| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Advances in Brief |
Departments of Surgery [O. N. T., A. J. D., L. T., J. M. D., T. J. F.], Medicine [A. J. D., E. K. Y.], and Pathology [R. A. S.], New York Presbyterian Hospital and Weill Medical College of Cornell University, and Strang Cancer Prevention Center [A. J. D., F. Z., T. J. F.], New York, New York 10021; and Searle Discovery Research, Monsanto Company, St. Louis, Missouri 63017 [J. L. M., B. M. W., A. T. K.]
| ABSTRACT |
|---|
|
|
|---|
| Introduction |
|---|
|
|
|---|
25,000 new cases of pancreatic cancer are diagnosed annually (1)
. Pancreatic cancer now ranks fourth and fifth as a cause of cancer death in men and women, respectively, in the United States (1)
. Unfortunately, >90% of pancreatic cancer patients present with metastatic disease or advanced local disease, precluding a curative surgical resection. Chemotherapy has not resulted in a significant survival benefit, and the 5-year survival rate is <1.3% in the United States (1)
, with a median survival of 4.1 months. On the basis of these observations, it is clear that new molecular targets are needed for the prevention and treatment of pancreatic cancer. Results from recent studies have established the presence of two distinct COX3 enzymes, a constitutive enzyme (COX-1) and an inducible form (COX-2). COXs catalyze the formation of prostaglandins from arachidonic acid. COX-1 is thought to be a housekeeping gene with essentially constant levels of expression, whereas COX-2 is an early response gene that, like c-jun and c-fos, is induced rapidly by growth factors, tumor promoters, oncogenes, and carcinogens (2) .
Multiple lines of evidence suggest that COX-2 is important in carcinogenesis. For example, COX-2 is up-regulated in transformed cells (3)
and in various forms of cancer (4, 5, 6, 7)
, whereas levels of COX-1 are relatively constant. Moreover, a null mutation for COX-2 caused a marked reduction in the number and size of intestinal polyps in APC
716 mice, a murine model of familial adenomatous polyposis (8)
. COX-2 knockout mice also developed
75% fewer chemically induced skin papillomas than control mice (9)
. In addition to the genetic evidence implicating COX-2 in carcinogenesis, newly developed selective inhibitors of COX-2 protect against gastrointestinal tumor formation (8
, 10)
. Here, we investigated whether COX-2 was up-regulated in pancreatic cancer. Our data show that levels of COX-2 are increased in adenocarcinoma of the pancreas and raise the possibility that selective inhibitors of COX-2 may be useful in the prevention or treatment of this disease.
| Materials and Methods |
|---|
|
|
|---|
Patient Samples.
Biopsy specimens were obtained at the time of surgery from 10 patients with adenocarcinoma of the exocrine pancreas. Tissue samples were taken from a nonnecrotic area of the tumor and from adjacent nontumorous tissue; samples were immediately frozen in liquid nitrogen and subsequently stored at -80°C. Informed consent was obtained from each patient. The study was approved by the Committee on Human Rights in Research at Weill Medical College of Cornell University.
Tissue Culture.
Three human pancreatic adenocarcinoma cell lines (Su 86.86, BxPC-3, and Panc-1) were obtained from American Type Culture Collection (Manassas, VA). The Su 86.86 and BxPC-3 cell lines were maintained in RPMI 1640; the Panc-1 cell line was maintained in DMEM supplemented with 10% FCS, 100 units/ml penicillin, and 100 µg/ml streptomycin. Cells were plated for experimental use in complete medium and allowed to attach and grow for 48 h in a 5% CO2/water-saturated incubator at 37°C. The medium was then replaced with serum-free medium. Twenty-four h later, cells were treated with vehicle or PMA under serum-free conditions.
Western Blotting.
Frozen tissue was thawed in ice-cold homogenization buffer containing 150 mM NaCl, 100 mM Tris-buffered saline (pH 8), 1% Tween 20, 50 mM diethyldithiocarbamate, 1 mM EDTA, 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml leupeptin, 10 µg/ml aprotinin, 10 µg/ml trypsin-chymotrypsin inhibitor, and 10 µg/ml pepstatin. Tissues were homogenized using a glass-on-glass tissue homogenizer. Homogenates were centrifuged at 11,750 x g for 10 min at 4°C to remove the particulate material.
Cellular lysates were prepared by treating cells with the same lysis buffer that was used for the tissue samples. Lysates were sonicated for 20 s on ice and centrifuged at 11,750 x g for 10 min to sediment the particulate material. The protein concentration of the supernatant was measured using the Lowry protein assay kit. Immunoblot analysis for COX-2 was performed as in previous studies (11) .
Construction of a COX-2 Competitor Template Containing a nt Deletion.
A competitive RT-PCR deletion construct (mimic) for COX-2 was synthesized using a mutant sense primer (nt 932955 attached to nt 11111130; 5'-GGTCTGGTGCCTGGTCTGATGATGGAGTGGCTATCACTTCAAAC-3') and an antisense primer (nt 16341655; 5'-GTCCTTTCAAGGAGAATGGTGC-3'), producing a 569-bp PCR product. The mutant sense primer contains the primer-binding sequence of endogenous target (from nt 932 to 955) attached to the end of an intervening DNA sequence (a 156-bp deletion from nt 956 to nt 1110). Thus, the mimic DNA has primer binding sequences that are identical to the target cDNA. The 569-bp mimic was further amplified using the sense primer (5'-GGTCTGGTGCCTGGTCTGATGATG-3') and the antisense primer (5'-GTCCTTTCAAGGAGAATGGTGC-3') in a reaction mixture containing 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 2 mM MgCl2, 0.2 mM dNTP, 2.5 units of AmpiTaq DNA polymerase, and 400 nM primers for 35 cycles consisting of denaturation at 94°C for 20 s, annealing at 60°C for 20 s, and extension at 72°C for 30 s in a Perkin Elmer 2400 thermal cycler. The PCR products were electrophoresed on 1% agarose gels and gel-purified using GenElute Agarose Spin Columns according to the manufacturers protocol.
RNA Isolation and Reverse Transcription.
Total RNA was isolated from pancreatic tissue (
50 mg) and cell monolayers using an RNeasy Mini Kits from Qiagen. One µg of total RNA was reverse-transcribed using the GeneAmp RNA PCR kit according to the manufacturers protocol.
Quantitative PCR for COX-2 in Human Pancreatic Tissue.
Each PCR was carried out in 25 µl of a reaction mix, containing 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 2 mM MgCl2, 0.2 mM dNTP, 2.5 units of Amplitaq DNA polymerase, and 400 nM primers (sense primer, 5'-GGTCTGGTGCCTGGTCTGATGATG-3'; antisense primer, 5'-GTCCTTTCAAGGAGAATGGTGC-3'). Five-µl aliquots of the reverse-transcribed cDNA samples and various known amounts of COX-2 mimic (between 0.0001 and 0.05 pg), adjusted to the abundance of the target cDNA, were added to the reaction mix and coamplified for 35 cycles: denaturation at 94°C for 20 s, annealing at 65°C for 20 s, extension at 72°C for 90 s, and final extension at 72°C for 10 min. Ten µl of PCR products, 724-bp fragments from endogenous target cDNA, and 569-bp fragments from mimic COX-2 were then separated by electrophoresis on 1% agarose gels and visualized by ethidium bromide staining.
Semiquantitative PCR for COX-2 and ß2-microglobulin in Pancreatic Cell Lines.
The semiquantitative analysis for COX-2 was performed using the same COX-2 primers as listed above in a 25-µl reaction mixture containing 5-µl aliquots of reverse transcribed cDNA samples, 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 2 mM MgCl2, 0.2 mM dNTP, 2.5 units of AmpliTaq DNA polymerase, and 400 nM primers for 35 cycles consisting of denaturation at 94°C for 20 s, annealing at 65°C for 20 s, extension at 72°C for 30 s, and final extension at 72°C for 10 min. A constitutively expressed gene, ß2-microglobulin, was used as an internal control, generating a 266-bp PCR product. The primers for ß2-microglobulin (from nt 75 to nt 340) were 5'-AGCAGAGAATGGAAAGTCAAA-3' (sense) and 5'-ATGCTGCTTACATGTCTCGAT-3' (antisense). The PCR conditions for ß2-microglobulin were identical to that for COX-2, except for annealing at 55°C for 20 s.
Immunohistochemistry.
Tissues from 10 patients with adenocarcinoma of the pancreas were fixed in formalin, embedded in paraffin, cut into 4-µm sections and mounted onto polylysine-coated slides. Sections were dewaxed in xylene, rehydrated in descending alcohols, and blocked for endogenous peroxidase (3% H2O2 in MeOH) and avidin/biotin (Vector Blocking Kit). The sections were permeabilized in TNB-BB [0.1 M Tris (pH 7.5), 0.15 M NaCl, 0.5% blocking agent, 0.3% Triton X-100, and 0.2% saponin) and incubated in primary antibody overnight at 4°C. The polyclonal antiserum to COX-2 (PG-27; Oxford Biomedical Research Inc.) was used at a 1:500 dilution in TNB-BB. Control sections were incubated with antisera in the presence of a 100-fold excess of human recombinant COX-2 protein or with isotype-matched IgG normal rabbit serum. Immunoreactive complexes were detected using tyramide signal and amplification (TSA-indirect) and visualized with the peroxidase substrate, AEC. Slides were then counter stained in aqueous hematoxylin, mounted in crystal mount, and coverslipped in 50:50 xylene/Permount.
Statistical Analysis.
Results were analyzed by the Wilcoxon signed rank test. A difference between groups of P < 0.05 was considered significant.
| Results |
|---|
|
|
|---|
|
|
|
| Discussion |
|---|
|
|
|---|
COX-2 can potentially predispose to carcinogenesis via multiple mechanisms. In extrahepatic tissues in which cytochrome P450 content is low, COX may be important for metabolism of carcinogens. For example, several classes of chemical carcinogens, e.g., dihydrodiol derivatives of polycyclic aromatic hydrocarbons, aromatic amines, and heterocyclic amines, are activated to mutagenic derivatives by COX (12) . The metabolism of carcinogens by COX-2 may be important, therefore, for understanding the link between cigarette smoking (1) or consumption of grilled or fried meat (1) and pancreatic cancer. Additionally, enhanced synthesis of prostaglandins, a consequence of up-regulation of COX-2, favors the growth of malignant cells by increasing cell proliferation (13) , promoting angiogenesis (14) , and inhibiting immune surveillance (15) . In intestinal epithelial cells, overexpression of COX-2 inhibits apoptosis (16) and increases the invasiveness of malignant cells (17) . Additional studies are needed to determine which of these mechanisms are important in adenocarcinoma of the pancreas.
It also is interesting to consider the possible link between the known genetic alterations in pancreatic cancer and COX-2. Mutations in the Ki-ras oncogene (18) are common in pancreatic cancer. Levels of COX-2 are increased in Ras-transformed epithelial cells (3 , 19) . It is reasonable to postulate, therefore, that activation of the Ras pathway contributes to the up-regulation of COX-2 in pancreatic cancer. Mutations of the Apc gene also occur in pancreatic cancer (20) . The potential significance of the link between COX-2 and Apc was highlighted by the finding that COX-2 deficiency protects against tumor formation in mice carrying a defective Apc gene (8) .
Recently, selective inhibitors of COX-2 have been developed. These compounds possess anticancer properties (8 , 10) and appear to be safer than traditional nonsteroidal anti-inflammatory drugs. On the basis of results of this study, it will be important to establish whether inhibiting COX-2 will be useful alone or in combination with chemotherapy or radiotherapy as a novel treatment for pancreatic cancer.
| FOOTNOTES |
|---|
1 This work was supported by the Alice Bohmfalk Charitable Trust to T. J. F. ![]()
2 To whom requests for reprints should be addressed, at New York Presbyterian Hospital-Cornell University, Room F-2024, 525 East 68th Street, New York, NY 10021. Phone: (212) 746-5130; Fax: (212) 746-8771; E-mail: tjfahey{at}mail.med.cornell.edu ![]()
3 The abbreviations used are: COX, cyclooxygenase; PMA, phorbol 12-myristate 13-acetate; RT-PCR, reverse transcription-PCR; nt, nucleotide(s). ![]()
Received 11/19/98. Accepted 1/14/99.
| REFERENCES |
|---|
|
|
|---|
716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell, 87: 803-809, 1996.[Medline]
This article has been cited by other articles:
![]() |
S. A. Danovi, H. H. Wong, and N. R. Lemoine Targeted therapies for pancreatic cancer Br. Med. Bull., September 1, 2008; 87(1): 97 - 130. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. Dhillon, B. B. Aggarwal, R. A. Newman, R. A. Wolff, A. B. Kunnumakkara, J. L. Abbruzzese, C. S. Ng, V. Badmaev, and R. Kurzrock Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer Clin. Cancer Res., July 15, 2008; 14(14): 4491 - 4499. [Abstract] [Full Text] [PDF] |
||||
![]() |
M.-R. Pan, M.-F. Hou, H.-C. Chang, and W.-C. Hung Cyclooxygenase-2 Up-regulates CCR7 via EP2/EP4 Receptor Signaling Pathways to Enhance Lymphatic Invasion of Breast Cancer Cells J. Biol. Chem., April 25, 2008; 283(17): 11155 - 11163. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Mehar, P. Macanas-Pirard, A. Mizokami, Y. Takahashi, G. E. N. Kass, and H. M. Coley The Effects of Cyclooxygenase-2 Expression in Prostate Cancer Cells: Modulation of Response to Cytotoxic Agents J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 1181 - 1187. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. F.G. de Maat, C. J.H. van de Velde, N. Umetani, P. de Heer, H. Putter, A. Q. van Hoesel, G. A. Meijer, N. C. van Grieken, P. J.K. Kuppen, A. J. Bilchik, et al. Epigenetic Silencing of Cyclooxygenase-2 Affects Clinical Outcome in Gastric Cancer J. Clin. Oncol., November 1, 2007; 25(31): 4887 - 4894. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. Carriere, E. S. Seeley, T. Goetze, D. S. Longnecker, and M. Korc The Nestin progenitor lineage is the compartment of origin for pancreatic intraepithelial neoplasia PNAS, March 13, 2007; 104(11): 4437 - 4442. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Jimeno, M. L. Amador, P. Kulesza, X. Wang, B. Rubio-Viqueira, X. Zhang, A. Chan, J. Wheelhouse, H. Kuramochi, K. Tanaka, et al. Assessment of celecoxib pharmacodynamics in pancreatic cancer Mol. Cancer Ther., December 1, 2006; 5(12): 3240 - 3247. [Abstract] [Full Text] [PDF] |
||||
![]() |
I. Sugihara, M. Yoshida, T. Shigenobu, H. Takagi, K. Maruyama, N. Takeuchi, M. Toda, M. Inoue, and H. Nakada Different Progression of Tumor Xenografts between Mucin-Producing and Mucin-Non-Producing Mammary Adenocarcinoma-Bearing Mice. Cancer Res., June 15, 2006; 66(12): 6175 - 6182. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. H. Byun, M. A. Lee, S. Y. Roh, B. Y. Shim, S. H. Hong, Y. H. Ko, S. J. Ko, I. S. Woo, J. H. Kang, Y. S. Hong, et al. Association between Cyclooxygenase-2 and Matrix Metalloproteinase-2 Expression in Non-Small Cell Lung Cancer Jpn. J. Clin. Oncol., May 1, 2006; 36(5): 263 - 268. [Abstract] [Full Text] [PDF] |
||||
![]() |
A Juuti, J Louhimo, S Nordling, A Ristimaki, and C Haglund Cyclooxygenase-2 expression correlates with poor prognosis in pancreatic cancer J. Clin. Pathol., April 1, 2006; 59(4): 382 - 386. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Chen, H. Hwang, M. E. Rose, R. G. Nines, and G. D. Stoner Chemopreventive Properties of Black Raspberries in N-Nitrosomethylbenzylamine-Induced Rat Esophageal Tumorigenesis: Down-regulation of Cyclooxygenase-2, Inducible Nitric Oxide Synthase, and c-Jun. Cancer Res., March 1, 2006; 66(5): 2853 - 2859. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. J. Tyson-Capper and G. N. Europe-Finner Novel Targeting of Cyclooxygenase-2 (COX-2) Pre-mRNA Using Antisense Morpholino Oligonucleotides Directed to the 3' Acceptor and 5' Donor Splice Sites of Exon 4: Suppression of COX-2 Activity in Human Amnion-Derived WISH and Myometrial Cells Mol. Pharmacol., March 1, 2006; 69(3): 796 - 804. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. F. Souza and S. J. Spechler Concepts in the Prevention of Adenocarcinoma of the Distal Esophagus and Proximal Stomach CA Cancer J Clin, November 1, 2005; 55(6): 334 - 351. [Abstract] [Full Text] [PDF] |
||||
![]() |
F. Fanfani, A. Fagotti, G. Ferrandina, G. Bifulco, F. Legge, D. Lorusso, L. Minelli, and G. Scambia Increased cyclooxygenase-2 expression is associated with better clinical outcome in patients submitted to complete ablation for severe endometriosis Hum. Reprod., October 1, 2005; 20(10): 2964 - 2968. [Abstract] [Full Text] [PDF] |
||||
![]() |
V. Marwaha, Y.-H. Chen, E. Helms, S. Arad, H. Inoue, E. Bord, R. Kishore, R. D. Sarkissian, B. A. Gilchrest, and D. A. Goukassian T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NF{kappa}B-dependent Repression of the COX-2 Promoter J. Biol. Chem., September 16, 2005; 280(37): 32379 - 32388. [Abstract] [Full Text] [PDF] |
||||
![]() |
V. Mollace, C. Muscoli, E. Masini, S. Cuzzocrea, and D. Salvemini Modulation of Prostaglandin Biosynthesis by Nitric Oxide and Nitric Oxide Donors Pharmacol. Rev., June 1, 2005; 57(2): 217 - 252. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. K. Altorki, J. L. Port, F. Zhang, D. Golijanin, H. T. Thaler, A. J. Duffield-Lillico, K. Subbaramaiah, and A. J. Dannenberg Chemotherapy Induces the Expression of Cyclooxygenase-2 in Non-Small Cell Lung Cancer Clin. Cancer Res., June 1, 2005; 11(11): 4191 - 4197. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Santini, B. Vincenzi, G. Tonini, S. Scarpa, F. Vasaturo, C. Malacrino, F. Vecchio, D. Borzomati, S. Valeri, R. Coppola, et al. Cyclooxygenase-2 Overexpression Is Associated with a Poor Outcome in Resected Ampullary Cancer Patients Clin. Cancer Res., May 15, 2005; 11(10): 3784 - 3789. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. Oyama, T. Fujimura, I. Ninomiya, T. Miyashita, S. Kinami, S. Fushida, T. Ohta, and M. Koichi A COX-2 inhibitor prevents the esophageal inflammation-metaplasia-adenocarcinoma sequence in rats Carcinogenesis, March 1, 2005; 26(3): 565 - 570. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. I. Patel, K. Subbaramaiah, B. Du, M. Chang, P. Yang, R. A. Newman, C. Cordon-Cardo, H. T. Thaler, and A. J. Dannenberg Celecoxib Inhibits Prostate Cancer Growth: Evidence of a Cyclooxygenase-2-Independent Mechanism Clin. Cancer Res., March 1, 2005; 11(5): 1999 - 2007. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Eibl, Y. Takata, L. G. Boros, J. Liu, Y. Okada, H. A. Reber, and O. J. Hines Growth Stimulation of COX-2-Negative Pancreatic Cancer by a Selective COX-2 Inhibitor Cancer Res., February 1, 2005; 65(3): 982 - 990. [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] |
||||
![]() |
H.-P. Lin, S. K. Kulp, P.-H. Tseng, Y.-T. Yang, C.-C. Yang, C.-S. Chen, and C.-S. Chen Growth inhibitory effects of celecoxib in human umbilical vein endothelial cells are mediated through G1 arrest via multiple signaling mechanisms Mol. Cancer Ther., December 1, 2004; 3(12): 1671 - 1680. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. D. Basu, L. B. Pathangey, T. L. Tinder, M. LaGioia, S. J. Gendler, and P. Mukherjee Cyclooxygenase-2 Inhibitor Induces Apoptosis in Breast Cancer Cells in an In vivo Model of Spontaneous Metastatic Breast Cancer Mol. Cancer Res., November 1, 2004; 2(11): 632 - 642. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. Ito, M. Duxbury, E. Benoit, T. E. Clancy, M. J. Zinner, S. W. Ashley, and E. E. Whang Prostaglandin E2 Enhances Pancreatic Cancer Invasiveness through an Ets-1-Dependent Induction of Matrix Metalloproteinase-2 Cancer Res., October 15, 2004; 64(20): 7439 - 7446. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. F. Souza, K. Shewmake, S. Pearson, G. A. Sarosi Jr., L. A. Feagins, R. D. Ramirez, L. S. Terada, and S. J. Spechler Acid increases proliferation via ERK and p38 MAPK-mediated increases in cyclooxygenase-2 in Barrett's adenocarcinoma cells Am J Physiol Gastrointest Liver Physiol, October 1, 2004; 287(4): G743 - G748. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. E. Zeytin, A. C. Patel, C. J. Rogers, D. Canter, S. D. Hursting, J. Schlom, and J. W. Greiner Combination of a Poxvirus-Based Vaccine with a Cyclooxygenase-2 Inhibitor (Celecoxib) Elicits Antitumor Immunity and Long-Term Survival in CEA.Tg/MIN Mice Cancer Res., May 15, 2004; 64(10): 3668 - 3678. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. D. WARNER and J. A. MITCHELL Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic FASEB J, May 1, 2004; 18(7): 790 - 804. [Abstract] [Full Text] [PDF] |
||||
![]() |
V. Quidville, N. Segond, E. Pidoux, R. Cohen, A. Jullienne, and S. Lausson Tumor Growth Inhibition by Indomethacin in a Mouse Model of Human Medullary Thyroid Cancer: Implication of Cyclooxygenases and 15-Hydroxyprostaglandin Dehydrogenase Endocrinology, May 1, 2004; 145(5): 2561 - 2571. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Lanza-Jacoby, A. P. Dicker, S. Miller, F. E. Rosato, J. T. Flynn, S. N. Lavorgna, and R. Burd Cyclooxygenase (COX)-2-dependent effects of the inhibitor SC236 when combined with ionizing radiation in mammary tumor cells derived from HER-2/neu mice Mol. Cancer Ther., April 1, 2004; 3(4): 417 - 424. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Wei, L. Wang, Y. He, H. Q. Xiong, J. L. Abbruzzese, and K. Xie Celecoxib Inhibits Vascular Endothelial Growth Factor Expression in and Reduces Angiogenesis and Metastasis of Human Pancreatic Cancer via Suppression of Sp1 Transcription Factor Activity Cancer Res., March 15, 2004; 64(6): 2030 - 2038. [Abstract] [Full Text] [PDF] |
||||
![]() |
O. N. Tucker, A. J. Dannenberg, E. K. Yang, and T. J. Fahey III Bile acids induce cyclooxygenase-2 expression in human pancreatic cancer cell lines Carcinogenesis, March 1, 2004; 25(3): 419 - 423. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. K. Kulp, Y.-T. Yang, C.-C. Hung, K.-F. Chen, J.-P. Lai, P.-H. Tseng, J. W. Fowble, P. J. Ward, and C.-S. Chen 3-Phosphoinositide-Dependent Protein Kinase-1/Akt Signaling Represents a Major Cyclooxygenase-2-Independent Target for Celecoxib in Prostate Cancer Cells Cancer Res., February 15, 2004; 64(4): 1444 - 1451. [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] |
||||