Prostaglandins and their derivatives are
signaling lipophilic molecules that are involved in diverse homeostatic and
reactive functions, including platelet aggregation, clot formation,
vasodilation, and gastric cytotoxic protection, as well as renal sodium and
water balance. The first step in the synthesis of prostaglandins is the
hydrolysis of membrane phospholipids to arachidonic acid by phospholipase A2.
Arachidonic acid is then converted to an unstable product, prostaglandin G2,
which is rapidly converted to prostaglandin H2 by the peroxidase activity of a
cyclooxygenase (COX). Prostaglandin H2 is converted by tissue-specific enzymes
to other prostaglandins and thromboxanes.
There are two isoforms of the COX enzyme encoded by two
different genes. Cyclooxygenase-1 (COX-1) is a constitutive enzyme that is
present in most normal tissues and mediates the synthesis of prostaglandins
required for normal physiologic functions. The gene for COX-1 is on human
chromosome 9. Cyclooxygenase-2 (COX-2) is an inducible form of the enzyme
that is not normally detected in most tissues and is coded by a gene on human
chromosome 1. Cyclooxygenase-2 is induced by cytokines, growth factors, tumor
promoters, and carcinogens. Cyclooxygenase-2 is also induced by several
oncogenes, such as v-Src, v-Ha-ras, HER2/neu and Wnt.[4-7]
Although prostaglandins are involved in many normal physiologic
functions, these moleculesand the COX enzymes involved in prostaglandin
productionmay also be involved in tumorigenesis. Indeed, there is evidence
that prostaglandins may contribute to tumorigenesis by inhibiting the immune
system, stimulating cell growth, enhancing angiogenesis, increasing mutagen
production, enhancing cell invasion, or inhibiting apoptosis. In this article,
we will discuss these mechanisms and will explore the role of COX-2 in
tumorigenesis. We will also review clinical trials that have investigated COX-2
inhibitors as chemoprotection agents and will discuss future directions in the
study of COX-2 as a therapeutic target in cancer management.
Prostaglandins have a variety of immunosuppressive effects. For
example, prostaglandin E2 diminishes the cytotoxic activity of natural killer
cells, inhibits T-cell and B-cell growth, and decreases the production of
cytokines including tumor necrosis factor-alpha. Huang et al showed that
pretreatment with a prostaglandin inhibitor prevents an increase in
interleukin-10 synthesis by peripheral blood lymphocytes. Furthermore,
prostaglandins may also interfere with antigen processing by dendritic cells.
The ability of prostaglandins to inhibit the immune system may allow tumors to
grow without surveillance and may contribute to tumorigenesis.
Enhanced prostaglandin synthesis may also contribute to
tumorigenesis by direct stimulation of cell growth. Data have shown that
prostaglandin E2 and prostaglandin F2-alpha can be mitogenic in BALB/c3T3
fibroblasts in the presence of epidermal growth factor. Furthermore,
proliferation of mammary epithelial cells can be stimulated in the presence of
epidermal growth factor by prostaglandin E1 and prostaglandin E2. In breast
tissue, prostaglandins may stimulate cell growth by stimulating the aromatase
gene, CYP19, and thus enhancing estrogen synthesis.[12,13] Interestingly,
enhanced expression of CYP19 and COX has been found in human breast cancer
Inhibition of Apoptosis
Prolonged survival of abnormal cells favors the accumulation of
genetic changes that may result in tumor formation. Therefore, inhibition of
apoptosis may increase the tumorigenic potential of initiated cells. Sheng et
al demonstrated that prostaglandin E2 may inhibit apoptosis by inducing
bcl-2. Recently it was shown that inhibition of COX-2 by celecoxib (Celebrex), a
selective COX-2 inhibitor, resulted in a decrease of production of prostaglandin
E2 and TXB2, and was associated with an increase in apoptosis in vivo.
Effects on Metastatic Potential
Enhanced COX-2 expression may also contribute to tumorigenesis
by increasing cell invasiveness. DuBois et al showed that COX-2
overexpression in rat intestinal epithelial cells increases cell adhesion to the
extracellular matrix. Recently, Stockton and Jacobson demonstrated that
COX-2 is required for NIH3T3 cell migration in a process that appears to be
regulated by the extracellular signal-regulated kinase 1/2. Furthermore, the
activity of enzymes responsible for digesting cellular basement membrane is
enhanced by COX-2 overexpression in the breast cancer cell line Hs578T and colon
cancer cells, which likely contributes to the increased ability of these cells
to invade through a layer of Matrigel.[19,20]
Increased Production of Mutagens
Another mechanism by which COX-2 overexpression may play a role
in carcinogenesis is an increase in the production of mutagens. One such potent
mutagen is malondialdehyde, which can be produced by isomerization of
prostaglandin H2. Malondialdehyde acts by forming adducts with deoxynucleotides,
which cause frame-shifts and base-pair substitutions. In addition, Wiese et
al showed that the peroxidase activity of cyclooxygenases can catalyze the
formation of mutagens by the oxidation of aromatic amines, heterocyclic amines,
and dihydrodiol derivatives of polycyclic hydrocarbons. Thus, COX-2
overexpression may lead to DNA damage that may eventually lead to
Cyclooxygenase-2 has also been implicated in enhanced
angiogenesis, which plays a role in carcinogenesis. Tumor growth depends on
increased blood supply via secretion of angiogenic promoters such as vascular
endothelial growth factor. Cyclooxygenase-2 overexpression in colon cancer cells
is correlated with increased production of vascular growth factors and formation
of capillary networks. This angiogenic effect of COX-2 can be blocked by
NS398, a selective COX-2 inhibitor. Williams et al demonstrated that tumor
formation is markedly decreased in COX-2 knockout mice compared with wild-type
mice. Furthermore, the pharmacologic inhibition of COX-2 leads to a decrease in
vascular endothelial growth factor production that may contribute to a decrease
in tumor formation. Masferrer et al showed that celecoxib, a selective COX-2
inhibitor, blocks corneal blood vessel formation in a rat model. Thus, COX-2
overexpression may increase tumor blood supply and may contribute to tumor
Cyclooxygenase-2 is upregulated in multiple human premalignant
and malignant conditions, including tumors of the colon, breast, stomach, lung,
pancreas, cervix, prostate, bladder, liver, skin, head and neck, and esophagus (Table
1).[26-40] There are multiple lines of evidence suggesting a link between
levels of COX-2 and tumorigenesis. Increased levels of COX-2 are detected in
premalignant intestinal tumors in experimental animal models. The knockout
of the COX-2 gene led to a marked reduction in the size and number of polyps in
APCD716 mice. In addition, APCD716 mice treated with a selective COX-2 inhibitor
had reduced adenoma formation. Further, COX-2 knockout mice develop fewer
skin papillomas than control mice. Taken together, these results suggest
that inhibition of COX-2 could be important in the prevention of a variety of
Synthetic and naturally occurring inhibitors of COX (eg,
sulindac [Clinoril], ibuprofen, flurbiprofen [Ansaid], indomethacin [Indocin])
have also been shown to protect against mammary, colon, oral, and esophageal
cancer in experimental animals.[44-50] For example, studies have shown that
flurbiprofen, an inhibitor of COX-1 and COX-2, can inhibit the growth of
transplanted mammary tumors and increase the mean survival duration in
mice. In addition to having therapeutic activity against established mammary
tumors, flurbiprofen inhibits mammary carcinogenesis induced by a low dose of
N-methyl-N-nitrosourea in rats. Other data have also demonstrated that
indomethacin, another inhibitor of both COX-1 and COX-2, has significant
chemoprotective activity in rats when administered during either the early or
late stage of mammary tumorigenesis. Importantly, epidemiologic studies have
shown that chronic intake of nonsteroidal anti-inflammatory drugs (NSAIDs)
reduces the incidence of various human cancers, including cancers of the colon,
breast, lung, esophagus, stomach, and bladder.[53-60]
Celecoxib has been evaluated as a possible chemopreventive agent
for the inhibition of tumorigenesis. In a study to evaluate the inhibitory
activity of celecoxib against azoxymethane-induced aberrant crypt foci formation
in the colon of rats, celecoxib significantly suppressed the total number of
aberrant crypt foci in rats compared with placebo. In a second study of
azoxymethane-treated rats, celecoxib reduced the incidence of colon cancer by
93% and tumor multiplicity by 97%. These animal data provide strong evidence
that celecoxib has cancer activity in the prevention of cancer when tested in a
defined model of tumorigenesis.
Recently, Harris et al compared the chemoprevention effects
of celecoxib with ibuprofen and placebo in the development and growth of
7,12-dimethyl-benz(a)anthracene (DMBA)-induced rat mammary tumors. Seven days
prior to receiving a single dose of 15 mg of DMBA by intubation, rats were fed
either a control diet or diets containing 1,500 ppm of celecoxib or 1,500 ppm of
ibuprofen. Both celecoxib and ibuprofen significantly increased tumor latency,
reduced tumor burden, and prevented tumor formation compared with placebo.
However, celecoxib was more potent than ibuprofen. At 105 days after DMBA
treatment, tumor incidence was 100% in control rats compared with 32% and 60% in
rats fed either celecoxib (P < .001) or ibuprofen (P < .001),
respectively. The control rats had an average of 3.2 tumors compared with 0.4
and 1.5 tumors in rats treated with celecoxib (P < .001) and ibuprofen
< .001), respectively. Additionally, the average tumor volume was 1.5 cm³ in
control rats vs 0.3 cm³ and 0.6 cm³ in rats treated with celecoxib (P < .001)
or ibuprofen (P < .001), respectively. The higher potency of celecoxib
suggests that this agent may have an in vivo advantage over other NSAIDs as a
The DMBA-induction model was also used to evaluate celecoxib for
efficacy against established tumors. Alshafie et al examined the effect of
celecoxib, given as a daily diet (1,500 ppm), on the growth of established DMBA-induced
tumors in rats over a 6-week treatment period. Tumors in the control group
continued to grow; whereas tumors in the celecoxib group markedly decreased in
size. The average reduction in tumor volume relative to baseline was
approximately 32% (P < .04). At the end of the 6-week treatment period,
average tumor volume was 1.45 cm³ and 0.13 cm³ in the control and celecoxib
groups, respectively. Tumor volume regression occurred in 90% of rats treated
with celecoxib. These results suggest that celecoxib has potent antitumor
activity and chemoprevention activity in this rat mammary carcinoma model.
1. Funk CD, Funk LB, Kennedy ME, et al: Human
platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning,
expression, and gene chromosomal assignment. FASEB J 5:2304-2312, 1991.
2. Kosaka T, Miyata A, Ihara H, et al: Characterization of the
human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2. Eur J Biochem
3. Herschman HR: Prostaglandin synthase 2. Biochim Biophys Acta
4. Xie W, Herschman HR: v-Src induces prostaglandin synthase 2
gene expression by activation of the c-Jun N-terminal kinase and the c-Jun
transcription factor. J Biol Chem 270:27622-27628, 1995.
5. Vadlamudi R, Mandal M, Adam L, et al: Regulation of
cyclooxygenase-2 pathway by HER2 receptor. Oncogene 18:305-314, 1999.
6. Sheng H, Williams CS, Shao J, et al: Induction of
cyclooxygenase-2 by activated Ha-ras oncogene in Rat-1 fibroblasts and the role
of mitogen-activated protein kinase pathway. J Biol Chem 273:22120-22127, 1998.
7. Howe LR, Subbaramaiah K, Chung WJ, et al: Transcriptional
activation of cyclooxygenase-2 in Wnt-1-transformed mouse mammary epithelial
cells. Cancer Res 59:1572-1577, 1999.
8. Huang M, Sharma S, Mao JT, et al: Non-small-cell lung
cancer-derived soluble mediators and prostaglandin E2 enhance peripheral blood
lymphocyte IL-10 transcription and protein production. J Immunol 157:5512-5520,
9. Stolina M, Sharma S, Zhu L: Lung cancer cyclooxygenase-2
dependent inhibition of dendritic cell maturation and function. Pro Am Assoc
Cancer Res 41:619, 2000.
10. Nolan RD, Danilowicz RM, Eling TE: Role of arachidonic acid
metabolism in the mitogenic response of BALB/c 3T3 fibroblasts to epidermal
growth factor. Mol Pharmacol 33:650-656, 1988.
11. Bandyopadhyay GK, Imagawa W, Wallace D, et al: Linoleate
metabolites enhance the in vitro proliferative response of mouse mammary
epithelial cells to epidermal growth factor. J Biol Chem 262:2750-2756, 1987.
12. Harris RE, Robertson FM, Abou-Issa HM, et al: Genetic
induction and upregulation of cyclooxygenase (COX) and aromatase (CYP19): An
extension of the dietary fat hypothesis of breast cancer. Medical Hypotheses
13. Zhao Y, Agarwal VR, Mendelson CR, et al: Estrogen
biosynthesis proximal to a breast tumor is stimulated by PG E2 via cyclic AMP,
leading to activation of promoter II of the CYP19 (aromatase) gene.
Endocrinology 137:5739-5742, 1996.
14. Brueggemeier RW, Quinn AL, Parrett ML, et al: Correlation of
aromatase and cyclooxygenase gene expression in human breast cancer specimens.
Cancer Lett 140:27-35, 1999.
15. Sheng H, Shao J, Morrow JD, et al: Modulation of apoptosis
and bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res
16. Leahy K, Ornberg R, Wang Y, et al: Cyclooxygenase-2
inhibition by celecoxib reduces proliferation and induces apoptosis in
epithelial cells. Cancer Res 62:625-631, 2002.
17. DuBois RN, Shao J, Tsujii M, et al: G1 delay in cells
overexpressing prostaglandin endoperoxide synthase-2. Cancer Res 56:733-737,
18. Stockton RA, Jacobson BS: Modulation of cell-substrate
adhesion by arachidonic acid: Lipoxygenase regulates cell spreading and
erk1/2-inducible cyclooxygenase regulates cell migration in NIH3T3 fibroblasts.
Mol Biol Cell 12:1937-1956, 2001.
19. Tsujii M, Kawano S, DuBois RN: Cyclooxygenase-2 expression
in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci U
S A 94:3336-3340, 1997.
20. Takahashi Y, Kawahara F, Noguchi M, et al: Activation of
matrix metalloproteinase-2 in human breast cancer cells overexpressing
cyclooxygenase-1 or -2. FEBS Lett 460:145-148, 1999.
21. Marnett LJ: Aspirin and the potential role of prostaglandins
in colon cancer. Cancer Res 52:5575-5589, 1992.
22. Wiese FW, Thompson PA, Kadlubar FF: Carcinogen substrate
specificity of human COX-1 and COX-2. Carcinogenesis 22:5-10, 2001.
23. Tsujii M, Kawano S, Tsuji S, et al: Cyclooxygenase regulates
angiogenesis induced by colon cancer cells. Cell 93:705-716, 1998.
24. Williams CS, Tsujii M, Reese J, et al: Host cyclooxygenase-2
modulates carcinoma growth. J Clin Invest 105:1589-1594, 2000.
25. Masferrer JL, Leahy KM, Koki AT, et al: Antiangiogenic and
antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60:1306-1311,
26. Eberhart CE, Coffey RJ, Radhika A, et al: Upregulation of
cyclooxygenase 2 gene expression in human colorectal adenomas and
adenocarcinomas. Gastroenterology 107:1183-1188, 1994.
27. Sano H, Kawahito Y, Wilder RL, et al: Expression of
cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res 55:3785-3789,
28. Hwang D, Scollard D, Byrne J, et al: Expression of
cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. J Natl Cancer Inst
29. Soslow RA, Dannenberg AJ, Rush D, et al: COX-2 is expressed
in human pulmonary, colonic, and mammary tumors. Cancer 89:2637-2645, 2000.
30. Ristimaki A, Honkanen N, Jankala H, et al: Expression of
cyclooxygenase-2 in human gastric carcinoma. Cancer Res 57:1276-1280, 1997.
31. Hida T, Yatabe Y, Achiwa H, et al: Increased expression of
cyclooxygenase-2 occurs frequently in human lung cancers, specifically in
adenocarcinomas. Cancer Res 58:3761-3764, 1998.
32. Wolff H, Saukkonen K, Anttila S, et al: Expression of
cyclooxygenase-2 in human lung carcinoma. Cancer Res 58:4997-5001, 1998.
33. Tucker ON, Dannenberg AJ, Yang EK, et al: Cyclooxygenase-2
expression is upregulated in human pancreatic cancer. Cancer Res 59:987-990,
34. Kulkarni S, Rader JS, Zhang F, et al: Cyclooxygenase-2 is
overexpressed in human cervical cancer. Clin Cancer Res 7:429-434, 2001.
35. Gupta S, Srivastava M, Ahmad N, et al: Overexpression of
cyclooxygenase-2 in human prostate adenocarcinoma. Prostate 42:73-78, 2000.
36. Mohammed SI, Knapp DW, Bostwick DG, et al: Expression of
cyclooxygenase-2 (COX-2) in human invasive transitional cell carcinoma (TCC) of
the urinary bladder. Cancer Res 59:5647-5650, 1999.
37. Koga H, Sakisaka S, Ohishi M, et al: Expression of
cyclooxygenase-2 in human hepatocellular carcinoma: Relevance to tumor
dedifferentiation. Hepatology 29:688-696, 1999.
38. Buckman SY, Gresham A, Hale P, et al: COX-2 expression is
induced by UVB exposure in human skin: Implications for the development of skin
cancer. Carcinogenesis 19:723-729, 1998.
39. Chan G, Boyle JO, Yang EK, et al: Cyclooxygenase-2
expression is upregulated in squamous cell carcinoma of the head and neck.
Cancer Res 59:991-994, 1999.
40. Wilson KT, Fu S, Ramanujam KS, et al: Increased expression
of inducible nitric oxide synthase and cyclooxygenase-2 in Barrett’s esophagus
and associated adenocarcinomas. Cancer Res 58:2929-2934, 1998.
41. Williams CS, Luongo C, Radhika A, et al: Elevated
cyclooxygenase-2 levels in Min mouse adenomas. Gastroenterology 111:1134-1140,
42. Oshima M, Dinchuk JE, Kargman SL, et al: Suppression of
intestinal polyposis in APC delta716 knockout mice by inhibition of
cyclooxygenase 2 (COX-2). Cell 87:803-809, 1996.
43. Tiano H, Chulada P, Spalding J, et al: Effects of
cyclooxygenase deficiency on inflammation and papilloma development in mouse
skin. Proc Am Assoc Cancer Res 38:1727, 1997.
44. Reddy BS, Maruyama H, Kelloff G: Dose-related inhibition of
colon carcinogenesis by dietary piroxicam, a nonsteroidal anti-inflammatory
drug, during different stages of rat colon tumor development. Cancer Res
45. Cornwall H, Odukoya O, Shklar G: Oral mucosal tumor
inhibition by ibuprofen. J Oral Maxillofac Surg 41:795-800, 1983.
46. McCormick DL, Moon RC: Inhibition of mammary carcinogenesis
by flurbiprofen, a nonsteroidal anti-inflammatory agent. Br J Cancer 48:859-861,
47. McCormick DL, Madigan MJ, Moon RC: Modulation of rat mammary
carcinogenesis by indomethacin. Cancer Res 45:1803-1808, 1985.
48. Boolbol SK, Dannenberg AJ, Chadburn A, et al:
Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a
murine model of familial adenomatous polyposis. Cancer Res 56:2556-2560, 1996.
49. Perkins TM, Shklar G: Delay in hamster buccal pouch
carcinogenesis by aspirin and indomethacin. Oral Surg Oral Med Oral Pathol
50. Huang MT, Lou YR, Ma W, et al: Inhibitory effects of dietary
curcumin on forestomach, duodenal, and colon carcinogenesis in mice. Cancer Res
51. Leaper DJ, French BT, Bennett A: Breast cancer and
prostaglandins: A new approach to treatment. Br J Surg 66:683-686, 1979.
52. Bennett A, Berstock DA, Carroll MA: Increased survival of
cancer-bearing mice treated with inhibitors of prostaglandin synthesis alone or
with chemotherapy. Br J Cancer 45:762-768, 1982.
53. Thun MJ, Namboodiri MM, Heath CW Jr: Aspirin use and reduced
risk of fatal colon cancer. N Engl J Med 325:1593-1596, 1991.
54. Greenberg ER, Baron JA, Freeman DH, et al: Reduced risk of
large-bowel adenomas among aspirin users. The Polyp Prevention Study Group. J
Natl Cancer Inst 85:912-916, 1993.
55. Logan RF, Little J, Hawtin PG, et al: Effect of aspirin and
nonsteroidal anti-inflammatory drugs on colorectal adenomas: Case-control study
of subjects participating in the Nottingham faecal occult blood screening
programme. BMJ 307:285-289, 1993.
56. Suh O, Mettlin C, Petrelli NJ: Aspirin use, cancer, and
polyps of the large bowel. Cancer 72:1171-1177, 1993.
57. Coogan PF, Rao SR, Rosenberg L, et al: The relationship of
nonsteroidal anti-inflammatory drug use to the risk of breast cancer. Prev Med
58. Schreinemachers DM, Everson RB: Aspirin use and lung, colon,
and breast cancer incidence in a prospective study. Epidemiology 5:138-146,
59. Castelao JE, Yuan JM, Gago-Dominguez M, et al: Nonsteroidal
anti-inflammatory drugs and bladder cancer prevention. Br J Cancer 82:1364-1369,
60. Farrow DC, Vaughan TL, Hansten PD, et al: Use of aspirin and
other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric
cancer. Cancer Epidemiol Biomarkers Prev 7:97-102, 1998.
61. Reddy BS, Rao CV, Seibert K: Evaluation of cyclooxygenase-2
inhibitor for potential chemopreventive properties in colon carcinogenesis.
Cancer Res 56:4566-4569, 1996.
62. Kawamori T, Rao CV, Seibert K, et al: Chemopreventive
activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon
carcinogenesis. Cancer Res 58:409-412, 1998.
63. Harris RE, Alshafie GA, Abou-Issa H, et al: Chemoprevention
of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res
64. Alshafie GA, Abou-Issa HM, Seibert K, et al:
Chemotherapeutic evaluation of celecoxib, a cyclooxygenase-2 inhibitor, in a rat
mammary tumor model. Oncol Rep 7:1377-1381, 2000.
65. Waddell WR, Loughry RW: Sulindac for polyposis of the colon.
J Surg Oncol 24:83-87, 1983.
66. Hawk E, Lubet R, Limburg P: Chemoprevention in hereditary
colorectal cancer syndromes. Cancer 86:2551-2563, 1999.
67. Steinbach G, Lynch PM, Phillips RK, et al: The effect of
celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N
Engl J Med 342:1946-1952, 2000.
68. Hixson LJ, Earnest DL, Fennerty MB, et al: NSAID effect on
sporadic colon polyps. Am J Gastroenterol 88:1652-1656, 1993.
69. Ladenheim J, Garcia G, Titzer D, et al: Effect of sulindac
on sporadic colonic polyps. Gastroenterology 108:1083-1087, 1995.
70. Matsuhashi N, Nakajima A, Fukushima Y, et al: Effects of
sulindac on sporadic colorectal adenomatous polyps. Gut 40:344-349, 1997.
71. Gann PH, Manson JE, Glynn RJ, et al: Low-dose aspirin and
incidence of colorectal tumors in a randomized trial. J Natl Cancer Inst
72. Hawk ET, Viner JL, Anderson WF: Development of cyclooxygen
inhibitors as cancer chemopreventives, in Perry MC (ed): American Society of
Clinical Oncology Educational Book 2001, pp 28-37. Baltimore, Lippincott
Williams & Wilkins, 2001.
73. Rubio CA: Antitumoral activity of indomethacin on
experimental esophageal tumors. J Natl Cancer Inst 72:705-707, 1984.
74. Fischer SM, Lo HH, Gordon GB, et al: Chemopreventive
activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin
against ultraviolet light-induced skin carcinogenesis. Mol Carcinog 25:231-240,
75. Rivers JK, McLean DI: An open study to assess the efficacy
and safety of topical 3% diclofenac in a 2.5% hyaluronic acid gel for the
treatment of actinic keratoses. Arch Dermatol 133:1239-1242, 1997.
76. Grubbs CJ, Lubet RA, Koki AT, et al: Celecoxib inhibits
N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder cancers in male
B6D2F1 mice and female Fischer-344 rats. Cancer Res 60:5599-5602, 2000.
77. Moore RJ, Zweifel BS, Heuvelman DM: Enhanced antitumor
activity by co-administration of celecoxib and the chemotherapeutic agents
cyclophosphamide and 5-FU. Proc Am Assoc Cancer Res 41:409, 2000.
78. Milas L, Kishi K, Hunter N, et al: Enhancement of tumor
response to gamma-radiation by an inhibitor of cyclooxygenase-2 enzyme. J Natl
Cancer Inst 91:1501-1504, 1999.
79. Subbaramaiah K, Norton L, Gerald W, et al: Cyclooxygenase-2
is overexpressed in HER-2/neu-positive breast cancer. Evidence for involvement
of AP-1 and PEA3. J Biol Chem. In press.
80. Harris RE, Robertson FM, Abou-Issa HM, et al: Genetic
induction and upregulation of cyclooxygenase (COX) and aromatase (CYP19): An
extension of the dietary fat hypothesis of breast cancer. Med Hypotheses
81. Moos PJ, Fitzpatrick FA: Taxane-mediated gene induction is
independent of microtubule stabilization: Induction of transcription regulators
and enzymes that modulate inflammation and apoptosis. Proc Natl Acad Sci U S A
82. Moos PJ, Muskardin DT, Fitzpatrick FA: Effect of taxol and
taxotere on gene expression in macrophages: Induction of the prostaglandin H
synthase-2 isoenzyme. J Immunol 162:467-473, 1999.
83. Subbaramaiah K, Hart JC, Norton L, et al:
Microtubule-interfering agents stimulate the transcription of cyclooxygenase-2.
Evidence for involvement of ERK1/2 and p38 mitogen-activated protein kinase
pathways. J Biol Chem 275:14838-14845, 2000.