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Celecoxib, a Cyclooxygenase 2 Inhibitor as a Potential Chemopreventive to UV-Induced Skin Cancer
A Study in the Hairless Mouse Model
Ida F. Orengo, MD;
Janette Gerguis, BSc;
Rhea Phillips, MD;
Adrian Guevara, BSc;
Alan T. Lewis, MD;
Homer S. Black, PhD
Arch Dermatol. 2002;138:751-755.
ABSTRACT
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Objective To assess the preventive effect of a cyclooxygenase 2 inhibitor, celecoxib
(Celebrex; G.D. Searle & Co, Skokie, Ill), in UV-induced skin cancer in
hairless mice.
Design Randomized dose-response study. A total of 75 SKH-HR-1 female hairless
mice, aged 2 months, were randomized into control, low-dose (200 mg twice
daily human dose equivalent), and high-dose (400 mg twice daily human dose
equivalent) celecoxib treatment groups. Animals received 1 J/cm2
daily (5 d/wk) total irradiation. The animals were evaluated weekly for appearance
of tumors, and the data were analyzed with respect to tumor latency period
and tumor multiplicity using statistical software and Wilcoxon rank sum analyses,
respectively. Prostaglandin E2 levels in the blood and skin were
assessed in each group.
Setting Veterans Affairs Medical Center, Research and Dermatology Services.
Intervention Animals received restricted diets containing the Food and Drug Administration–approved
human equivalent doses of 200 mg (low dose) and 400 mg (high dose) of celecoxib
twice daily. Controls received no drug. Tumors were induced in all animals
with an equivalent UV dose.
Main Outcome Measures Animals were evaluated weekly for the appearance of tumors, and data
were analyzed with regard to tumor latency period and tumor multiplicity.
Constitutive prostaglandin E2 levels in blood and epidermis were
assessed in each group.
Results Low doses and high doses of celecoxib significantly lengthened the tumor
latency period (P<.03 and P<.003, respectively) and reduced tumor multiplicity (P<.005 and P<.001, respectively) compared
with controls. There were no differences in the constitutive levels of blood
or epidermal prostaglandin E2 in the low- or high-dose treated
animals compared with controls when analyzed at study termination.
Conclusions Celecoxib is an effective and safe chemopreventive agent in UV carcinogenesis.
The epidemiologic, laboratory, and animal studies of the influence of celecoxib
on cancer incidence and its low association with systemic adverse effects
have led to a potentially new therapeutic approach for the prevention of skin
cancer.
INTRODUCTION
CYCLOOXYGENASE (COX) 1 and COX-2 enzymes are prostaglandin synthases
that catalyze the conversion of arachidonic acid to prostaglandins.1 Prostaglandin E2 (PGE2), in
particular, is a proinflammatory and immune-regulating eicosanoid, the cutaneous
levels of which increase on UV irradiation.2
Indeed, the COX-2 gene has been shown to be highly
inducible by cytokines, growth factors, and tumor promoters3-6
and is overexpressed in many types of human neoplastic tissues, including
esophageal, gastric, colon, breast, and lung tissue.7-16
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin,
and piroxicam inhibit the COX-1 and COX-2 isozymes.17
Recent investigations have indicated that regular NSAID administration reduces
the relative risk of death from colorectal cancer by 40% to 50%.18-21
Similar trials have shown that regular aspirin and ibuprofen ingestion decreased
breast cancer incidence rates by 40% and 50%, respectively.22
This evidence implies a potential chemotherapeutic role for NSAIDs. Concomitant
inhibition of COX-1, however, blocks cytoprotective prostaglandin production
by the gastric mucosa, resulting in gastrointestinal bleeding and ulceration.23-24 A preferred mechanism of action would
be the selective inhibition of the COX-2 isozyme, avoiding the undesirable
gastrointestinal adverse effects of nonselective anti-inflammatories. Celecoxib,
the first specific COX-2 enzyme inhibitor approved for the treatment of arthritis,
may have the chemopreventive properties of anti-inflammatories without the
unwanted gastrointestinal adverse effects of the nonselective NSAIDs.25-26
Basal and squamous cell carcinomas, the 2 most common human skin cancers,
are etiologically related to UV exposure.27-29
UV-induced prostaglandin synthesis and up-regulation of COX-2 may be contributing
factors to the initiation and promotion of skin carcinogenesis.30
Immunohistochemical studies have revealed COX-2 overexpression in cutaneous
squamous cell carcinomas compared with biopsy specimens of skin not exposed
to the sun. In addition, Buckman et al31 demonstrated,
via Western blot analysis, acute UV induction of COX-2 synthesis in human
epidermis. The association of COX-2 up-regulation in inflamed and cancerous
tissues implies the potential of specific COX-2 inhibitors in chemoprevention.
Thus, a controlled study was undertaken to evaluate the influence of celecoxib
(Celebrex; G.D. Searle & Co, Skokie, Ill), a selective COX-2 inhibitor,
on UV-induced carcinogenesis in the hairless mouse.
MATERIALS AND METHODS
ANIMALS AND IRRADIATION
A total of 75 SKH-HR-1 female hairless mice, aged 2 months, were randomized
into 3 groups of 25 animals each: control, low-dose celecoxib treatment, and
high-dose celecoxib treatment. On randomization, each animal was identified
by abdominal tattoo and weighed. Thereafter, body weights were recorded biweekly
and mortality records maintained. After a 2-week run-in period of the respective
treatments, animals were irradiated with Kodacel 401 filtered FS-40 sunlamps
(Westinghouse, Bloomfield, NJ). The Kodacel 401 filters all UV-C radiation,
resulting in a radiance spectrum of 290 to 360 nm32
(approximately 80% in the UV-B region). Animals received 1 J/cm2
total irradiation daily (5 d/wk), as determined by an Eppley circular thermopile.
This level of irradiation is suberythemic, equivalent to about 0.8 of a minimum
erythemal dose. Irradiation continued for 11 weeks when 55 J/cm2
had been delivered, at which point irradiation was halted.
DIET AND DRUG TREATMENT
Isocaloric semisynthetic diets were fed to each group of animals for
a 2-week run-in period and for the duration of the study. The diet has been
described previously33 and is composed of approximately
27% casein, 38% corn starch, 12% corn oil, with the remainder consisting of
mineral and vitamin mixtures and nonnutritive filler. Fat content of 12% was
chosen because this level is roughly equivalent to consumption of 40% of total
calories as fat—a level similar to that consumed by the US population.
This level of fat is also known to promote UV carcinogenesis in the mouse.34 From preliminary feeding trials it was determined
that animals would completely consume a weight of the diet equivalent to 15
kcal/d. Thus, an equivalent weight in grams of the semisynthetic diet was
dispensed daily per animal.
The COX-2 inhibitor celecoxib was administered in the diet. Because
the weight of the diet representing the daily energy requirement was shown
to be completely consumed, drug intake was more uniform when administered
in this manner than by supplying the drug in a diet that would be consumed
ad libitum.
The Celebrex capsules used contained 200 mg of celecoxib. Capsules were
opened and the contents carefully removed and weighed. Contents of each capsule
contained 74% active ingredient; the remainder was nonactive filler. According
to the manufacturer's data sheet,35 50 mg of
drug per kilogram of body weight in female mice provides a total absorption
equivalent to human exposure of 200 mg twice daily. Using the calculated percentage
of active ingredient and drug equivalents, we weighed quantities of capsule
ingredients and thoroughly mixed them with the semisynthetic diet to provide
the human equivalent doses of 200 and 400 mg of celecoxib. Thus, 1.25 mg of
drug per mouse and 2.5 mg of drug per mouse was delivered daily to provide
the equivalent of 200 mg and 400 mg human twice-daily exposure.
TUMOR EVALUATION AND STATISTICS
Animals were evaluated weekly for the appearance of tumors using a 1-mm-diameter
lesion as biological end point. Histologically, tumor types were either papillomas
or squamous cell carcinomas. Tumor data were analyzed using the SAS Life Table
Analysis program (tumor latency, median tumor time)36
and the Wilcoxon rank sum analysis37 for tumor
multiplicity (number of tumors per animal). Comparison of body weights among
all treatment groups was performed using analysis of variance.
PGE2 ANALYSIS
Nine animals from each of the 3 groups (control and 2 treatment groups)
were killed at week 28. Blood was collected by cardiac puncture into tubes
containing ethylenediaminetetraacetic acid and indomethacin. Epidermis was
isolated from nonirradiated abdominal skin by blunt dissection after a brief
treatment at 55°C.38 Triplicate tissue
samples, blood or epidermis, were prepared by pooling tissues from 3 animals
each of the 9 from the respective groups.
Tissue PGE2 levels were determined using the Biotrak prostaglandin
E2 iodine 125 (125I) assay system from Amersham Pharmacia
Biotech (Piscataway, NJ). Briefly, whole blood was centrifuged and plasma
removed. Epidermal samples were homogenized in buffer containing ethylenediaminetetraacetic
acid and indomethacin, centrifuged, and supernatant recovered. Plasma and
epidermal homogenates were, thereafter, handled similarly. To 0.5-mL samples,
0.5 mL of water-ethanol (1:4, vol/vol) and 10 µL of acetic acid was
added. Samples were centrifuged at 2500g for 2 minutes,
and the supernatant loaded onto primed C18 minicolumns. The columns were washed
with 1 volume of water and hexane, respectively, and the samples eluted twice
with 0.75 mL of ethyl acetate. Samples were dried under nitrogen.
The dried samples were reconstituted with 100 µL of phosphate-buffered
gelatin saline (pH 7.0) with 100 µL of methyl oximation reagent added.
Samples were incubated at 60°C for 1 hour to allow completion of the methyl
oximation reaction. Following oximation, the samples were diluted to a final
volume of 500 µL with the phosphate-buffered gelatin saline and assayed.
The assay uses the competition between unlabeled methyl-oximated PGE2 and a fixed quantity of 125I-labeled PGE2 (oximated
derivative for a specific antibody raised against oximated PGE2).
A standard curve was generated from which sample values were determined. Significance
was tested using a 2-tailed t test.
RESULTS
The influence of the COX-2 inhibitor celecoxib on UV carcinogenesis
is shown in Figure 1 and Figure 2. Tumor incidence plots for low (200-mg
equivalent) and high (400-mg equivalent) doses are represented in Figure 1. The effect of celecoxib on tumor
multiplicity is shown in Figure 2.
Both high and low doses significantly lengthened the tumor latency period
(median time of tumor incidence) and reduced tumor multiplicity (number of
tumors per animal) compared with controls. Although the high-dose treatment
resulted in a longer tumor latency period and lower tumor multiplicity than
low-dose treatment, the differences were not statistically significant. The
median tumor time for the control, low-dose, and high-dose groups were 18.8,
22.7, and 24 weeks, respectively. The mean ± SD number of tumors per
animal for these groups were 2.46 ± 2.7, 0.71 ± 1.1, and 0.44
± 0.8, respectively.
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Figure 1. Influence of celecoxib on tumor
incidence. The tumor latency period was significantly longer for both low-dose
(P<.03) and high-dose (P<.003)
celecoxib regimens.
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Figure 2. Influence of celecoxib on tumor
multiplicity. Error bars indicate SD. Tumor multiplicity (number of tumors
per animal) was significantly decreased (P<.05) in both celecoxib
treatment regimens.
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Long-term administration of celecoxib resulted in no statistically significant
differences in mortality. Over the course of the 28-week experiment, 1 animal
died in the low-dose group at week 20, and 2 animals in the control group
died at weeks 24 and 28. No animals died in the high-dose group. A loss in
body weight occurred in all groups on transfer of the animals from commercial
rodent chow to the semisynthetic diet (week 0 to week 2), after which there
was an overall gain (Figure 3).
There were no systemic differences in body weights between control and treatment
groups. Nor were there differences in constitutive levels of blood or epidermal
PGE2 in low-dose (not shown) or high-dose treated animals, compared
with controls, 17 weeks after UV irradiation had been halted (Figure 4). These results indicate that celecoxib has no effect on
the synthesis of normal housekeeping levels of requisite and cytoprotective
prostaglandins.
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Figure 3. Comparison of body weights and
rate of weight gain among animals receiving control and active-treatment diets.
There were no systemic statistically significant differences among groups.
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Figure 4. Influence of celecoxib on constitutive
prostaglandin E2 (PGE2) levels at experiment termination
(week 28). A, Prostaglandin E2 levels in the blood; B, PGE2 levels in the epidermis. No significant differences were observed
in either blood or epidermal constitutive PGE2 levels. Error bars
indicate SD.
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COMMENT
Recognition of the potential role of COX-catalyzed reactions in carcinogenesis
has resulted from convergent evidence, epidemiologic and experimental, that
has shown an inverse relationship between regular NSAID intake and the development
of colon, breast, esophageal, rectal, and lung cancers.18-22
The chemopreventive mechanisms of NSAIDs have been partially elucidated. The
NSAIDs are thought to exert their anticarcinogenic effect by inhibiting the
biosynthesis of certain products of arachidonic acid metabolism, notably prostaglandins.17 Accumulating evidence suggests prostaglandins are
pathogenically linked to carcinogenesis via their influence on cell proliferation,
tumor growth, and immune responsiveness.6-7,39
Experimental work by DuBois et al40 demonstrated
significantly elevated COX-2 messenger RNA and protein levels in chemically
induced colonic tumors. Furthermore, Tsujii and DuBois41
reported that cells that overexpressed the COX-2
gene developed altered adhesion properties and resisted undergoing apoptosis.
The adhesion and apoptotic effects were reversible with NSAID administration.
In addition, Oshima et al8 demonstrated a greater
than 6-fold reduction of intestinal polyp development in COX-2 null mice compared
with COX-2 wild-type mice. Moreover, clinical evidence revealed that the NSAID
sulindac suppressed colonic and rectal polyp formation in humans with familial
adenomatous polyposis.42 These studies suggest
a pivotal role of COX-2 in colonic carcinogenesis.
Similarly, significant COX-2 gene overexpression
in human breast tumor cells has been reported.43
Animal studies have illustrated a significant reduction of tumor burden and
size that paralleled inhibition of genetic expression of COX-2 with ibuprofen.44 An inverse relationship between NSAID administration
and chemically induced breast carcinogenesis in animals has also been shown.45
Likewise, prostaglandin up-regulation and COX-2 expression have been
pathogenically linked to UV carcinogenesis. Evidence of this association comes
from the finding that significantly increased expression of COX-2 occurs in
squamous cell carcinomas and actinic keratoses when compared with nonlesional
skin.31 Western blot analysis revealed UV-irradiation
induction of COX-2 in human epidermis.31
Indeed, it has been shown that COX inhibition by NSAIDs leads to suppression
of skin tumorigenesis in animal studies. Bisset et al46
reported a delay in the appearance of UV-B–induced tumors in hairless
mice treated with topical naprosyn and ibuprofen. In agreement with these
findings, Lowe et al47 demonstrated suppression
of photocarcinogenesis in mice with topical indomethacin. Subsequent studies
have shown that orally administered indomethacin reduces tumor incidence and
tumor burden in UV-irradiated hairless mice.48-49
These studies imply a primary role of COX and prostaglandins as facilitators
of cutaneous carcinogenesis in addition to a chemopreventive role of NSAIDs.
As noted previously, the aforementioned NSAIDs are nonspecific in their
activity and inhibit the cytoprotective actions of the COX-1 isozyme. Adverse
effects of long-term oral NSAID administration are not uncommon and include
gastrointestinal bleeding and ulceration and renal toxic effects. Celecoxib,
a specific COX-2 inhibitor, exhibits a lower adverse-effect profile than other
NSAIDs and could avert many of these problems.
Pentland et al50 demonstrated a significant
difference in tumor burden in UV-irradiated mice treated with celecoxib. In
their study, celecoxib was orally administered 6 weeks after UV irradiation
was completed and at a time when 90% of the animals exhibited at least 1 tumor.
Ten weeks thereafter, the celecoxib-treated mice had only 56% of the tumor
burden exhibited by the control group. These results imply an effect on the
postinitiation events of UV carcinogenesis and suggest that celecoxib has
potential benefit as an intervention therapy to prevent the appearance of
subsequent skin cancers arising from clonal expansion of previously initiated
cells. Fischer et al51 have provided evidence
that celecoxib acts during UV initiation as well. In UV-irradiated mice fed
AIN-76 diets (approximately 12% of total caloric intake as fat) containing
150 or 500 ppm celecoxib, a dose-dependent reduction in tumor yield resulted.
Indomethacin at 4 ppm was as effective as 500 ppm celecoxib in reducing this
tumor parameter. In this respect, it is interesting to note that these investigators
found that neither celecoxib nor indomethacin altered the level of COX-2 expression,
although both significantly reduced the levels of UV-increased PGE2
levels.
In the present study, we used a semisynthetic diet that provided approximately
40% of total intake of calories through fat, not unlike that consumed by the
general US public. This factor is important because endogenous PGE2
levels are influenced by total fat intake,52
and level of fat intake is directly related to UV carcinogenic expression.53 Suberythemic levels (about 0.8 of a mouse minimum
erythema) of UV were administered. The animals' diet was restricted to an
energy intake adequate to meet their requirements for normal growth and development
but that was completely consumed, assuring delivery of the designated drug
levels. The specific COX-2 inhibitor celecoxib, based on published 0- to 24-hour
absorption data for the mouse, was administered at equivalent levels currently
prescribed for humans (ie, 200 and 400 mg twice daily). Celecoxib treatment
significantly increased the UV-induced tumor latency period in a dose-dependent
manner. Tumor multiplicity was significantly reduced, by about the same magnitude,
at both doses. Constitutive levels of PGE2 in blood and nonirradiated
abdominal epidermis were unaffected by the drug at experiment termination,
some 17 weeks after UV irradition was administered. There were no obvious
deleterious effects of long-term drug treatment with respect to growth rate
or mortality.
In toto, celecoxib has been shown to be an effective and safe chemopreventive
agent to UV carcinogenesis in the hairless mouse model at doses equivalent
to those prescribed in humans. These findings warrant further human investigations
to explore this potential. The inherent pharmacologic selectivity of celecoxib
on the COX-2 isozyme and limited effect on COX-1 at human therapeutic levels
should theoretically result in minimal gastrointestinal and renal cytotoxic
effects with long-term administration compared with NSAIDs. The epidemiologic,
laboratory, and animal studies of the influence of celecoxib on carcinogenesis
and its low association with systemic adverse effects have pointed to a potentially
new therapeutic approach for the treatment and prevention of skin cancers.
AUTHOR INFORMATION
Accepted for publication October 9, 2001.
We thank Paul Lenz of Pfizer Pharmaceuticals, Peapack, NJ, for the generous
gift of Celebrex used in these studies.
Corresponding author and reprints: Ida F. Orengo, MD, Department
of Dermatology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030
(e-mail: iorengo{at}bcm.tmc.edu).
From the Department of Dermatology, Baylor College of Medicine (Drs
Orengo, Phillips, Lewis, and Black, Ms Gerguis, and Mr Guevara), and the Photobiology
Laboratory, Veterans Affairs Medical Center (Drs Orengo and Black, and Ms
Gerguis), Houston, Tex.
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