, nontransformed epithelial cells,
stromal cells, vascular endothelial cells and inflammatory
infiltrates are constituents of colon tissue and all of these cell
types are reported to have elevated levels of COX-2
compared with the normal colon tissues [95]. On the
contrary, subsequent studies have demonstrated that the
increased expression of COX-2 in colon cancer originates
mainly from the interstitial cells (i.e., macrophages), whereas
little COX-2 expression is found in epithelial cancer cells
[96, 97].
Several mechanisms have been suggested for the
enhanced COX-2 gene expression in colon cancer, including
mutations of APC and ras, activation of EGF receptor and
IGF-I receptor pathways and heregulin/HER-2 receptor
pathway, direct induction by the Epstein-Barr virus
oncoprotein and latent membrane protein 1 [98-100]. For
2184 Current Pharmaceutical Design, 2003, Vol. 9, No. 27
instance, Oshima et al. assessed the development of
intestinal adenomas in APC∆ 716 knockout mice (a model in
which a targeted truncation deletion in the tumor suppressor
gene APC causes intestinal polyposis) in a wild type and
homozygous null COX-2 genetic background. The number
and size of polyps were dramatically reduced (six to eight-
fold) in the COX-2 null mice compared with COX-2 wild-
type mice [101].
In vitro, the functional consequences of COX-2 over-
expression have been analyzed in the rat intestinal cell line
(RIE cells), the gastrocolonic cell lines HT-29 and HCA-7
and in the human colon cell line Caco-2 transfected with
COX-2. Overall, these experiments have revealed that cells
over-expressing COX-2 undergo phenotypic changes that
could enhance their tumorigenic potential, such as exhibition
of an increased adhesion to extracellular matrix proteins and
resistance to apoptosis [102, 103]. The proliferative activity
of COX-2 is believed to be primarily mediated by PGs.
Along these lines, the human gastrocolonic cancer cell line,
HT-29, shows increased proliferation in the presence of PGs
in the culture medium [104]. Moreover, in vivo, colonocyte
proliferation is significantly stimulated by the injection of
the stable derivative of PGE2, dimethyl PGE 2, into normal
mice [104]. A conclusive proof of the role of COX-2 in cell
growth is provided by the use of selective COX-2 inhibitors.
The effects of the highly selective COX-2 inhibitor, SC-
58125, was tested in two different cell lines, only one of
which had a high level of COX-2 expression and activity. It
was observed that SC-58125 decreased cell growth only in
the COX-2 expressing cell line [105].
In vivo, in human and experimental animals, a body of
evidence support the concept that inhibition of COX, and, in
particular COX-2, protects against colon cancer.
Epidemiological studies have demonstrated the association
between regular long-term consumption of NSAIDs, in
particular aspirin, and reduced incidence of colon cancer [33,
106-108]. Aspirin and sulindac have also been shown to
reduce the number and size of its nonmalignant precursor,
the adenomatous colonic polyp, in patients with familial
adenomatous polyposis (FAP) [109, 110]. Moreover, a
recent paper provides evidence of a protective association
between aspirin and NSAIDs and esophageal cancer [111].
These epidemiological data are considered robust, because
separate studies differing in locale, design and population
have consistently yielded similar results. Parallel studies in
animal models of colon carcinogenesis have also proven that
aspirin, as well as other traditional NSAIDs, such as
piroxicam, indomethacin, sulindac, ibuprofen and
ketoprofen, inhibit chemically-induced colon cancer in rats
and mice [33]. The mechanism by which NSAIDs reduce the
risk of cancer is likely related to the inhibition of COX-2. In
fact, a randomized clinical trial has shown that the selective
COX-2 inhibitor, celecoxib, effectively inhibits the growth
of adenomatous polyps and causes regression of existing
polyps in patients with hereditary FAP [112]. Studies in
rodents have also demonstrated that selective
pharmacological inhibition of COX-2 activity prevents
chemically-induced carcinogenesis and intestinal polyp
formation in an experimental model of FAP [113-115]. In
Min mice and rats exposed to chemical carcinogens, selective
COX-2 inhibitors induce apoptosis as well as stimulate
Joan Clària
apoptosis and suppress growth in many carcinomas,
including cultured human cancers of the stomach, esophagus,
tongue, brain, lung and pancreas [116].
Recent studies indicate that angiogenesis, which is the
development of new blood vessels and an essential step in
tumor growth, requires COX-2 [84]. In fact, COX-2
overexpressing cells produce large amounts of vascular
endothelial growth factor (VEGF), a key proangiogenic
factor, which stimulates both endothelial migration and in
vitro angiogenesis [102]. These effects may be blocked by
selective COX-2 inhibitors, highlighting the potential
application of these compounds in blocking developing
tumors [113]. On the other hand, mice lacking the COX-2
gene have deficient VEGF expression, reduced tumor
angiogenesis and decreased tumor growth [117]. Moreover,
selective inhibition of COX-2, but not COX-1, suppresses
the growth of corneal capillary blood vessels in rats exposed
to basic fibroblast growth factor and inhibits the growth of
several human tumors implanted in mice [117, 118]. Taken
together, these results support the notion of the benefit of
selective COX-2 inhibition as an anti-angiogenic therapy.
In addition to the well-documented implication of COX-
2 in colon cancer, several investigations have recently
examined its potential role in other epithelial cancers. These
studies have provided strong evidence that COX-2 may also
be implicated in breast, head and neck, lung, pancreatic and
gastric cancers and suggest that the beneficial effects of
COX-2 inhibitors may extend to these other cancers [119-
122]. Indeed, celecoxib consistently and dose-dependently
inhibits tumor growth and the number of lung metastasis in
the syngenic Lewis lung carcinoma model [116].
Interestingly, in animal studies, celecoxib has been shown to
potentiate the antitumor activity of conventional
chemotherapy and radiation [123, 124].
COX-2 and the Kidney
PGs play multiple roles in the adult kidney. PGE 2 and
PGI2 are powerful renal vasodilators that modulate intrarenal
vascular tone and influence glomerular hemodynamics and
renal perfusion [125, 126]. Moreover, PGE2 modulates renal
sodium through direct inhibition of sodium reabsorption in
tubular epithelial cells [125, 126]. PGE2 also modulates
renal water homeostasis by antagonizing the hydroosmotic
effect of antidiuretic hormone in the collecting duct [125,
126]. Finally, PGs are involved in the renal responses to
loop diuretics and in the regulation of renin secretion [126,
127]. Since PG synthesis is initiated by COX-1 and COX-2,
and both COX isoforms are constitutively expressed in the
kidneys [128, 129], it was of interest to establish which
COX isoform is involved in the maintenance of renal
function under normal conditions. The distribution of COX-
1 in the renal area differs significantly from that of COX-2.
In this regard, COX-1 is preferentially expressed in the renal
vasculature and in the medullary and papillary collecting
ducts in humans, monkeys, dogs, rabbits and rats, whereas
COX-2 expression is consistently focal, and limited to the
macula densa of the juxtaglomerular apparatus, epithelial
cells of the thick ascending limb and papillary interstitial
cells of rats, rabbits and dogs [128, 129]. In the adult human
kidney, expression of COX-2 protein has been observed in
Cyclooxygenase-2 Biology
endothelial and smooth muscle cells of arteries and veins,
and intra-glomerularly in podocytes, but not in macula densa
cells [130].
At present, it is hypothesized that only PGs derived from
COX-1 are involved in normal renal function. The marketed
selective COX-2 inhibitors, rofecoxib and celecoxib, have
been evaluated in randomized controlled trials in terms of
their effects on renal PGs, renal function and occurrence of
adverse renal events. Most of the studies have reported that
selective COX-2 inhibition does not significantly impair
renal function in healthy subjects [131]. Nevertheless, it is
worthy to note that in healthy elderly patients, a population
more susceptible to renal NSAID-damaging effects, both
celecoxib and rofecoxib induce a reduction in urinary sodium
excretion similar to that of indomethacin and naproxen [132,
133]. Although the role of COX-2-derived PGs in the kidney
is still under debate, the finding that mice lacking the COX-
2 gene develop mild to severe nephropathy during the first
weeks after birth [134, 135], supports the eventuality that
COX-2-derived PGs may play a physiological role in the
kidney other than maintenance of circulatory and excretory
functions.
The incidence of renal side effects secondary to NSAID
treatment is low, and the role of PGs in renal homeostasis is
hardly noticeable in healthy subjects. In contrast,
administration of NSAIDs to patients with unbalanced
effective arterial blood volume represents a major clinical
problem since renal function in these patients is critically
dependent on PGs [37]. In these circumstances, which
include low sodium diet, hemorrhagic hypovolemia and
edematous conditions associated with congestive heart
failure, nephrotic syndrome and decompensated liver
cirrhosis, NSAIDs induce a pronounced impairment in renal
plasma flow, glomerular filtration rate, urine volume and
urinary sodium excretion. Since selective COX-2 inhibitors
have been developed to effectively inhibit COX-2 while
sparing physiologic PG production from COX-1, these novel
compounds could potentially be the anti-inflammatory of
choice in these patients. In this regard, in recent studies in
rats with carbon tetrachloride-induced cirrhosis and ascites, an
experimental model that closely reproduces human liver
disease, selective COX-2 inhibition with celecoxib did not
seriously compromise renal function [48, 49]. Interestingly,
in these animals COX-1 protein expression was found to be
unchanged whereas COX-2 protein levels were consistently
upregulated [49]. Therefore, these results indicate that despite
abundant renal COX-2 protein expression, the maintenance of
renal function in altered effective arterial blood volume
conditions, such as liver cirrhosis is mainly dependent on
COX-1-derived PGs.
COX-2 and the Brain
PGs have long been recognized as mediators of fever.
Fever is produced by PGE 2, acting on temperature-sensing
neurons in the preoptic area [136]. The endogenous fever-
producing PGE2 is thought to originate from COX-2 induced
by lipopolysaccharide or interleukin-1 in endothelial cells
lining the cerebral blood vessels [137]. In fact,
intraperitoneal injection of lipopolysaccharide to rats induces
COX-2 in brain endothelial cells in parallel with the
Current Pharmaceutical Design, 2003, Vol. 9, No. 27 2185
appearance of fever [138]. Moreover, selective inhibitors of
COX-2 are potent antipyretic agents [139].
PGs are also now recognized as mediators of
inflammatory reactions in neural tissue and more recently of
brain function. Constitutive COX-2 immunoreactivity and
COX-2 mRNA expression have been detected in neurons and
specially in the forebrain [140]. The expression of COX-2 in
the brain is particularly high in neonates [141]. Since brains
of neonates have higher levels of cerebral PGs than those of
adults [141], and since these PGs are involved in the
regulation of blood flow in the newborn [142], this
phenomenon suggests that COX-2 is likely to be important
in the modulation of blood flow at this stage of life.
Furthermore, COX-2 is thought to play a key role in the
final stages of development and brain modeling when COX-
2 becomes active in a manner that coincides with the
imprinting of environmental influences [143].
Intense nerve stimulation, leading to seizures, induces
COX-2 mRNA in discrete neurons of the hippocampus,
whereas acute stress raises levels in the cerebral cortex [140,
144]. The actual role of COX-2 and PGs in these sites is not
understood, but associations between COX-2 induction and
neural degeneration after glutamate stimulation, seizures and
spreading depression waves suggest that COX-2 may play
more of a role in the selective loss of neural connections than
in their formation [145]. Finally, current studies show that
COX-2 potentiates brain parenchymal amyloid plaque
formation leading to Alzheimer’s disease, thus supporting a
therapeutic potential for NSAIDs and COXIBs in the
treatment of this neurological disease [146].
COX-2 and the Reproductive Function
PGs are important for inducing uterine contractions
during labor. NSAIDs, such as indomethacin, delay
premature labor by inhibiting the production of PGs [147].
However, the inhibition of PGs with indomethacin led to a
high mortality among infants because of premature closure of
the ductus arteriosus, a circulatory shunt maintained by PGs
that allows the output of the left ventricle to bypass the fetal
lungs [147, 148]. PGs originating from COX-2 may play a
role in the birth process because COX-2 mRNA in the
amnion and placenta increases markedly immediately before
and after the initiation of labor [149]. Theoretically, selective
inhibitors of COX-2 are able to reduce PG synthesis in fetal
membranes and could be useful in delaying premature labor
without the unwanted side effects of traditional NSAIDs.
However, COX-2 also plays a role in ovulation, the
successful rupture of the follicle and in the implantation of
the embryo in the uterine endometrium [150]. Indeed, COX-
2 null mice show multiple failures in reproductive function,
including ovulation, fertilization, implantation and
decidualization [151].
COX-2 and Inflammation and Arthritis
The most important action of PGs is their role in
inflammation [4]. In response to an inflammatory insult, the
release of PGs, and more importantly PGE 2, constitutes a
key event in the development of the three cardinal signs of
inflammation: swelling/redness, pain and fever. Given its
2186 Current Pharmaceutical Design, 2003, Vol. 9, No. 27
potent vasodilatory properties, PGE2 increases tissue blood
flow, which results in the characteristic erythema (redness) of
inflammation [4]. On the other hand, together with other
soluble factors including bradykinin, histamine and
leukotrienes, PGE2 increases vascular permeability
contributing to fluid extravasation and the appearance of
edema (swelling) [4]. PGE2 also sensitizes afferent nerve
fibers acting both at peripheral sensory neurons and at central
sites within the spinal cord and brain to evoke hyperalgesia
(pain) [4]. Finally PGE2 is a potent pyretic mediator
involved in the appearance of fever [136]. Moreover, PGs
also contribute to the amplification of the inflammatory
response by enhancing and prolonging signals produced by
pro-inflammatory agents, such as bradykinin, histamine,
neurokinins and complement.
Although the importance of COX and PGs in
inflammation has been known for years, the inducibility of
COX and PG formation has only fully been appreciated
recently with the uncovering of the properties of COX-2.
COX-2 was originally discovered as a transcript that was
upregulated during inflammation and cellular transformation
[19-21]. Animal models of inflammatory arthritis provided
the first available information regarding expression of COX-
2 in acute and chronic inflammation, indicating that
increased expression of COX-2 is responsible for the
increased PG production seen in inflamed joint tissues [75].
COX-2 induction was observed in both human osteoarthritis-
affected cartilage as well as in synovial tissue taken from
patients with rheumatoid arthritis [152, 153]. The critical
role of COX-2 in inflammation led to the rational design of
the first clinical trials for selective COX-2 inhibitors in
patients with osteoarthritis and rheumatoid arthritis [42-45].
The results of these drug-screening studies are sufficient to
guarantee that COX-2 inhibitors achieve the same anti-
inflammatory efficacy as traditional NSAIDs [42-45].
COX-2 and the Cardiovascular System
The major effects of PGs on the cardiovascular system are
on the smooth muscle cells and platelets where prostacyclin
(PGI2) has opposite biologic properties to those of TXA 2.
Thus, on the vasculature and especially on veins, PGI2
mainly promotes vasorelaxation while TXA2 acts as a
vasoconstrictor [4]. It was classically considered that PGI2
produced by vascular endothelial and smooth muscle cells
was formed via COX-1. However, recent work has
demonstrated that PGI2 in vascular cells is produced by
COX-2 as well as COX-1 [28]. Treatment of volunteers with
a selective COX-2 inhibitor decreased urinary excretion of
PGI2 without affecting TXA2 [132]. These results raised the
possibility of an increased risk of cardiovascular events
associated with COXIBs. However, two major randomized
trials have recently shown that the relative risk of a
cardiovascular event with selective COX-2 inhibitors is
similar to that of traditional NSAIDs [154, 155]. On the
other hand, in platelets, TXA2 induces platelet aggregation
whereas PGI2 strongly inhibits aggregation. It is widely
recognized that platelets express only COX-1. Nevertheless,
in certain stages of megakaryogenesis, COX-2, as well as
COX-1 are detected [156]. The biological significance of this
phenomenon is, at present, unclear.
Joan Clària
ABBREVIATIONS
COX = Cyclooxygenase
COXIBs = Selective COX-2 inhibitors
FAP = Familial adenomatous polyposis
LT = Leukotrienes
NSAIDs = Non-steroidal anti-inflammatory drugs
PGs = Prostaglandins
TX = Thromboxane
VEGF = Vascular endothelial growth factor
REFERENCES
References 157-159 are related articles recently published in
Current Pharmaceutical Design.
[1] Goldblatt MW. A depressor substance in seminal fluid. J Soc
Chem Ind (London) 1993; 52: 1056-1057 .
[2] von Euler US. A depressor substance in the vesicular gland. J
Physiology 1935; 84: 21P.
[3] Bergström S, Danielsson H, Samuelsson B. The enzymatic
formation of prostaglandin E2 from arachidonic acid. Biochim
Biophys Acta 1964; 90: 207-210.
[4] Hecker M, Foegh ML, Ramwell PW. The eicosanoids:
Prostaglandins, Thromboxanes, Leukotrienes and related
compounds. In Basic and Clinical Pharmacology. Katzung, B.G.
Eds; Appleton & Lange, Norwalk, CT, 1995; pp 290-304.
[5] Vane JR. Inhibition of prostaglandin synthesis as a mechanism of
action for aspirin-like drugs. Nat New Biology 1991; 231: 232-
235.
[6] Ferreira SH, Moncada S, Vane JR. Indomethacin and aspirin
abolish prostaglandin release from the spleen. Nat New Biology
1971; 231: 237-239.
[7] Smith JB, Willis AL. Aspirin selectively inhibits prostaglandin
production in human platelets. Nat New Biology 1971; 231: 235-
237.
[8] Ohki S, Ogino N, Yamamoto S, Hayaishi O. Prostaglandin
hydroperoxidase, an integral part of prostaglandin endoperoxide
synthetase from bovine vesicular gland microsomes. J Biol Chem
1979; 254: 829-836.
[9] Smith WL, Song I. The enzymology of prostaglandin
endoperoxide H synthases-1 and -2. Prostaglandins Other Lipid
Mediat 2002; 68-69: 115-28.
[10] Jakobsson PJ, Thoren S, Morgenstern R, Samuelsson B.
Identification of human prostaglandin E synthase: a microsomal,
glutathione-dependent, inducible enzyme, constituting a potential
novel drug target. Proc Natl Acad Sci USA 1999; 96: 7220-7225.
[11] Mancini JA, Blood K, Guay J, Gordon R, Claveau D, Chan CC, et
al. Cloning, expression, and up-regulation of inducible rat
prostaglandin synthase during lipopolysaccharide-induced pyresis
and adjuvant-induced arthritis. J Biol Chem 2001; 276: 4469-4475 .
[12] Kozak KR, Rowlinson SW, Marnett LJ. Oxygenation of the
endocannabinoid, 2-arachidonylglycerol, to glyceryl prostaglandins
by cyclooxygenase-2. J Biol Chem 2000; 275: 3744-33749.
[13] Clària J, Serhan CN. Aspirin triggers previously undescribed
bioactive eicosanoids by human endothelial cell-leukocyte
interactions. Proc Natl Acad Sci USA 1995; 92: 9475-9479.
[14] Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick
G, et al. A family of bioactive products of omega-3 fatty acid
transformation circuits initiated by aspirin treatment that counter
proinflammation signals. J Exp Med 2002; 196: 1025-103.
[15] Morita I, Schindler M, Regier MK, Otto JC, Hori T, DeWitt DL, et
al. Different intracellular locations for prostaglandin
endoperoxide H synthase-1 and -2. J Biol Chem 1995; 270: 10902-
10908.
[16] Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid
biology. Science. 2001; 294 : 1871-1875.
[17] Hirai H, Tanaka K, Yoshie O, Ogawa K, Kenmotsu K, Takamori
Y, et al. Prostaglandin D2 selectively induces chemotaxis in T
Cyclooxygenase-2 Biology
helper type 2 cells, eosinophils, and basophils via seven-
transmembrane receptor CRTH2. J Exp Med 2001; 193: 255-261.
[18] Monneret G, Gravel S, Diamond M, Rokach J, Powell WS.
Prostaglandin D2 is a potent chemoattractant for human
eosinophils that acts via a novel DP receptor. Blood 2001; 98:
1942-1948.
[19] Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR.
TIS10, a phorbol ester tumor promoter-inducible mRNA from
Swiss 3T3 cells, encodes a novel prostaglandin
synthase/cyclooxygenase homologue. J Biol Chem 1991; 266:
12866-12872.
[20] Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL.
Expression of a mitogen-responsive gene encoding prostaglandin
synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA.
1991; 88: 2692-2696.
[21] O'Banion MK, Sadowski HB, Winn V, Young DA. A serum- and
glucocorticoid-regulated 4-kilobase mRNA encodes a of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and
cyclooxygenase-related protein. J Biol Chem 1991; 266: 23261-
23267.
[22] Funk CD, Funk LB, Kennedy ME, Pong AS, Fitzgerald GA.
Human platelet/erythroleukemia cell prostaglandin G/H synthase:
cDNA cloning, expression, and gene chromosomal assignment.
FASEB J. 1991; 5 : 2304-2312.
[23] Yokoyama C, Tanabe T. Cloning of human gene encoding
prostaglandin endoperoxide synthase and primary structure of the
enzyme. Biochem Biophys Res Commun 1989; 165 : 888-8.
[24] Jones DA, Carlton DP, McIntyre TM, Zimmerman GA, Prescott
SM. Molecular cloning of human prostaglandin endoperoxide
synthase type II and demonstration of expression in response to
cytokines. J Biol Chem 1993; 268: 9049-9054.
[25] Tay A, Squire JA, Goldberg H, Skorecki K. Assignment of the
human prostaglandin-endoperoxide synthase 2 (PTGS2) gene to
1q25 by fluorescence in situ hybridization. Genomics. 1994; 23:
718-719.
[26] Tanabe T, Tohnai N. Cyclooxygenase isozymes and their gene
structures and expression. Prostaglandins Other Lipid Mediat
2002; 68-69: 95-114.
[27] Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl
Acad Sci USA 1992; 89: 7384-7388.
[28] Morita I. Distinct functions of COX-1 and COX-2. Prostaglandins
Other Lipid Mediat 2002; 68-69: 165-175.
[29] Willoughby DA, Moore AR, Colville-Nash PR. COX-1, COX-2,
and COX-3 and the future treatment of chronic inflammatory
disease. Lancet 2000; 355: 646-648.
[30] Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J,
Elton TS, et al. COX-3, a cyclooxygenase-1 variant inhibited by
acetaminophen and other analgesic/antipyretic drugs: cloning,
structure, and expression. Proc Natl Acad Sci USA 2002; 99:
13926-13931.
[31] Flower RJ, Moncada S, Vane JR, Gillman AG, Goodman LS, Rall
TW, et al. Analgesic-antipyretics and anti-inflammatory agents:
drugs employed in the treatment of gout. In The Pharmacological
Basis of Therapeutics., editors. New York: Macmillan, 1992; pp
674.
[32] Payan DG, Katzung BG. Nonsteroidal anti-inflammatory drugs;
nonopioid analgesics; drugs used in gout. In Basic and Clinical
Pharmacology Katzung, B.G., Ed. Norwalk: Appleton & Lange,
1995; pp 536-559.
[33] Thun MJ, Henley SJ, Patrono C. Nonsteroidal anti-inflammatory
drugs as anticancer agents: mechanistic, pharmacologic, and
clinical issues. J Natl Cancer Inst 2002; 94: 252-266.
[34] Bazan NG, Colangelo V, Lukiw WJ. Prostaglandins and other lipid
mediators in Alzheimer's disease. Prostaglandins Other Lipid
Mediat 2002; 68-69: 197-210.
[35] Lanas A. Cyclo-oxygenase-1/cyclo-oxygenase-2 non selective
non-steroidal anti-inflammatory drugs: epidemiology of
gastrointestinal events. Dig Liver Dis 2001; 33 Suppl 2, S29-34.
[36] Giercksky KE, Huseby G, Rugstad HE. Epidemiology of NSAID-
related gastrointestinal side effects. Scand. J. Gastroenterol. Suppl
1989; 163: 3-8.
[37] Arroyo V, Ginés P, Rimola A, Gaya J. Renal function
abnormalities, prostaglandins, and effects of nonsteroidal anti-
inflammatory drugs in cirrhosis with ascites. An overview with
emphasis on pathogenesis. Am. J. Med. 1986; 81: 104-122.
[38] Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W,
et al. Pharmacological and biochemical demonstration of the role
Current Pharmaceutical Design, 2003, Vol. 9, No. 27 2187
of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad
Sci USA 1994; 91: 12013-1201.
[39] Gilroy DW, Tomlinson A, Willoughby DA. Differential effects of
inhibitors of cyclooxygenase (cyclooxygenase 1 and
cyclooxygenase 2) in acute inflammation. Eur J Pharmacology
1998; 355: 211-217.
[40] Smith CJ, Zhang Y, Koboldt CM, Muhammad J, Zweifel BS,
Shaffer A, et al. Pharmacological analysis of cyclooxygenase-1 in
inflammation. Proc Natl Acad Sci USA 1998; 95: 13313-13318.
[41] Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane
JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather
than cyclo-oxygenase-2 are associated with human
gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci
USA 1999; 967563-756.
[42] Simon LS, Lanza FL, Lipsky PE, Hubbard RC, Talwalker S,
Schwartz BD, et al. Preliminary study of the safety and efficacy
safety in two placebo-controlled trials in osteoarthritis and
rheumatoid arthritis, and studies of gastrointestinal and platelet
effects. Arthritis Rheum. 1998; 41: 1591-1602.
[43] Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE,
Hubbard RC, et al. Anti-inflammatory and upper gastrointestinal
effects of celecoxib in rheumatoid arthritis: a randomized
controlled trial. JAMA 1999; 282: 1921-1928.
[44] Emery P, Zeidler H, Kvien TK, Guslandi M, Naudin R, Stead H, et
al. Celecoxib versus diclofenac in long-term management of
rheumatoid arthritis: randomised double-blind comparison. Lancet
1999 ; 354 : 2106-2111.
[45] Feldman M, McMahon AT. Do cyclooxygenase-2 inhibitors
provide benefits similar to those of traditional nonsteroidal anti-
inflammatory drugs, with less gastrointestinal toxicity? Ann Intern
Med 2000; 132: 134-143.
[46] Malmstrom K, Daniels S, Kotey P, Seidenberg BC, Desjardins PJ.
Comparison of rofecoxib and celecoxib, two cyclooxygenase-2
inhibitors, in postoperative dental pain: a randomized, placebo-
and active-comparator-controlled clinical trial. Clin Ther 1999;
21: 1653-1663.
[47] Lanas A. Clinical experience with cyclooxygenase-2 inhibitors.
Rheumatology 2002; Supp 1, 16-22.
[48] Bosch-Marcé M, Clària J, Titos E, Masferrer JL, Altuna R, Poo
JL, et al. Selective inhibition of cyclooxygenase-2 spares renal
function and prostaglandin synthesis in cirrhotic rats with ascites.
Gastroenterology 1999; 116: 1167-1175.
[49] López-Parra M, Clària J, Planagumà A, Titos E, Masferrer JL,
Koki A, et al. Cyclooxygenase-1 derived prostaglandins are
involved in the maintenance of renal function in rats with cirrhosis
and ascites. Brit J Pharm 2002; 135: 891-900.
[50] Barton SF, Langeland FF, Snabes MC, LeComte D, Kuss ME,
Dhadda SS, et al. Efficacy and safety of intravenous parecoxib
sodium in relieving acute postoperative pain following
gynecologic laparotomy surgery. Anesthesiology 2002; 97: 306-
314.
[51] Rasmussen GL, Steckner K, Hogue C, Torri S, Hubbard RC.
Intravenous parecoxib sodium foracute pain after orthopedic
knee surgery. Am J Orthop 2002; 31: 336-343.
[52] Redfern JS, Lee E, Feldman M. Effect of indomethacin on gastric
mucosal prostaglandins in humans. Correlation with mucosal
damage. Gastroenterology 1987; 92: 969-977.
[53] Robert A, Nezamis JE, Phillips JP. Inhibition of gastric secretion
by prostaglandins. Am J Dig Dis 1967; 12: 1073-1076.
[54] Banerjee AK, Phillips J, Winning WM. E-type prostaglandins and
gastric acid secretion in the rat. Nat New Biol 1972; 238: 177-179.
[55] Eberhart CE, Dubois RN. Eicosanoids and the gastrointestinal
tract. Gastroenterology 1995; 109: 285-301.
[56] Redfern JS, Feldman M. Role of endogenous prostaglandins in
preventing gastrointestinal ulceration: induction of ulcers by
antibodies to prostaglandins. Gastroenterology 1989; 96: 596-605.
[57] Olson GA, Leffler CW, Fletcher AM. Gastroduodenal ulceration
in rabbits producing antibodies to prostaglandins. Prostaglandins
1985; 29: 475-480.
[58] Sawaoka H, Kawano S, Tsuji S, Tsuji M, Sun W, Gunawan ES, et
al. Helicobacter pylori infection induces cyclooxygenase-2
expression in human gastric mucosa. Prostaglandins Leukot Essent
Fatty Acids. 1998; 59: 313-316.
[59] McCarthy CJ, Crofford LJ, Greenson J, Scheiman JM.
Cyclooxygenase-2 expression in gastric antral mucosa before and
2188 Current Pharmaceutical Design, 2003, Vol. 9, No. 27
after eradication of Helicobacter pylori infection. Am J
Gastroenterology 1999; 94: 1218-1223.
[60] Romano M, Ricci V, Memoli A, Tuccillo C, Di Popolo A, Sommi P,
et al. Helicobacter pylori up-regulates cyclooxygenase-2 mRNA
expression and prostaglandin E2 synthesis in MKN 28 gastric
mucosal cells in vitro. J Biol Chem 1998; 273: 28560-28563.
[61] Xiao F, Furuta T, Takashima M, Shirai N, Hanai H. Effects of
cyclooxygenase-2 inhibitor on gastric acid secretion in
Helicobacter pylori-infected C57BL/6 mice. Scand J Measurement of arachidonate and its metabolites extracted from
Gastroenterology 2001; 36: 577-583.
[62] Burakoff R, Percy WH. Studies in vivo and in vitro on effects of
PGE2 on colonic motility in rabbits. Am J Physiology 1992; 262:
G23-G29.
[63] Moore PK. Eicosanoids and gastrointestinal motility. In
Eicosanoids and the gastrointestinal tract. Hillier, K., Ed. M.T.P,
Boston, 1998; pp 145-162.
[64] Bennett A, Eley KG, Stockley HL. The effects of prostaglandins
on guinea-pig isolated intestine and their possible contribution to
muscle activity and tone. Br J Pharmacology 1975; 54: 197-204.
[65] Soffer EE, Launspach J. Effect of misoprostol on postprandial
intestinal motility and orocecal transit time in humans. Dig Dis Sci
1993; 38: 851-855.
[66] Milton-Thompson GJ, Cummings JH, Newman A, Billings JA,
Misiewicz JJ. Colonic and small intestinal response to intravenous
prostaglandin F2 alpha and E2 in man. Gut 1995; 16: 42-46.
[67] Shahbazian A, Schuligoi R, Heinemann A, Peskar BA, Holzer P.
Disturbance of peristalsis in the guinea-pig isolated small intestine
by indomethacin, but not cyclo-oxygenase isoform-selective
inhibitors. Br J Pharmacology 2001; 132: 1299-13097.
[68] Takeuchi K, Suzuki K, Araki H, Mizoguchi H, Sugamoto S,
Umdeda M. Roles of endogenous prostaglandins and nitric oxide
in gastroduodenal ulcerogenic responses induced in rats by
hypothermic stress. J Physiology Paris 1999 ; 93 : 423-431.
[69] Josephs MD, Cheng G, Ksontini R, Moldawer LL, Hocking MP.
Products of cyclooxygenase-2 catalysis regulate postoperative
bowel motility. J Surg Res 1999; 86: 50-54.
[70] Schwarz NT, Kalff JC, Turler A, Engel BM, Watkins SC, Billiar
TR, et al. Prostanoid production via COX-2 as a causative
mechanism of rodent postoperative ileus. Gastroenterology 2001;
121: 1354-1371.
[71] Donowitz M. Arachidonic acid metabolites and their role in
inflammatory bowel disease. An update requiring addition of a
pathway. Gastroenterology 1985; 88: 580-587.
[72] Kaufmann HJ, Taubin HL. Nonsteroidal anti-inflammatory drugs
activate quiescent inflammatory bowel disease. Ann Intern Med
1987; 107: 513-516.
[73] Wallace JL, Keenan CM, Cucala M, Mugridge KG, Parente L.
Mechanisms underlying the protective effects of interleukin 1 in
experimental nonsteroidal anti-inflammatory drug gastropathy.
Gastroenterology 1992; 102: 1176-1185.
[74] Masferrer JL, Zweifel BS, Manning P,T, Hauser SD, Leahy KM,
Smith WG, et al. Selective inhibition of inducible cyclooxygenase
2 in vivo is antiinflammatory and nonulcerogenic. Proc Natl Acad
Sci USA 1994; 91: 3228-3232.
[75] Anderson GD, Hauser SD, McGarity KL Bremer ME, Isakson PC,
Gregory SA. Selective inhibition of cyclooxygenase (COX)-2
reverses inflammation and expression of COX-2 and interleukin 6
in rat adjuvant arthritis. J Clin Invest 1996; 97: 2672-2679.
[76] Reuter BK, Asfaha S, Buret A, Sharkey KA, Wallace JL.
Exacerbation of inflammation-associated colonic injury in rat
through inhibition of cyclooxygenase-2. J Clin Invest 1996; 98 :
2076-2085.
[77] Hendel J, Nielsen OH. Expression of cyclooxygenase-2 mRNA in
active inflammatory bowel disease. Am J Gastroenterology 1997;
92: 1170-1173.
[78] Mahadevan U, Loftus EV Jr, Tremaine WJ, Sandborn WJ. Safety
of selective cyclooxygenase-2 inhibitors in inflammatory bowel
disease. Am J Gastroenterology 2002; 97: 910-914.
[79] Wallace JL. Prostaglandin biology in inflammatory bowel disease.
Gastroenterology Clin North Am 2001; 30: 971-980 .
[80] Bonner GF. Exacerbation of inflammatory bowel disease
associated with use of celecoxib. Am J Gastroenterology 2001;
96: 1306-1308.
[81] Dubois RN. Nonsteroidal anti-inflammatory drug use and sporadic
colorectal adenomas. Gastroenterology 1995; 108: 1310-1314.
Joan Clària
[82] Levy GN. Prostaglandin H synthases, nonsteroidal anti-
inflammatory drugs, and colon cancer. FASEB J 1997; 11: 234-
247.
[83] Kawai N, Tsujii M, Tsuji S. Cyclooxygenases and colon cancer.
Prostaglandins Other Lipid Mediat 2002; 68-69: 187-96 .
[84] Prescott SM. Is cyclooxygenase-2 the alpha and the omega in
cancer? J Clin Invest 2000 ; 105 : 1511-1513.
[85] Bennett A, Civier A, Hensby CN, Melhuish PB, Stamford IF.
human normal and malignant gastrointestinal tissues. Gut 1987; 28:
315-318.
[86] Rigas B, Goldman IS, Levine L. Altered eicosanoid levels in
human colon cancer. J Lab Clin Med 1993; 122: 518-523.
[87] Pugh S, Thomas GA. Patients with adenomatous polyps and
carcinomas have increased colonic mucosal prostaglandin E2.
Gut 1994; 35: 675-678.
[88] Rao CV, Simi B, Wynn TT, Garr K, Reddy BS. Modulating effect
of amount and types of dietary fat on colonic mucosal
phospholipase A2, phosphatidylinositol-specific phospholipase C
activities, and cyclooxygenase metabolite formation during
different stages of colon tumor promotion in male F344 rats.
Cancer Res 1986; 56: 532-537.
[89] Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S,
Dubois RN. Up-regulation of cyclooxygenase 2 gene expression
in human colorectal adenomas and adenocarcinomas.
Gastroenterology 1994; 107; 1183-1188.
[90] Kargman SL, O'Neill GP, Vickers PJ, Evans JF, Mancini JA, Jothy
S. Expression of prostaglandin G/H synthase-1 and -2 protein in
human colon cancer. Cancer Res 1995; 55: 2556-2559.
[91] Kutchera W, Jones DA, Matsunami N, Groden J, McIntyre TM,
Zimmerman GA, et al. Prostaglandin H synthase 2 is expressed
abnormally in human colon cancer: evidence for a transcriptional
effect. Proc Natl Acad Sci USA 1996; 93: 4816-4820.
[92] Gustafson-Svard C, Lilja I, Hallbook O, Sjodahl R.
Cyclooxygenase-1 and cyclooxygenase-2 gene expression in
human colorectal adenocarcinomas and in azoxymethane induced
colonic tumours in rats. Gut 1996; 38: 79-84.
[93] Dubois RN, Radhika A, Reddy BS, Entingh AJ. Increased
cyclooxygenase-2 levels in carcinogen-induced rat colonic
tumors. Gastroenterology 1996; 110: 1259-1262.
[94] Williams CS, Luongo C, Radhika A, Zhang T, Lamps LW, Nanney
LB, et al. Elevated cyclooxygenase-2 levels in Min mouse
adenomas. Gastroenterology 1986; 111: 1134-1140.
[95] Muller-Decker K, Albert C, Lukanov T, Winde G, Marks F,
Furstenberger G. Cellular localization of cyclo-oxygenase
isozymes in Crohn's disease and colorectal cancer. Int J
Colorectal Dis 1999; 14: 212-218.
[96] Shattuck-Brandt RL, Varilek GW, Radhika A, Yang F,
Washington MK, Dubois RN. Cyclooxygenase 2 expression is
increased in the stroma of colon carcinomas from IL-10(-/-)
mice. Gastroenterology 2000; 118: 337-345.
[97] Bamba H, Ota S, Kato A, Adachi A, Itoyama S, Matsuzaki F. High
expression of cyclooxygenase-2 in macrophages of human
colonic adenoma. Int J Cancer 1999; 83: 470-475.
[98] Di Popolo A, Memoli A, Apicella A, Tuccillo C, di Palma A,
Ricchi P, et al. IGF-II/IGF-I receptor pathway up-regulates COX-
2 mRNA expression and PGE2 synthesis in Caco-2 human colon
carcinoma cells. Oncogene 2000; 19: 5517-5524.
[99] Vadlamudi R, Mandal M, Adam L, Steinbach G, Mendelsohn J,
Kumar R. Regulation of cyclooxygenase-2 pathway by HER2
receptor. Oncogene 1999; 18: 305-314.
[100] Murono S, Inoue H, Tanabe T, Joab I, Yoshizaki T, Furukawa M,
et al. Induction of cyclooxygenase-2 by Epstein-Barr virus latent
membrane protein 1 is involved in vascular endothelial growth
factor production in nasopharyngeal carcinoma cells. Proc Natl
Acad. Sci USA 2001; 98: 6905-6910.
[101] Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B,
Kwong E, et al. Suppression of intestinal polyposis in Apc
delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-
2). Cell 1996; 87: 803-809.
[102] Tsujii M, Dubois RN. Alterations in cellular adhesion and
apoptosis in epithelial cells overexpressing prostaglandin
endoperoxide synthase 2. Cell 1995; 83: 493-501.
[103] Dubois RN, Shao J, Tsujii M, Sheng H, Beauchamp RD. G1 delay
in cells overexpressing prostaglandin endoperoxide synthase-2.
Cancer Res 1996; 56: 733-737.
Cyclooxygenase-2 Biology
[104] Qiao L, Kozoni V, Tsioulias GJ, Koutsos MI, Hanif R, Shiff SJ, et
al. Selected eicosanoids increase the proliferation rate of human
colon carcinoma cell lines and mouse colonocytes in vivo.
Biochim Biophys Acta 1995; 1258: 215-2.
[105] Sheng H, Shao J, Kirkland SC, Isakson P, Coffey RJ, Morrow J, et
al. Inhibition of human colon cancer cell growth by selective
inhibition of cyclooxygenase-2. J. Clin. Invest 1997; 99 : 2254-
2259.
[106] Thun MJ, Namboodiri MM, Calle EE, Flanders WD, Heath CWJr.
Aspirin use and risk of fatal cancer. Cancer Res 1993; 53: 1322-
1327.
[107] Giovannucci E, Egan KM, Hunter DJ, Stampfer MJ, Colditz GA,
Willett WC, et al. Aspirin and the risk of colorectal cancer in
women. N Engl J Med 1995; 333: 609-614.
[108] Schreinemachers DM, Everson RB. Aspirin use and lung, colon,
and breast cancer incidence in a prospective study. Epidemiology
1994; 5: 138-146.
[109] Rigau J, Pique JM, Rubio E, Planas R, Tarrech JM, Bordas JM.
Effects of long-term sulindac therapy on colonic polyposis. Ann
Intern Med 1991; 115: 952-954.
[110] Suh O, Mettlin C, Petrelli NJ. Aspirin use, cancer, and polyps of
the large bowel. Cancer 1993; 72: 1171-1177.
[111] Corley DA, Kerlikowske K, Verma R, Buffler P. Protective
association of aspirin/NSAIDs and esophageal cancer: a
systematic review and meta-analysis. Gastroenterology 2003; 124:
47-56.
[112] Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E,
Gordon GB, et al. The effect of celecoxib, a cyclooxygenase-2
inhibitor, in familial adenomatous polyposis. N Engl J Med 2000;
342: 1946-1952.
[113] Kawamori T, Rao CV, Seibert K, Reddy BS. Chemopreventive
activity of celecoxib, a specific cyclooxygenase-2 inhibitor,
against colon carcinogenesis. Cancer Res 1998; 58: 409-412.
[114] Jacoby RF, Seibert K, Cole CE, Kelloff G, Lubet RA. The
cyclooxygenase-2 inhibitor celecoxib is a potent preventive and
therapeutic agent in the min mouse model of adenomatous
polyposis. Cancer Res 2000; 60: 5040-5044.
[115] Oshima M, Murai N, Kargman S, Arguello M, Luk P, Kwong E, et
al. Chemoprevention of intestinal polyposis in the Apcdelta716
mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor.
Cancer Res 2001; 61: 1733-1740.
[116] Koki AT, Khan NK, Woerner BM, Seibert K, Harmon JL,
Dannenberg AJ, et al. Characterization of cyclooxygenase-2
(COX-2) during tumorigenesis in human epithelial cancers:
evidence for potential clinical utility of COX-2 inhibitors in
epithelial cancers. Prostaglandins Leukot Essent Fatty Acids 2002;
66: 13-18.
[117] Williams CS, Tsujii M, Reese J, Dey SK, Dubois RN. Host
cyclooxygenase-2 modulates carcinoma growth. J Clin Invest
2000 ; 105 : 1589-1594.
[118] Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL,
Woerner BM, et al. Antiangiogenic and antitumor activities of
cyclooxygenase-2 inhibitors. Cancer Res 2000; 60: 1306-1311.
[119] Subbaramaiah K, Telang N, Ramonetti, JT, Araki, R, DeVit, B,
Weksler BB, et al. Transcription of cyclooxygenase-2 is
enhanced in transformed mammary epithelial cells. Cancer Res
1996; 56: 4424-4429.
[120] Chan G, Boyle JO, Yang EK, Zhang F, Sacks PG, Shah JP, et al.
Cyclooxygenase-2 expression is up-regulated in squamous cell
carcinoma of the head and neck. Cancer Res 1999; 59: 991-994.
[121] Tucker ON, Dannenberg AJ, Yang EK, Zhang F, Teng L, Daly
JM, et al. Cyclooxygenase-2 expression is up-regulated in human
pancreatic cancer. Cancer Res 1999; 59: 987-990.
[122] Ristimaki A, Honkanen N, Jankala H, Sipponen P, Harkonen M.
Expression of cyclooxygenase-2 in human gastric carcinoma.
Cancer Res 1997; 57: 1276-1280.
[123] Milas L, Kishi K, Hunter N, Mason K, Masferrer JL, Tofilon PJ.
Enhancement of tumor response to gamma-radiation by an
inhibitor of cyclooxygenase-2 enzyme. J. Natl. Cancer Inst 1999;
91: 1501-1504.
[124] Trifan OC, Durham WF, Salazar VS, Horton J, Levine BD,
Zweifel BS, et al. Cyclooxygenase-2 inhibition with celecoxib
enhances antitumor efficacy and reduces diarrhea side effect of
CPT-11. Cancer Res 2002; 62: 5778-5784 .
[125] Schlondorff D, Ardaillou R. Prostaglandins and other arachidonic
acid metabolites in the kidney. Kidney Int 1986; 29: 108-119.
Current Pharmaceutical Design, 2003, Vol. 9, No. 27 2189
[126] Mattix HJ, Badr KF. Arachidonic acid metabolites and the kidney.
In The Kidney, Brenner, B.M. and Rector, F.C.; Eds.; Saunders:
Philadelphia, 2000; pp 756.
[127] Katyama S, Attallah AA, Stahl RA, Bloch DL, Lee JB. Mechanism
of furosemide-induced natriuresis by direct stimulation of renal
prostaglandin E 2 . Am J Physiology 1984; 247: F555-561.
[128] O´Neill GP, Ford-Hutchinson AW. Expression of mRNA for
cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS
Lett 1993; 330: 156-160.
[129] Khan KN, Venturini CM, Bunch RT, Brassard JA, Koki AT,
Morris DL, et al. Interspecies differences in renal localization of
cyclooxygenase isoforms: implications in nonsteroidal
antiinflammatory drug-related nephrotoxicity. Toxicology
Pathology 1998; 26: 612-620.
[130] Kömhoff M, Gröne HJ, Klein T, Seyberth HW, Nüssing RM.
Localization of cyclooxygenase-1 and -2 in adult and fetal human
kidney: implication for renal function. Am J Physiology 1997; 272:
F460-F468.
[131] Whelton A, Maurath CJ, Verburg KM, Geis GS. Renal safety and
tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor. Am
J Ther 2000; 7: 159-17.
[132] Catella-Lawson F, McAdam B, Morrison BW, Kapoor S, Kujubu
D, Antes L, et al. Effects of specific inhibition on yclooxygenase-
2 on sodium balance, hemodynamics and vasoactive eicosanoids.
J Pharm Exp Ther 1999; 289: 735-741.
[133] Whelton A, Schulman G, Wallemark C, Drower EJ, Isakson PC,
Verburg KM, et al. Effects of celecoxib and naproxen on renal
function in the elderly. Arch Intern Med 2000; 160: 1465-1470.
[134] Morham SG, Langenbach R, Loftin CD, Tiano HF, Vouloumanos
N, Jennette JC, et al. Prostaglandin synthase 2 gene disruption
causes severe renal pathology in the mouse. Cell 1995; 83: 473-
482.
[135] Dinchuk JE, Car BD, Focht RJ, Johnston JJ, Jaffee BD, Covington
MB, et al. Renal abnormalities and an altered inflammatory
response in mice lacking cyclooxygenase II. Nature 1995; 378:
406-409.
[136] Milton AS. Antipyretic actions of aspirin. In Aspirin and other
salicylates, Vane, J.R. and Botting, R.M.; Eds; Chapman&Hall,
London, 1992; pp 213-244.
[137] Cao C, Matsumara K, Yamagata K, Watanabe Y. Endotelial cells
of the brain vasculature express cyclooxygenase-2 mRNA in
response to systemic interleukin-1b: a posible site of prostaglandin
synthesis responsible for fever. Brain Res 1996; 733: 263-272.
[138] Cao C, Matsumara K, Yamagata K, Watanabe Y. Involvement of
cyclooxygenase-2 in LPS-induced fever and regulation of its
mRNA by LPS in the rat brain. Am J Physiology 1997; 271:
R1712-R1725.
[139] Futaki N, Yoshikawa K, Hamasaka Y. NS-398, a novel non-
steroidal anti-inflammatory drug with potent analgesic and
antipyretic effects which causes minimal stomach lesions. Gen
Pharmacology 1993; 24: 105-110.
[140] Yamagata K, Andreasson KI, Kaufman WE, Barnes CA.
Expression of a mitogen-inducible cyclooxygenase in brain
neurons: regulation by synaptic activity and glucocorticoids.
Neuron 1993; 11: 371-386 .
[141] Peri KG, Hardy P, Li DY, Varma DR, Chemtob S. Prostaglandin
G/H synthase-2 is a major contributor of brain prostaglandins in
the newborn. J Biol Chem 1995; 270: 24615-20.
[142] Chemtob S, Beharry K, Rex J, Varma DR, Aranda JV. Prostanoids
determine the range of cerebral blood flow autoregulation of
newborn piglets. Stroke 1990; 21: 777-84.
[143] Kaufmann WE, Worley PF, Pegg J, Bremer M, Isakson P.
Cyclooxygenase-2 expression during rat neocortical development
and in Rett syndrome. Brain Dev 1997; 19: 25-34.
[144] Marcheselli VL, Bazan NG. Sustained induction of prostaglandin
endoperoxide synthase-2 by seizures in hippocampus. J Biol Chem
1996; 271: 24794-9.
[145] Miettinen S, Fusco FR, Yrjanheikki J, Keinanen R, Hirvonen T,
Roivainen R, et al. Spreading depression and focal brain ischemia
induce cyclooxygenase-2 in cortical neurons through N-methyl-
D-aspartic acid-recptors and phospholipase A2. Proc Natl Acad
Sci USA 1997; 94: 6500-6505.
[146] Stewart WF, Kawas C, Corrada M, Metter EJ. Risk of
Alzheimer´s disease and duration of NSAID use. Neurology
1997; 48: 626-632.
2190 Current Pharmaceutical Design, 2003, Vol. 9, No. 27 Joan Clària

[147] Zuckerman H, Reiss U, Rubinstein I. Inhibition of human [154] Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R,
premature labor by 94 indomethacin Obstet Gynecology 1974 ; Davis B, et al. Comparison of upper gastrointestinal toxicity of
44 : 787-92. rofecoxib and naproxen in patients with rheumatoid arthritis.
[148] Hammerman C. Patent ductus arteriosus. Clinical relevance of VIGOR Study Group. N Engl J Med 2000; 343: 1520-8, 2.
prostaglandins and prostaglandin inhibitors in PDA [155] Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T,
pathophysiology and treatment. Clin Perinatology 1995; 22: 457- Whelton A, et al. Gastrointestinal toxicity with celecoxib vs
79. nonsteroidal anti-inflammatory drugs for osteoarthritis and
[149] Gibb W, Sun M. Localization of prostaglandin H synthase type 2 rheumatoid arthritis: the CLASS study: A randomized controlled
protein and mRNA in term human fetal membranes and decidua. J trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;
Endocrinology 1996; 150: 97-503. 284: 1247-1255.
[150] Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van [156] Rocca B, Secchiero P, Ciabattoni G, Ranelletti FO, Catani L,
De Putte LB, et al. Cyclooxygenase in biology and disease. Guidotti L, et al. Cyclooxygenase-2 expression is induced during
FASEB J 1998; 12: 1063-1073. human megakaryopoiesis and characterizes newly formed
[151] Lim H, Paria BC, Das SK, Dinchuk JE, Langenbach R, Trzaskos platelets. Proc Natl Acad Sci USA 2002; 99: 7634-7639.
JM, et al. Multiple female reproductive failures in [157] Oshima M, Taketo MM. COX selectivity and animal models for
cyclooxygenase 2-deficient mice. Cell 1997; 91: 197-208. colon cancer. Curr Pharm Design 2002; 8(12): 1021-34.
[152] Amin AR, Attur M, Patel RN, Thakker GD, Marshall PJ, Rediske [158] Rodriguez-Tellez M, Arguelles F, Herrerias JM Jr, Ledro D,
J, et al. Superinduction of cyclooxygenase-2 activity in human Esteban J, Herrerias JM. Antiinflamatory agents less dangerous
osteoarthritis-affected cartilage. Influence of nitric oxide. J Clin for gastrointestinal tract. Curr Pharm Design 2001; 7(10): 951-76.
Invest 1997; 99: 1231-1237. [159] Takeuchi K, Tanaka A, Suzuki K, Mizoguchi H. Gastrointestinal
[153] Kang RY, Freire-Moar J, Sigal E, Chu CQ. Expression of sparing anti-inflammatory drugs--effects on ulcerogenic and
cyclooxygenase-2 in human and an animal model of rheumatoid healing responses. Curr Pharm Design 2001; 7(1): 49-69.
arthritis. Br J Rheumatology 1996; 35: 711-718.
.