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Epidemiology and Prevention |
Departments of Oncological Pathology [H. S., A. D., W. K., Y. S., M. T., Y. K.], and of Oral and Maxillofacial Surgery [H. S., K. Y., T. E., M. S.], Nara Medical University, Kashihara, Nara 634-8521, Japan
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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6-fold in squamous cell
carcinomas (SCCs). Immunohistochemically, COX-2 protein was diffusely
present in SCCs and dysplasia but expressed only in basal cells in
hyperplasia and papillomas. In basal cells of normal epithelia, it was
also occasionally weakly stained. NIM dose-dependently decreased at
doses of 150 and 300 ppm, the incidences of SCCs to 4 of 12 (33.3%)
and 1 of 13 (7.7%) and their multiplicity to 0.33 ± 0.49 and 0.08 ± 0.28 per rat, respectively, as compared
with 4-NQO alone group values of 9 of 11 (81.8%) and 1.00 ± 0.77. A lesser decrease was observed with 600 ppm, the values
being 5 of 12 (41.7%) and 0.50 ± 0.67. NIM did not
significantly affect the development of hyperplasias, dysplasias, and
papillomas. These results clearly indicate chemopreventive potential of
a selective COX-2 inhibitor against the postinitiation development of
SCCs in rat tongue carcinogenesis. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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COXs,3 rate-limiting enzymes for producing prostanoids, consist of two isomers, COX-1 and -2, and have been postulated to be target molecules for NSAIDs (10, 11, 12) . COX-2, in contrast to COX-1, which is a constitutively expressed housekeeping gene generally contributing to normal physiological functions in most tissues, is an inducible immediate early gene that has recently been postulated to be involved not only in inflammation but also in carcinogenesis, with impact on cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, and immunological surveillance (10, 11, 12, 13) . In fact, evidence of up-regulated expression of COX-2 mRNA and protein in various human and animal tumor tissues such as colon, stomach, breast, skin, pancreas, lung, and urinary bladder, and prevention by specific COX-2 inhibitors of these carcinogenesis (12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23) as well as by double knockout of the COX-2 gene of colon carcinogenesis in APC gene knockout mice (24) , strongly support the hypothesis that COX-2 could be a chemopreventive target molecule (12, 13) .
Up-regulated expression of COX-2 in human SCCs of head and neck, including the tongue, has recently been reported (25) . In the present study, the expression of COX-2 protein in a 4-NQO-induced rat tongue carcinogenesis model and the chemopreventive potential of the specific COX-2 inhibitor NIM were investigated.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Animals, Diet, and Drinking Water.
Fischer 344 male rats (Japan SLC Inc., Hamamatsu, Japan), 6 weeks old
at the commencement of the experiments, were housed, three to a plastic
cage, with hardwood chips for bedding, in an air-conditioned room with
a 12-h light/12-h dark cycle. Drinking water containing 4-NQO was
prepared twice a week by dissolving the carcinogen in distilled water
and was given in light-opaque bottles. Diets containing NIM 150, 300,
or 600 ppm were prepared once a week by mixing the compound with
a powdered basal diet CE-2 (Japan Clea Co., Ltd., Tokyo, Japan) and
were given to the animals in stainless steel containers. The diet and
water were available ad libitum, and body weights and food
consumption were measured weekly.
Specimens Used for Western Blot and Immunohistochemical Analyses.
Forty-four animals were divided into two groups. Group 1 (38 rats) was
given drinking water containing 10 ppm 4-NQO and the basal diet for 24
weeks, and group 2 (6 rats) served as a control without 4-NQO. All of
the animals were killed under ether anesthesia 24 weeks after the
commencement of the experiment. Their tongues were longitudinally cut
into three slices after fixation in 10% phosphate-buffered formalin
for 48 h, routinely embedded in paraffin, and serially sectioned
at 3–4 µm. The sections were used for immunohistochemistry and H&E
staining. Relatively large tongue tumors from five rats in group 1 were
excised using a scalpel, frozen in liquid nitrogen, and submitted to
Western blot analysis after histological diagnosis. Normal tongue
epithelium, exfoliated according to the method of Telser et
al. (26)
, was also submitted as a control for the
Western blot analysis. Briefly, fresh normal tongues from two rats of
group 2 were longitudinally cut into three slices after roughly
removing muscle layers and were incubated in 10 volumes of a PBS-EDTA
inhibitor solution (pH 7.4) [0.05 M
(Na2H/KH2),
PO4, 0.15 M NaCl, 20
mM EDTA, 100 µg/ml soybean trypsin inhibitor]
at 37°C for 2 h, and then overnight in a fresh PBS-EDTA
inhibitor solution at 4°C. The tongue epithelium was peeled off from
the muscle layers using fine forceps, and stored at -80°C until use.
Partitions were fixed in 10% phosphate-buffered formalin and submitted
to H&E staining.
Western Blot Analysis.
Particulate fractions were obtained from the tongue samples basically
according to the method of Liu et al. (27)
.
Briefly, the frozen tissues were homogenized in ice-cold homogenization
buffer [50 mM Tris-HCl (pH 8.0), 2
mM octyl glucoside, 10 mM
EDTA, 1 mM diethyldithiocarbamic acid, 1
mM phenylmethylsulfonyl fluoride, 1
mM sodium vanadate, 60 µg/ml soybean trypsin
inhibitor, 2 µg/ml leupeptin, and 2 µg/ml pep- statin], all from
Sigma Chemical Co., and then centrifuged at 100,000 x g for 1 h at 4°C using a Beckman TLA-100.2 rotor
(Beckman Instruments Inc., Palo Alto, CA). The resultant crude pellets
were further homogenized in the same buffer as mentioned above (except
with 20 mM Tris, 45 mM
octyl glucoside, 50 mM EDTA, and 0.1
mM diethyldithiocarbamic acid) and were sonicated
for 20 s several times using a ultrasonic cell disruptor (Heat
System Ultrasonics, Farmingdale, NY). The sonicates were centrifuged at
13,000 x g for 25 min at 4°C, and the
resultant supernatants were stored at -80°C until use. Protein
concentrations were determined using Coomassie Brilliant Blue G-250
solution (Nacalai Tesque, Kyoto, Japan).
Supernatant samples containing 100 µg protein were mixed 1:1 with sample buffer [4% SDS, 20% glycerol, 12% ß-mercaptoethanol, 0.05% bromphenol blue, and 100 mM Tris-HCl (pH 6.8)], boiled for 5 min, electrophoresed using a 4.75% stack and a 10% running polyacrylamide gel, and electrophoretically transferred to polyvinylidene difluoride membranes (IPVH000 10; Millipore, Bedford, MA). The membranes were blocked with 5% nonfat dry milk in 0.05 M TBS-T (pH 7.6) and were incubated with primary antibodies to COX-2 (PG26) and COX-1 for 1 h at dilutions of 1:1000 or 1:80 in TBS-T. Secondary horseradish peroxidase-linked sheep antimouse and donkey antirabbit (Amersham Life Science Inc., Tokyo) IgG antibodies were then used, and the membranes were analyzed by the enhanced chemiluminescence detection system (Amersham Life Science Inc.). COX-2 and COX-1 proteins from sheep placenta and ram seminal vesicles (Cayman Chemical Company, Ann Arbor, MI), respectively, were used as COX-2- and COX-1-positive controls.
Immunohistochemical Analysis.
For the immunohistochemical COX-2 analysis, paraffin sections were
deparaffinized, treated with 0.05% protease XXVII (Sigma Chemical Co.)
in 50 mM TBS (pH 7.6) at 37°C for 5 min for the antigen
retrieval, blocked with 0.3%
H2O2 in methanol for 45 min
and incubated with a primary antibody to COX-2 (C22420) (1:100 dilution
in TBS) for 2 h. Immunoreactivity was detected using a Dako LSAB2
kit for use with rat specimens (Dako Co., Carpinteria, CA) and
3,3'-diaminobenzidine hydrochloride (Sigma Chemical Co.) followed by
counterstaining with Mayer’s hematoxylin. Immunohistochemical COX-1
analysis was basically the same as for COX-2, except that antigens were
retrieved by microwaving for 50 min in 0.01 M citrate
buffer (pH 6.0), and that after blocking nonspecific binding with 5%
normal goat serum in TBS-0.25% Triton X-100 for 20 min, tissues were
incubated with a primary antibody to COX-1 (1:60 dilution in TBS-0.25%
Triton X-100) with detection of immunoreactivity using a Vectastain
Elite ABC kit (Vector Laboratories, Burlingame, CA). A nonimmune serum,
mouse IgG1 (Dako Japan Inc., Kyoto) or rabbit IgG (Dako Japan Inc.), as
well as antibodies preabsorbed with the antigens, were used as controls
for the primary antibody binding. In the preabsorption experiment,
COX-2 antibody was preabsorbed by incubating with 4 times molar ratios
of COX-2 or COX-1 proteins from sheep placenta and ram seminal vesicles
(Cayman Chemical Company), respectively, and COX-1 antibody with 4
times molar ratios of the antigen peptide (IBL, Gunma, Japan), at 4°C
overnight.
Studies on the Chemopreventive Potential of NIM.
The experimental protocol is shown in Fig. 1
. Sixty animals were divided into six groups, with 11–13 rats each for
groups 1–4 and 6 rats each for groups 5 and 6. Animals in groups 1–4
were given 25–35 ppm 4-NQO in their drinking water for 12 weeks (25
ppm for the first 2 weeks, 30 ppm for the next 2 weeks, and 35 ppm for
the other 8 weeks). Then, group 1 was fed the basal diet, and groups
2–4 received diets containing 150, 300, and 600 ppm, respectively, of
NIM for 14 weeks. Animals in groups 5 and 6 served as controls and were
given tap water for the first 12 weeks, followed by 600 ppm NIM and
basal diet, respectively. All of the animals were killed under ether
anesthesia 26 weeks after the commencement of the experiment. Their
tongues were excised, fixed in 10% phosphate-buffered formalin for
48 h, and longitudinally cut into three slices. The livers and
kidneys from all of the animals were also excised, weighed, and fixed.
All of these tissues were routinely processed for embedding in paraffin
and sectioned for H&E staining. The tongue lesions were histologically
diagnosed by three experts independently, basically according to the
criteria of WHO (28)
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2, or Fisher’s exact test. |
RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The density of each band was quantified using NIH image,
and the results are presented in Fig. 2B
. Histological
assessment of the exfoliated normal tongue epithelium revealed
well-preserved architecture without muscle layers (Fig. 3A)
. The normal epithelial cells barely expressed COX-2
protein, whereas SCCs exhibited substantial binding of specific
antibodies, 6-fold that of normal epithelial cells (Fig. 2)
.
In contrast, COX-1 protein was highly expressed both in the normal
epithelial cells and SCCs, with SCCs exhibiting 2-fold that of
normal epithelial cells (Fig. 2)
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. The staining was classified into five grades: - (negative),
no staining; ±, less than 10% of the area weakly positive; +, weakly
positive; ++, moderately positive; and +++, strongly positive. In the
normal epithelium, basal cells were occasionally weakly positive for
COX-2 protein (Fig. 3B)
. In approximately 50% of the
hyperplastic lesions (Fig. 3C)
and 100% of squamous cell
papillomas (Fig. 3E)
examined, only basal cells were
positive for COX-2 (Table 1)
. In contrast, in all of the dysplasias
(Fig. 3D)
and SCCs (Fig. 3F)
examined, not only
basal but also other tumor cells were moderately or strongly positive
for COX-2 (Table 1)
. In SCCs, stromal cells were also moderately
positive for COX-2 (Fig. 3F)
. In all cases, COX-2 protein
was localized in the nuclear membrane and cytoplasm. With nonimmune
serum, staining was negative (data not shown). Preabsorption of the
COX-2 antibody with COX-2 but not COX-1 proteins abrogated the staining
(data not shown). Immunohistochemistry further revealed that in the
normal epithelium, cells in the basal strongly, as well as upper layers
weakly, were positive for COX-1 protein (Fig. 3G)
. Similar
stainability for COX-1 was obtained for hyperplasias, dysplasias, and
papillomas (data not shown). In SCCs, tumor cells and stromal cells
were strongly positive (Fig. 3H)
. In all cases COX-1 protein
was localized in the cytoplasm and nuclear membrane. Nonimmune serum
gave negative staining, and preabsorption of the COX-1 antibody with
the antigen peptide abrogated the staining (data not shown). \
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. NIM did not significantly affect the final body weights and liver and
kidney weights at any doses. There were no significant differences in
the average intake of 4-NQO among the 4-NQO-treated groups, and intake
of NIM was dose dependent.
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. The tongues from group 1 (4-NQO alone),
especially in their dorsal posterior aspect of the base, exhibited
whitish protuberant nodular lesions, varying in size from larger than
10 mm to smaller than 1 mm in diameter (Fig. 3I)
. Their
numbers and sizes tended to be decreased in the groups treated with
NIM, particularly in group 3 (4-NQO + 300 ppm NIM; Fig. 3J
).
Data for incidences and numbers of histologically diagnosed tongue
lesions and size distributions of SCCs are summarized in Table 3
. Representative histological findings for SCCs and dysplasias
developing in groups 1 and 3, respectively, are shown in Fig. 3, K and L
. NIM at doses of 150 and 300 ppm,
dose-dependently significantly decreased the incidence and multiplicity
of SCCs but not those of hyperplasias, dysplasias, and papillomas
(Table 3)
. The highest dose, 600 ppm NIM, also exhibited a tendency to
decrease, but without statistical significance, the incidence,
multiplicity, and size of SCCs, with the majority of SCCs being less
than 3 mm in diameter (Table 3)
. No tongue lesions were observed in the
animals without 4-NQO treatment, from groups 5 and 6.
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DISCUSSION |
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4 times the maximum
tolerated dose in humans of 200 mg per person per day
(30)
. The present results are the first, to the authors’ knowledge, to provide direct evidence of involvement of COX-2 in rat tongue carcinogenesis, in line with the preventive effects of the NSAIDs piroxicam and indomethacin, reported earlier (8 , 33) , as well as with the suppressive effect of another selective COX-2 inhibitor, JTE-522, on the growth of a xenografted human oral SCC cell line in nude mice (34) . The present preventive potential of 600 ppm being lower than that of 300 ppm NIM, without histological findings of tissue injury, may simply reflect variations within statistical uncertainty because of the relatively small numbers of animals, but it may be partly attributable to the existence of certain limited effective doses and warrants further study. Moreover, the lack of significant effects on the incidence and multiplicity of dysplasia, despite increased COX-2 protein expression, may suggest a most important role for the enzyme in the progression of dysplasia to SCC or roles of the enzyme expressed in the stromal cells. Discrepancies from the previous reports that indomethacin and piroxicam decreased the incidence of dysplasia or hyperplasia, as well as of SCC (33) , might partly be attributable to the fact that, in the present study, these lesions had already developed by the time of cessation of the 4-NQO exposure, which at termination was at a much higher dose of 25–35ppm than the 10 ppm used in the previous report. In this context, it should be noted that retinoids reportedly can cause regression of dysplastic lesions like leukoplakia in humans (5, 6, 7) , probably because of stimulation of squamous cell differentiation and apoptosis (35) . However, various degrees of dysplasia are included in the clinical descriptive term leukoplakia, with only 3–6% progressing to SCCs (28) . Nevertheless, taking into account the possible involvement of inhibitory effects of retinoids on COX-2 expression in their cancer chemopreventive potential (36, 37) , we conclude that the lack of NIM impact on dysplasia clearly warrants further study.
COX-2 is known to be induced by cytokines and growth factors including
transforming growth factor 
and EGF, and mutated Ras
activation (13
, 36, 37, 38, 39)
. In fact, mitogenic signaling
through EGFR induces COX-2, probably through activation of the
Ras-mitogen-activated protein kinase pathway, which can be prevented by
a selective COX-2 inhibitor (39, 40)
. When we take into
account the evidence of elevated expression of EGFR with infrequent
gene amplification in hyperplastic and dysplastic lesions,
normal-looking epithelia adjacent to tumor, and SCCs during head and
neck tumorigenesis, including the oral cavity in humans
(41, 42, 43)
, we conclude that there is a possibility that
EGFR is involved in COX-2 elevation, although the
EGFR-immunohistochemical findings, particularly those of no distinction
between hyperplasias and dysplasias, reported earlier
(42)
, do not parallel the present COX-2 findings. The
relatively low frequencies of Ha- but not Ki- nor N-ras mutations
reported for 4-NQO-induced tongue (24%) as well as human oral SCCs
(10–35%; 43, 44
), may suggest that mutated Ras
activation is unlikely to play a major role in the induction of COX-2
in these lesions.
In conclusion, our present results clearly indicate COX-2 protein to be highly expressed in the dysplastic precancerous lesions and SCCs in 4-NQO-induced rat tongue carcinogenesis, and to play important roles in the development of malignancies in this model, judging from the observed impact of the specific inhibitor NIM. The results, thus, provide that selective COX-2 inhibitors with less adverse effects on the gastrointestinal tract than nonspecific NSAIDs, could be promising candidates for chemopreventive agents active against human oral cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported in part by a
Grant-in-Aid (09253104) for Scientific Research on Priority Areas and a
Grant-in-Aid (10671898) for Scientific Research (C) from the
Ministry of Education, Science, Sports and Culture of Japan;
Grants-in-Aid (10-36 and S10-1) for Cancer Research from the Ministry
of Health and Welfare of Japan; and 2nd-Term Comprehensive 10-Year
Strategy for Cancer Control, Cancer Prevention from the Ministry of
Health and Welfare of Japan. 
2 To whom requests for reprints should be
addressed, at the Department of Oncological Pathology, Cancer Center,
Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521,
Japan. Phone: 81-744-22-3051; Fax: 81-744-25-7308; E-mail: adenda{at}nmu-gw.cc.naramed-u.ac.jp
3 The abbreviations used are: COX,
cyclooxygenase; NSAID, nonsteroidal anti- inflammatory drug; 4-NQO,
4-nitroquinoline-1-oxide; NIM, nimesulide; SCC, squamous cell
carcinoma; EGF, epidermal growth factor; EGFR, EGF receptor; TBS,
Tris-buffered saline; TBS-T, TBS containing 0.1% Tween 20.
Received 5/23/00. Accepted 12/ 6/00.
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REFERENCES |
|---|
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
716 knockout mice by inhibition of cyclooxygenase 2 (COX-2).. Cell, 87: 803-809, 1996.[Medline]
-dependent signaling pathway in the induction of tissue transglutaminase and apoptosis. J. Biol. Chem., 270: 6022-6029, 1995. and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer.. Cancer Res., 53: 3579-3584, 1993.This article has been cited by other articles:
|
|
 |
|
  V. A. Papadimitrakopoulou, W. N. William Jr., A. J. Dannenberg, S. M. Lippman, J. J. Lee, F. G. Ondrey, D. E. Peterson, L. Feng, A. Atwell, A. K. El-Naggar, et al. Pilot Randomized Phase II Study of Celecoxib in Oral Premalignant Lesions Clin. Cancer Res., April 1, 2008; 14(7): 2095 - 2101. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Choi and J.N. Myers Molecular Pathogenesis of Oral Squamous Cell Carcinoma: Implications for Therapy Journal of Dental Research, January 1, 2008; 87(1): 14 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Makita, M. Mutoh, T. Maruyama, K. Yonemoto, A. Kobayashi, H. Fujitsuka, M. Toida, T. Shibata, S. Miyamoto, Y. Yasui, et al. A prostaglandin E2 receptor subtype EP1-selective antagonist, ONO-8711, suppresses 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis Carcinogenesis, March 1, 2007; 28(3): 677 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Sun, S. Sood, N. Li, D. Ramji, P. Yang, R. A. Newman, C. S. Yang, and X. Chen Involvement of the 5-lipoxygenase/leukotriene A4 hydrolase pathway in 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamster cheek pouch, and inhibition of carcinogenesis by its inhibitors Carcinogenesis, September 1, 2006; 27(9): 1902 - 1908. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Choe, X. Zhang, H. J. C. Shin, D. M. Shin, and Z. Chen Interaction between epidermal growth factor receptor- and cyclooxygenase 2-mediated pathways and its implications for the chemoprevention of head and neck cancer Mol. Cancer Ther., September 1, 2005; 4(9): 1448 - 1455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Stoner, H. Qin, T. Chen, P. S. Carlton, M. E. Rose, R. M. Aziz, and R. Dixit The effects of L-748706, a selective cyclooxygenase-2 inhibitor, on N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis Carcinogenesis, September 1, 2005; 26(9): 1590 - 1595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Li, S. Sood, S. Wang, M. Fang, P. Wang, Z. Sun, C. S. Yang, and X. Chen Overexpression of 5-Lipoxygenase and Cyclooxygenase 2 in Hamster and Human Oral Cancer and Chemopreventive Effects of Zileuton and Celecoxib Clin. Cancer Res., March 1, 2005; 11(5): 2089 - 2096. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Moraitis, B. Du, M. S. De Lorenzo, J. O. Boyle, B. B. Weksler, E. G. Cohen, J. F. Carew, N. K. Altorki, L. Kopelovich, K. Subbaramaiah, et al. Levels of Cyclooxygenase-2 Are Increased in the Oral Mucosa of Smokers: Evidence for the Role of Epidermal Growth Factor Receptor and Its Ligands Cancer Res., January 15, 2005; 65(2): 664 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Dannenberg, S. M. Lippman, J. R. Mann, K. Subbaramaiah, and R. N. DuBois Cyclooxygenase-2 and Epidermal Growth Factor Receptor: Pharmacologic Targets for Chemoprevention J. Clin. Oncol., January 10, 2005; 23(2): 254 - 266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Y. Y. Fong, L. Zhang, Y. Jiang, and J. L. Farber Dietary Zinc Modulation of COX-2 Expression and Lingual and Esophageal Carcinogenesis in Rats J Natl Cancer Inst, January 5, 2005; 97(1): 40 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Goodin and S. J. Shiff NSAIDs for the Chemoprevention of Oral Cancer: Promise or Pessimism?: Commentary re J. L. Mulshine et al., Randomized, Double-Blind, Placebo-Controlled, Phase IIB Trial of the Cyclooxygenase Inhibitor Ketorolac as an Oral Rinse in Oropharyngeal Leukoplakia. Clin. Cancer Res., 10: 1565-1573, 2004. Clin. Cancer Res., March 1, 2004; 10(5): 1561 - 1564. [Full Text] [PDF]
|
|
|
|
|
|
J. L. Mulshine, J. C. Atkinson, R. O. Greer, V. A. Papadimitrakopoulou, C. Van Waes, S. Rudy, J. W. Martin, S. M. Steinberg, D. J. Liewehr, I. Avis, et al. Randomized, Double-Blind, Placebo-Controlled Phase IIB Trial of the Cyclooxygenase Inhibitor Ketorolac as an Oral Rinse in Oropharyngeal Leukoplakia Clin. Cancer Res., March 1, 2004; 10(5): 1565 - 1573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Shaik, A. Chatterjee, and M. Singh Effect of a Selective Cyclooxygenase-2 Inhibitor, Nimesulide, on the Growth of Lung Tumors and Their Expression of Cyclooxygenase-2 and Peroxisome Proliferator- Activated Receptor-{gamma} Clin. Cancer Res., February 15, 2004; 10(4): 1521 - 1529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q.-T. Le and A. J. Giaccia Therapeutic Exploitation of the Physiological and Molecular Genetic Alterations in Head and Neck Cancer Clin. Cancer Res., October 1, 2003; 9(12): 4287 - 4295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N.K. Altorki, R.S. Keresztes, J.L. Port, D.M. Libby, R.J. Korst, D.B. Flieder, C.A. Ferrara, D.F. Yankelevitz, K. Subbaramaiah, M.W. Pasmantier, et al. Celecoxib, a Selective Cyclo-Oxygenase-2 Inhibitor, Enhances the Response to Preoperative Paclitaxel and Carboplatin in Early-Stage Non-Small-Cell Lung Cancer J. Clin. Oncol., July 15, 2003; 21(14): 2645 - 2650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. A. Minter, J. W. Eveson, S. Huntley, D. J. E. Elder, and A. Hague The Cyclooxygenase 2-selective Inhibitor NS398 Inhibits Proliferation of Oral Carcinoma Cell Lines by Mechanisms Dependent and Independent of Reduced Prostaglandin E2 Synthesis Clin. Cancer Res., May 1, 2003; 9(5): 1885 - 1897. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Carlton, R. Gopalakrishnan, A. Gupta, B. W. Liston, S. Habib, M. A. Morse, and G. D. Stoner Piroxicam Is an Ineffective Inhibitor of N-Nitrosomethylbenzylamine-induced Tumorigenesis in the Rat Esophagus Cancer Res., August 1, 2002; 62(15): 4376 - 4382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yanaida, H. Kohno, K. Yoshida, Y. Hirose, Y. Yamada, H. Mori, and T. Tanaka Dietary silymarin suppresses 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats Carcinogenesis, May 1, 2002; 23(5): 787 - 794. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Denda, W. Kitayama, A. Murata, H. Kishida, Y. Sasaki, O. Kusuoka, T. Tsujiuchi, M. Tsutsumi, D. Nakae, H. Takagi, et al. Increased expression of cyclooxygenase-2 protein during rat hepatocarcinogenesis caused by a choline-deficient, L-amino acid-defined diet and chemopreventive efficacy of a specific inhibitor, nimesulide Carcinogenesis, February 1, 2002; 23(2): 245 - 256. [Abstract] [Full Text] [PDF]
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