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Carcinogenesis |
Division of Nutritional Carcinogenesis and Chemoprevention Program, American Health Foundation, Valhalla, New York 10595 [B. S. R., Y. H., C. V. R.]; Chemoprevention Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892 [R. L., V. S., G. K.]; and Searle Research and Development, St. Louis, Missouri 63137 [S. P., K. S.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The mechanism by which traditional NSAIDs act to reduce the risk of
colon carcinogenesis is not clearly understood. Accumulating evidence
points to inhibition of arachidonic acid metabolism via COX enzymes,
which, in turn, modulates the synthesis of PGs that affect cell
proliferation, tumor growth, and immune responsiveness (12
, 13)
. Two mammalian isozymes encoded by different genes, COX-1
and COX-2, are known to be present in colon tumors of humans and
rodents (13, 14, 15, 16, 17, 18)
and to catalyze the conversion of
arachidonic acid to PGs. We have previously shown increased levels of
COX-2 mRNA and protein in chemically induced colon tumors
(17)
. Intestinal adenomas from
Apcmin and Apc
716 mice
were also found to have elevated COX-2 levels (10
, 18)
.
Several studies have revealed that although both isozymes carry out
essentially the same catalytic reaction, many of the inflammatory,
inducible effects of COX appear to be mediated by COX-2, whereas the
normal physiological functions of COX are carried out by COX-1
(19, 20, 21)
. The expression of COX-1 does not fluctuate due
to stimuli, whereas cytokines, mitogens, growth factors, and tumor
promoters induce COX-2 expression (19, 20, 21)
. Prolonged
administration of traditional NSAIDs also causes unwanted side effects,
such as gastrointestinal bleeding, ulceration, and renal toxicity,
which are manifested mainly by the blocking of COX-1 activity
(13
, 22 , 23)
. A study by Tsujji and DuBois
(24)
indicated that colonic epithelial cells that
overexpress the COX-2 gene develop altered adhesion properties and
resist undergoing apoptosis. This can be reversed by treatment with
NSAIDS, suggesting that overexpression of COX-2 is probably involved in
the development and progression of colonic neoplasms. Such a mechanism
appears to explain, at least in part, both the therapeutic and toxic
effects of traditional NSAIDs in humans. Because most of the NSAIDs
inhibit the activity of both COX-1 and COX-2, which accounts for their
chemopreventive effects as well as their adverse side effects, it is
likely that inhibitors of COX-2, which do not inhibit COX-1 at
therapeutic doses in humans, can serve as effective chemopreventive
agents without causing side effects (23, 24, 25)
. In this
context, it is noteworthy that the development of intestinal adenomas
was strikingly (more than 6-fold) reduced in the COX-2 null mice
compared to their occurrence in COX-2 wild-type mice; this suggests
that COX-2 plays a key role in polyp formation (18)
.
Additional evidence in support of a role for COX-2 comes from studies
showing that administration of the COX-2 inhibitor MF Tricyclic
inhibited the number and size of intestinal tumors in
Apc716 mice, a model in which a targeted
truncation deletion in the tumor suppressor gene APC causes intestinal
polyposis (18)
. We reported earlier that celecoxib, a
COX-2 inhibitor with significant anti-inflammatory and analgesic
properties (26
, 27)
, significantly inhibited colonic
preneoplastic lesions in rats (28)
. We had also observed
that continuous administration of 1500 ppm celecoxib throughout the
initiation and postinitiation phases significantly diminished the
incidence and multiplicity of AOM-induced colonic adenocarcinomas in
F344 rats (29)
.
The studies cited above clearly demonstrate the potential chemopreventive activity of celecoxib against colon carcinogenesis when this COX-2 inhibitor was administered during the initiation and postinitiation stages of carcinogenesis. However, the multistep nature of carcinogenesis provides opportunities for intervention with agents targeted at specific mechanisms involved in the initiation, promotion, and progression stages of cancers. Because there were no studies on the efficacy of celecoxib during the promotion/progression stage, at which point premalignant lesions are known to have developed, it was important to verify whether celecoxib treatment can still be effective long after the carcinogen administration in experimental carcinogenesis. Determining this in model assays is important with regard to the eventual clinical use of celecoxib in secondary colon cancer prevention among patients with colonic polyps. Because no dose-related study on the inhibition of colon carcinogenesis by celecoxib has been reported in any previous publications, we deemed it important to conduct this dose-response assay and to determine the efficacy of different levels of celecoxib to identify the lowest dose with optimum efficacy. Furthermore, we analyzed the steady-state plasma levels of celecoxib in rats after chronic administration of different doses of this agent in the diet.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) was kindly supplied by Searle Research and Development (St. Louis, MO).
Weanling male F344 rats were received from the Charles River Breeding
Laboratories (Kingston, NY). All ingredients of the semipurified diet
were purchased from Dyets Inc. (Bethlehem, PA) and stored at 4°C
before preparation of experimental diets. Celecoxib was added to
modified AIN-76A diet at 500, 1000, or 1500 ppm dose levels for the
dose-response study and at the 1500 ppm level for the tumor
promotion/progression study. The modified AIN-76A diet consisted of
20% casein, 0.3% DL-methionine, 52% corn starch, 13%
dextrose, 5% corn oil, 5% alphacel, 3.5% AIN mineral mixture, 1%
AIN vitamin mixture, and 0.2% choline bitartrate (6)
. All
control diets and the experimental diets containing celecoxib were
prepared weekly in our laboratory and were stored in a cold room.
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). Our studies in AOM-induced colon carcinogenesis indicate that colonic
neoplasms have developed by week 14 after carcinogen administration
(6
, 30) . The highest dose for the dose-response study and
for the promotion/progression protocol was selected on the basis of our
previous assay, which had used 1500 ppm of celecoxib (29)
.
The experimental methods were as described previously (29
, 30)
. A total of 180 male F344 rats were received at weaning,
quarantined for 1 week, and had free access to the AIN-76A diet. After
quarantine, all rats were randomly distributed so that the body weights
in each group were evenly distributed (36 animals for each AOM-treated
group and 6 animals for each saline-treated group). Beginning at 5
weeks of age, the rats in the initiation and postinitiation study had
access to their respective control and experimental diets containing
500, 1000, or 1500 ppm celecoxib, whereas the rats in the assay for the
efficacy of celecoxib in the promotion/progression stage were fed the
control diet at this stage. At 7 weeks of age, the rats scheduled to
receive carcinogen treatment were injected s.c. with a solution of AOM
at a dose rate of 15 mg/kg body weight, once weekly for 2 successive
weeks. Rats intended for vehicle treatment received an equal volume of
normal saline. Starting 14 weeks after the second AOM treatment, the
groups of rats designated for the intervention during the promotion and
progression stage and maintained thus far on the control diet began to
receive the experimental diet supplemented with 1500 ppm celecoxib. All
dietary regimens were continued until termination of the experiment 50
weeks after the second AOM treatment. Body weights were recorded every
week for the first 10 weeks and then every 4–6 weeks. Dying or
moribund rats were killed and necropsied. As scheduled, all rats were
killed by asphyxiation with CO2 and necropsied. At the time
of sacrifice, blood was drawn by cardiac puncture from animals fed the
control and the experimental diets to study the effects of different
levels of celecoxib in the diet on its levels in blood plasma. Blood
plasma was quickly frozen in liquid nitrogen and stored at -80°C
until analysis. All organs were examined grossly for tumors under the
dissection microscope. Colon tumors were noted grossly for their
location, number, and size, and the length, width, and depth of each
tumor were measured with calipers. Estimates of tumor volume were
determined using the formula V = L x W x D x 
/6 where
L is length, W is width, and D is
depth of colon tumor (6)
.
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Analysis of Blood Plasma for Celecoxib.
Plasma samples (0.3 ml) containing celecoxib and an internal standard
were treated with 100 µl of 1.0 N phosphoric acid and
extracted in a cation exchange/hydrophobic mixed mode solid-phase
extraction column (Jones Chromatography, Lakewood, CO) preconditioned
with 2x 1 ml of acetonitrile followed by 2x 1 ml of water. The sample
was eluted from the extraction column with 1.0 ml of 1% ammonium
hydroxide in methanol. The extract was evaporated under nitrogen, and
the sample was taken up in 200 µl of high-performance liquid
chromatography mobile phase acetonitrile:0.01 M sodium
phosphate buffer (pH 9; 50:50, v/v). An aliquot of the sample extract
was injected onto a reverse-phase high-performance liquid
chromatography, C18 NOVA PAKTM column (15 cm x 3.9 mm, 4 m; Waters Associates, Milford, MA) using a
15 x 3.2-mm, 7 m RP-18 New Guard Cartridge
(Brownlee Labs, Inc., Santa Clara, CA). The mobile phase
acetonitrile:0.01 M sodium phosphate buffer (pH 9; 50:50,
v/v) was run at 1.0 ml/min. The analyte was quantified by peak height
ratio to that of the internal standard using a fluorescence detector
with excitation at 240 nm and emission at 380 nm. The analyte was
compared against a standard curve (0.01–10 µg celecoxib/ml) prepared
as described above.
Statistical Analysis.
Body weights, colon tumor incidence (percentage of animals with
tumors), multiplicity (mean number of tumors/animal), and tumor volumes
were determined for the animals fed the control diet and for those
given experimental diets containing celecoxib. Body weights, tumor
multiplicity, and tumor volume were analyzed and compared by Welch’s
t test; tumor incidence was analyzed by Fisher’s exact
probability test.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, the body weights of rats treated with AOM and fed the control diet or
the experimental diets containing different levels of celecoxib were
comparable throughout the study. In saline-treated animals, chronic
administration of various levels of celecoxib did not produce any gross
changes in several organs that would indicate toxicity.
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Efficacy of Various Levels of Celecoxib Administered during
Initiation and Postinitiation Stages.
The results summarized in Table 2
indicate that in rats treated with AOM and fed the control diet, more
than 95% of the colon tumors were adenocarcinomas, and the rest were
adenomas. None of the saline-treated animals fed the control diet or
experimental diets with celecoxib developed colon tumors (data not
shown in the table). Administration of celecoxib at 500, 1000, and 1500
ppm dose levels during the initiation and postinitiation stages
significantly inhibited the incidence of total colon tumors (adenomas
plus adenocarcinomas) and adenocarcinomas (P < 0.01 and P < 0.001; tumor inhibition
ranged from 53–78%) when compared with the incidence in rats fed the
control diet. These results were analyzed by the linear correlation
method, and a correlation coefficient of r = -0.93, which is significant at P < 0.05,
was obtained, indicating a dose-dependent inhibition of colon tumor
incidence with increasing levels of celecoxib in the diet.
Multiplicities of colon adenocarcinomas and total colon tumors were
also significantly suppressed in the rats receiving celecoxib at 500,
1000, or 1500 ppm dose levels (P < 0.001 and
P < 0.0001; 67–84% inhibition). These
results were also analyzed using a linear correlation method for a
dose-dependent effect. This analysis yielded the correlation
coefficient of r = -0.96 for multiplicity of
adenocarcinomas with increasing levels of celecoxib from 0–1500 ppm,
suggesting a dose-related inhibition (P < 0.05). The incidences and multiplicities of adenomas could not be
compared among different groups because of the low yield of this
lesion. Data summarized in Table 3
demonstrate that colon tumor volume was significantly reduced in the
rats that were given celecoxib during the initiation and postinitiation
stages (P < 0.0001).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The results of this study are in agreement with our earlier investigation, which had shown that administration of 1500 ppm celecoxib during the initiation and postinitiation periods profoundly inhibited colon carcinogenesis (29) . This study shows that the suppression of colon carcinogenesis by celecoxib is dose dependent. To our knowledge, this study is the first one to demonstrate a dose-response effect of celecoxib in a preclinical model. It is noteworthy that the difference in the incidence and multiplicity of adenocarcinomas between the lowest (500 ppm) and highest (1500 ppm) doses of celecoxib is limited (55% versus 77% and 69% versus 83% compared to control), suggesting that celecoxib is very effective, even at the lower dose level. The present study also demonstrates for the first time that celecoxib given in the diet during the promotion/progression period is still an effective inhibitor of colon carcinogenesis. This suggests that the administration of celecoxib may retard the growth and/or development of existing neoplastic lesions in the colon. This study extends our earlier findings that NSAIDs such as piroxicam, sulindac, and the naturally occurring antiinflammatory agent curcumin given to rats during the promotion/progression stage inhibit colon tumorigenesis (6 , 30 , 32) . Importantly, celecoxib did not induce any gastrointestinal and renal toxicity, unlike nonselective NSAIDs; thus, it provides an advantage over NSAIDs that are not selectively targeted at COX-2 inhibition. This underscores the potential usefulness of celecoxib as a chemopreventive agent for individuals at high risk for colon cancer development.
With regard to the mode of action of celecoxib against colon carcinogenesis, several reports indicate that PGs produced through COX activity have a role in the pathogenesis of colon cancer because they modulate signal transduction pathways (14 , 20 , 24) and affect cell proliferation, tumor growth, and immune responsiveness (12) . COX also appears to play a role in the regulation of angiogenesis as it relates to neoplastic tumor cells (33) so that COX inhibitors may possibly block the growth of blood vessels in and around the developing tumors. The available data support the hypothesis that COX-2 may have a key role in colon tumor growth and progression. Several studies have shown that COX-2 but not COX-1 gene expression and protein expression are markedly elevated in most human colon tumors and also in chemically induced colon tumors in rats as compared with accompanying normal mucosa (15, 16, 17) . In vitro studies demonstrate that COX-2 expression contributes significantly to the tumorigenic potential of epithelial cells by increasing adhesion to the extracellular matrix and making these cells resistant to apoptosis (25) . In addition, a highly selective COX-2 inhibitor decreased cell growth in both in vitro and in vivo assays only in the COX-2-expressing cell line (34) . Thus, the suppression of colon carcinogenesis by celecoxib is mediated by the inhibition of COX-2 activity.
In summary, administration of celecoxib during the initiation and postinitiation stages significantly inhibits colon tumor incidence and multiplicity in a dose-dependent manner. Importantly, administration of celecoxib at the lower dose level significantly suppressed adenocarcinomas in the colon. The study described here demonstrates for the first time that administration of celecoxib during the promotion/progression stage still significantly inhibits colon tumor development and tumor burden, suggesting indirectly that the chemopreventive efficacy of this agent is achieved even during the later phases of colon tumor development in this model. Although our understanding of the exact mechanism of the chemopreventive action of celecoxib is still evolving, the development of preventive strategies on the basis of experimental studies will serve as a practical approach to design chemoprevention trials in humans. The results described here make a strong case for the use of celecoxib as a chemopreventive agent for the secondary prevention of colon cancer in high-risk individuals, such as patients with sporadic polyps and FAP.
ACKNOWLEDGMENTS
We thank Laura Nast for preparing the manuscript, Ilse Hoffmann
for editing it, and the staff of the Research Animal Facility and
Histopathology Facility for expert technical assistance.
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FOOTNOTES |
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1 Supported in part by USPHS Grant CA-17613 and
Grant NO1-CN-65119 from the National Cancer Institute. 
2 To whom requests for reprints should be
addressed, at the American Health Foundation, One Dana Road, Valhalla,
NY 10595.
3 The abbreviations used are: NSAID, nonsteroidal
anti-inflammatory drug; COX, cyclooxygenase; AOM, azoxymethane; FAP,
familial adenomatous polyposis; PG, prostaglandin.
Received 9/16/99. Accepted 11/12/99.
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E. Puxeddu, N. Mitsutake, J. A. Knauf, S. Moretti, H. W. Kim, K. A. Seta, D. Brockman, L. Myatt, D. E. Millhorn, and J. A. Fagin Microsomal Prostaglandin E2 Synthase-1 Is Induced by Conditional Expression of RET/PTC in Thyroid PCCL3 Cells through the Activation of the MEK-ERK Pathway J. Biol. Chem., December 26, 2003; 278(52): 52131 - 52138. [Abstract] [Full Text] [PDF]
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G. Ferrandina, F. O. Ranelletti, F. Legge, L. Lauriola, V. Salutari, M. Gessi, A. C. Testa, U. Werner, P. Navarra, G. Tringali, et al. Celecoxib Modulates the Expression of Cyclooxygenase-2, Ki67, Apoptosis-Related Marker, and Microvessel Density in Human Cervical Cancer: A Pilot Study Clin. Cancer Res., October 1, 2003; 9(12): 4324 - 4331. [Abstract] [Full Text] [PDF]
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B. A. Narayanan, M. S. Condon, M. C. Bosland, N. K. Narayanan, and B. S. Reddy Suppression of N-Methyl-N-nitrosourea/Testosterone-induced Rat Prostate Cancer Growth by Celecoxib: Effects on Cyclooxygenase-2, Cell Cycle Regulation, and Apoptosis Mechanism(s) Clin. Cancer Res., August 1, 2003; 9(9): 3503 - 3513. [Abstract] [Full Text] [PDF]
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 H. Nishihara, S. Kizaka-Kondoh, P. A. Insel, and L. Eckmann Inhibition of apoptosis in normal and transformed intestinal epithelial cells by cAMP through induction of inhibitor of apoptosis protein (IAP)-2 PNAS, July 22, 2003; 100(15): 8921 - 8926. [Abstract] [Full Text] [PDF]
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S. S. W. Ng, M. Gutschow, M. Weiss, S. Hauschildt, U. Teubert, T. K. Hecker, F. A. Luzzio, E. A. Kruger, K. Eger, and W. D. Figg Antiangiogenic Activity of N-substituted and Tetrafluorinated Thalidomide Analogues Cancer Res., June 15, 2003; 63(12): 3189 - 3194. [Abstract] [Full Text] [PDF]
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Y. E.M. Dommels, M. M.G. Haring, N. G.M. Keestra, G. M. Alink, P. J. van Bladeren, and B. van Ommen The role of cyclooxygenase in n-6 and n-3 polyunsaturated fatty acid mediated effects on cell proliferation, PGE2 synthesis and cytotoxicity in human colorectal carcinoma cell lines Carcinogenesis, March 1, 2003; 24(3): 385 - 392. [Abstract] [Full Text] [PDF]
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G.-H. Lai, Z. Zhang, and A. E. Sirica Celecoxib Acts in a Cyclooxygenase-2-independent Manner and in Synergy with Emodin to Suppress Rat Cholangiocarcinoma Growth in Vitro through a Mechanism Involving Enhanced Akt Inactivation and Increased Activation of Caspases-9 and -3 Mol. Cancer Ther., March 1, 2003; 2(3): 265 - 271. [Abstract] [Full Text] [PDF]
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S. I. Mohammed, B. A. Craig, A. J. Mutsaers, N. W. Glickman, P. W. Snyder, A. E. deGortari, D. L. Schlittler, K. T. Coffman, P. L. Bonney, and D. W. Knapp Effects of the Cyclooxygenase Inhibitor, Piroxicam, in Combination with Chemotherapy on Tumor Response, Apoptosis, and Angiogenesis in a Canine Model of Human Invasive Urinary Bladder Cancer Mol. Cancer Ther., February 1, 2003; 2(2): 183 - 188. [Abstract] [Full Text] [PDF]
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M. A. C. Sabino, J. R. Ghilardi, J. L. M. Jongen, C. P. Keyser, N. M. Luger, D. B. Mach, C. M. Peters, S. D. Rogers, M. J. Schwei, C. de Felipe, et al. Simultaneous Reduction in Cancer Pain, Bone Destruction, and Tumor Growth by Selective Inhibition of Cyclooxygenase-2 Cancer Res., December 15, 2002; 62(24): 7343 - 7349. [Abstract] [Full Text] [PDF]
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X. H. Liu, A. Kirschenbaum, M. Lu, S. Yao, A. Dosoretz, J. F. Holland, and A. C. Levine Prostaglandin E2 Induces Hypoxia-inducible Factor-1alpha Stabilization and Nuclear Localization in a Human Prostate Cancer Cell Line J. Biol. Chem., December 13, 2002; 277(51): 50081 - 50086. [Abstract] [Full Text] [PDF]
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L. R. Kisley, B. S. Barrett, A. K. Bauer, L. D. Dwyer-Nield, B. Barthel, A. M. Meyer, D. C. Thompson, and A. M. Malkinson Genetic Ablation of Inducible Nitric Oxide Synthase Decreases Mouse Lung Tumorigenesis Cancer Res., December 1, 2002; 62(23): 6850 - 6856. [Abstract] [Full Text] [PDF]
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R. K. Wali, D. Stoiber, L. Nguyen, J. Hart, M. D. Sitrin, T. Brasitus, and M. Bissonnette Ursodeoxycholic Acid Inhibits the Initiation and Postinitiation Phases of Azoxymethane-induced Colonic Tumor Development Cancer Epidemiol. Biomarkers Prev., November 1, 2002; 11(11): 1316 - 1321. [Abstract] [Full Text] [PDF]
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L. R. Kisley, B. S. Barrett, L. D. Dwyer-Nield, A. K. Bauer, D. C. Thompson, and A. M. Malkinson Celecoxib reduces pulmonary inflammation but not lung tumorigenesis in mice Carcinogenesis, October 1, 2002; 23(10): 1653 - 1660. [Abstract] [Full Text] [PDF]
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 F. Cipollone and C. Patrono Cyclooxygenase-2 Polymorphism: Putting a Brake on the Inflammatory Response to Vascular Injury? Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1516 - 1518. [Full Text] [PDF]
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K. Muller-Decker, G. Neufang, I. Berger, M. Neumann, F. Marks, and G. Furstenberger Transgenic cyclooxygenase-2 overexpression sensitizes mouse skin for carcinogenesis PNAS, September 17, 2002; 99(19): 12483 - 12488. [Abstract] [Full Text] [PDF]
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K.-i. Sunayama, H. Konno, T. Nakamura, H. Kashiwabara, T. Shoji, T. Tsuneyoshi, and S. Nakamura The role of cyclooxygenase-2 (COX-2) in two different morphological stages of intestinal polyps in APC{Delta}474 knockout mice Carcinogenesis, August 1, 2002; 23(8): 1351 - 1359. [Abstract] [Full Text] [PDF]
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J. G. Edwards, S. P. Faux, S. M. Plummer, K. R. Abrams, R. A. Walker, D. A. Waller, and K. J. O'Byrne Cyclooxygenase-2 Expression Is a Novel Prognostic Factor in Malignant Mesothelioma Clin. Cancer Res., June 1, 2002; 8(6): 1857 - 1862. [Abstract] [Full Text] [PDF]
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 T. Niki, T. Kohno, S. Iba, Y. Moriya, Y. Takahashi, M. Saito, A. Maeshima, T. Yamada, Y. Matsuno, M. Fukayama, et al. Frequent Co-Localization of Cox-2 and Laminin-5 {gamma}2 Chain at the Invasive Front of Early-Stage Lung Adenocarcinomas Am. J. Pathol., March 1, 2002; 160(3): 1129 - 1141. [Abstract] [Full Text] [PDF]
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M. J. Thun, S. J. Henley, and C. Patrono Nonsteroidal Anti-inflammatory Drugs as Anticancer Agents: Mechanistic, Pharmacologic, and Clinical Issues J Natl Cancer Inst, February 20, 2002; 94(4): 252 - 266. [Abstract] [Full Text] [PDF]
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K. M. Leahy, R. L. Ornberg, Y. Wang, B. S. Zweifel, A. T. Koki, and J. L. Masferrer Cyclooxygenase-2 Inhibition by Celecoxib Reduces Proliferation and Induces Apoptosis in Angiogenic Endothelial Cells in Vivo Cancer Res., February 1, 2002; 62(3): 625 - 631. [Abstract] [Full Text] [PDF]
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C. V. Rao, C. Indranie, B. Simi, P. T. Manning, J. R. Connor, and B. S. Reddy Chemopreventive Properties of a Selective Inducible Nitric Oxide Synthase Inhibitor in Colon Carcinogenesis, Administered Alone or in Combination with Celecoxib, a Selective Cyclooxygenase-2 Inhibitor Cancer Res., January 1, 2002; 62(1): 165 - 170. [Abstract] [Full Text] [PDF]
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R. C. Young and C. M. Wilson Cancer Prevention: Past, Present, and Future Clin. Cancer Res., January 1, 2002; 8(1): 11 - 16. [Abstract] [Full Text] [PDF]
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 E. Fritsche, S. J. Baek, L. M. King, D. C. Zeldin, T. E. Eling, and D. A. Bell Functional Characterization of Cyclooxygenase-2 Polymorphisms J. Pharmacol. Exp. Ther., November 1, 2001; 299(2): 468 - 476. [Abstract] [Full Text] [PDF]
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 B. C. Gottschling, R. R. Maronpot, J. R. Hailey, S. Peddada, C. R. Moomaw, J. E. Klaunig, and A. Nyska The Role of Oxidative Stress in Indium Phosphide-Induced Lung Carcinogenesis in Rats Toxicol. Sci., November 1, 2001; 64(1): 28 - 40. [Abstract] [Full Text] [PDF]
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 I. TEGEDER, J. PFEILSCHIFTER, and G. GEISSLINGER Cyclooxygenase-independent actions of cyclooxygenase inhibitors FASEB J, October 1, 2001; 15(12): 2057 - 2072. [Abstract] [Full Text] [PDF]
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G. Lal, C. Ash, K. Hay, M. Redston, E. Kwong, B. Hancock, T. Mak, S. Kargman, J. F. Evans, and S. Gallinger Suppression of Intestinal Polyps in Msh2-deficient and Non-Msh2-deficient Multiple Intestinal Neoplasia Mice by a Specific Cyclooxygenase-2 Inhibitor and by a Dual Cyclooxygenase-1/2 Inhibitor Cancer Res., August 1, 2001; 61(16): 6131 - 6136. [Abstract] [Full Text] [PDF]
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K. Saukkonen, O. Nieminen, B. van Rees, S. Vilkki, M. Harkonen, M. Juhola, J.-P. Mecklin, P. Sipponen, and A. Ristimaki Expression of Cyclooxygenase-2 in Dysplasia of the Stomach and in Intestinal-type Gastric Adenocarcinoma Clin. Cancer Res., July 1, 2001; 7(7): 1923 - 1931. [Abstract] [Full Text] [PDF]
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S. Murono, H. Inoue, T. Tanabe, I. Joab, T. Yoshizaki, M. Furukawa, and J. S. Pagano Induction of cyclooxygenase-2 by Epstein-Barr virus latent membrane protein 1 is involved in vascular endothelial growth factor production in nasopharyngeal carcinoma cells PNAS, May 24, 2001; (2001) 121016998. [Abstract] [Full Text] [PDF]
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J. Bigler, J. Whitton, J. W. Lampe, L. Fosdick, R. M. Bostick, and J. D. Potter CYP2C9 and UGT1A6 Genotypes Modulate the Protective Effect of Aspirin on Colon Adenoma Risk Cancer Res., May 1, 2001; 61(9): 3566 - 3569. [Abstract] [Full Text]
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G. A. Piazza, W. J. Thompson, R. Pamukcu, H. W. Alila, C. M. Whitehead, L. Liu, J. R. Fetter, W. E. Gresh Jr., A. J. Klein-Szanto, D. R. Farnell, et al. Exisulind, a Novel Proapoptotic Drug, Inhibits Rat Urinary Bladder Tumorigenesis Cancer Res., May 1, 2001; 61(10): 3961 - 3968. [Abstract] [Full Text]
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Z. Li, Y. Shimada, A. Kawabe, F. Sato, M. Maeda, I. Komoto, T. Hong, Y. Ding, J. Kaganoi, and M. Imamura Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by JTE-522, a selective COX-2 inhibitor Carcinogenesis, April 1, 2001; 22(4): 547 - 551. [Abstract] [Full Text] [PDF]
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M. Li, X. Wu, and X.-C. Xu Induction of Apoptosis in Colon Cancer Cells by Cyclooxygenase-2 Inhibitor NS398 through a Cytochrome c-dependent Pathway Clin. Cancer Res., April 1, 2001; 7(4): 1010 - 1016. [Abstract] [Full Text]
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H. Shiotani, A. Denda, K. Yamamoto, W. Kitayama, T. Endoh, Y. Sasaki, M. Tsutsumi, M. Sugimura, and Y. Konishi Increased Expression of Cyclooxygenase-2 Protein in 4-Nitroquinoline-1-oxide-induced Rat Tongue Carcinomas and Chemopreventive Efficacy of a Specific Inhibitor, Nimesulide Cancer Res., February 1, 2001; 61(4): 1451 - 1456. [Abstract] [Full Text]
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M. Oshima, N. Murai, S. Kargman, M. Arguello, P. Luk, E. Kwong, M. M. Taketo, and J. F. Evans Chemoprevention of Intestinal Polyposis in the Apc{{Delta}}716 Mouse by Rofecoxib, a Specific Cyclooxygenase-2 Inhibitor Cancer Res., February 1, 2001; 61(4): 1733 - 1740. [Abstract] [Full Text]
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W. K. Hong, M. R. Spitz, and S. M. Lippman Cancer Chemoprevention in the 21st Century: Genetics, Risk Modeling, and Molecular Targets J. Clin. Oncol., November 1, 2000; 18(90001): 9s - 18. [Full Text] [PDF]
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C. J. Grubbs, R. A. Lubet, A. T. Koki, K. M. Leahy, J. L. Masferrer, V. E. Steele, G. J. Kelloff, D. L. Hill, and K. Seibert Celecoxib Inhibits N-Butyl-N-(4-hydroxybutyl)-nitrosamine-induced Urinary Bladder Cancers in Male B6D2F1 Mice and Female Fischer-344 Rats Cancer Res., October 1, 2000; 60(20): 5599 - 5602. [Abstract] [Full Text]
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 B J R WHITTLE COX-1 and COX-2 products in the gut: therapeutic impact of COX-2 inhibitors Gut, September 1, 2000; 47(3): 320 - 325. [Full Text] [PDF]
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R. F. Jacoby, K. Seibert, C. E. Cole, G. Kelloff, and R. A. Lubet The Cyclooxygenase-2 Inhibitor Celecoxib Is a Potent Preventive and Therapeutic Agent in the Min Mouse Model of Adenomatous Polyposis Cancer Res., September 1, 2000; 60(18): 5040 - 5044. [Abstract] [Full Text]
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I. Shureiqi, D. Chen, J. J. Lee, P. Yang, R. A. Newman, D. E. Brenner, R. Lotan, S. M. Fischer, and S. M. Lippman 15-LOX-1: a Novel Molecular Target of Nonsteroidal Anti-inflammatory Drug-Induced Apoptosis in Colorectal Cancer Cells J Natl Cancer Inst, July 19, 2000; 92(14): 1136 - 1142. [Abstract] [Full Text] [PDF]
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H. Sheng, J. Shao, M. K. Washington, and R. N. DuBois Prostaglandin E2 Increases Growth and Motility of Colorectal Carcinoma Cells J. Biol. Chem., May 18, 2001; 276(21): 18075 - 18081. [Abstract] [Full Text] [PDF]
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L. R. Howe, H. C. Crawford, K. Subbaramaiah, J. A. Hassell, A. J. Dannenberg, and A. M. C. Brown PEA3 Is Up-regulated in Response to Wnt1 and Activates the Expression of Cyclooxygenase-2 J. Biol. Chem., June 1, 2001; 276(23): 20108 - 20115. [Abstract] [Full Text] [PDF]
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S. Murono, H. Inoue, T. Tanabe, I. Joab, T. Yoshizaki, M. Furukawa, and J. S. Pagano Induction of cyclooxygenase-2 by Epstein-Barr virus latent membrane protein 1 is involved in vascular endothelial growth factor production in nasopharyngeal carcinoma cells PNAS, June 5, 2001; 98(12): 6905 - 6910. [Abstract] [Full Text] [PDF]
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