celecoxib, Celebrex
Celecoxib Inhibits Angiogenesis by Inducing Endothelial Cell Apoptosis in Human Pancreatic Tumor Xenografts.

Raut CP, Nawrocki S, Lashinger LM, Davis DW, Xiong H, Ellis LM, McConkey DJ.

Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Previous studies suggest that antagonists of cyclooxygenases 1 and 2 (COX-1, -2) inhibit angiogenesis in tumor xenografts, but the molecular mechanisms involved remain unclear. Here we characterized the effects of non-selective (indomethacin) and selective (NS398, celecoxib) cyclooxygenase inhibitors on parameters of angiogenesis in human pancreatic adenocarcinoma cells. COX-1 expression was constitutive in 9/9 pancreatic cancer cell lines, whereas COX-2 and cytosolic phospholipase A2 (cPLA(2)) expression were observed in 4/9 cell lines (BxPC3, Capan2, Cfpac1, and L3.6 pl). Production of the COX product, prostaglandin E2, correlated with expression of cPLA(2) and COX-2 and was blocked by non-steroidal anti-inflammatory drugs (NSAIDs, indomethacin or NS398). In contrast to the findings of others, neither indomethacin nor NS398 affected tumor cell secretion of angiogenic factors (VEGF, bFGF, IL-8) at concentrations that produced maximal inhibition of PGE(2) production, and higher concentrations increased angiogenic factor production. We also studied the effects of celecoxib in orthotopic L3.6 pl xenografts. Immunofluorescence analyses revealed high-level expression of COX-2 in endothelial cells in L3.6 pl xenografts that increased following therapy with celecoxib, whereas the tumor cells expressed uniformly low levels of COX-2. Celecoxib did not decrease tumor-associated VEGF levels in orthotopic human L3.6 pl xenografts, but the drug did decrease tumor microvessel density (MVD) and increase apoptosis in tumor-associated endothelial cells in a dose-dependent fashion. Together, our results demonstrate that the anti-angiogeneic effects of NSAIDs in human pancreatic cancer cells are exerted via direct effects on endothelial cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15477758&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Transfer of celecoxib into human milk.

Hale TW, McDonald R, Boger J.

Department of Pediatrics, Texas Tech University School of Medicine, Amarillo, TX, USA.

The aim of this study was to investigate the transfer of celecoxib into human milk. In one group of 3 breastfeeding patients on celecoxib at steady state, milk levels were determined at set intervals over 24 hours. Plasma levels were determined in 2 of their infants, age 17 and 22 months. In a second group of 2 subjects, intravenous lines were placed and a single 200-mg dose of celecoxib was followed by multiple paired plasma and milk samples over 8 hours. The mean milk-to-plasma ratio for celecoxib was 0.23 (95% confidence interval [CI]: 0.15-0.31). The average concentration of celecoxib in milk during the 8-hour dosing interval was 66 microg/L (95% CI: 41-89). The absolute infant dose averaged 9.8 microg/kg/d (95% CI: 6.2-13.4); the mean relative infant dose was 0.30%. Therefore, the average clinical dose transferred to the infant daily would be approximately 0.3% of the weight-adjusted maternal dose. The authors suggest that the use of celecoxib in breastfeeding mothers at these doses is very unlikely to cause untoward effects in breastfed infants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15479658&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Suppression of Peutz-Jeghers polyposis by inhibition of cyclooxygenase-2.

Udd L, Katajisto P, Rossi DJ, Lepisto A, Lahesmaa AM, Ylikorkala A, Jarvinen HJ, Ristimaki AP, Makela TP.

Molecular Cancer Biology Research Program, Biomedicum Helsinki, Finland.

BACKGROUND & AIMS: Peutz-Jeghers syndrome (PJS) is typically manifested as severe gastrointestinal polyposis. Polyps in PJS patients and in Lkb1(+/-) mice that model PJS polyposis are frequently characterized by elevated cyclooxygenase-2 (COX-2). This study was designed to determine whether COX-2 inhibition would reduce tumor burden in Lkb1(+/-) mice or Peutz-Jeghers patients. METHODS: Genetic interactions between Cox-2 and Lkb1 in polyp formation were analyzed in mice with combined deficiencies in these genes. Pharmacologic inhibition of COX-2 was achieved by supplementing the diet of Lkb1(+/-) mice with 1500 ppm celecoxib between 3.5-10 and 6.5-10 months. In PJS patients, COX-2 was inhibited with a daily dose of 2 x 200 mg celecoxib for 6 months. RESULTS: Total polyp burden in Lkb1(+/-) mice was significantly reduced in a Cox-2(+/-) (53%) and in a Cox-2(-/-) (54%) background. Celecoxib treatment initiating before polyposis (3.5-10 months) led to a dramatic reduction in tumor burden (86%) and was associated with decreased vascularity of the polyps. Late treatment (6.5-10 months) also led to a significant reduction in large polyps. In a pilot clinical study, a subset of PJS patients (2/6) responded favorably to celecoxib with reduced gastric polyposis. CONCLUSIONS: These data establish a role for COX-2 in promoting Peutz-Jeghers polyposis and suggest that COX-2 chemoprevention may prove beneficial in the treatment of PJS.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15480979&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Increased expression of cyclooxygenase (COX)-2 in DMBA-induced hamster cheek pouch carcinogenesis and chemopreventive effect of a selective COX-2 inhibitor celecoxib.

Nishimura N, Urade M, Hashitani S, Noguchi K, Manno Y, Takaoka K, Sakurai K.

Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo, Japan.

BACKGROUND: In recent years, overexpression of cyclooxygenase (COX)-2 protein and mRNA has been reported in various cancer tissues. Therefore, it has been suggested that COX-2 is related to carcinogenesis. METHODS: Hamsters were treated by painting a buccal pouch with a 0.5% DMBA solution dissolved in acetone. Basal diet or diets containing 150, 500 and 1500 ppm of celecoxib, a selective COX-2 inhibitor, were given ad libitum to hamsters, and tumor development was observed. RESULTS: Immunohistochemical and Western blot analyses revealed that COX-2 expression was increased toward the carcinogenesis. Although all hamsters developed squamous cell carcinoma, the onset of tumor formation was delayed in a dose-dependent manner. Also, tumor growth was retarded and survived animals were increased in the group of celecoxib treatment. Histologically, administration of celecoxib increased the apoptotic cells in the tumor parenchyma and significantly inhibited the angiogenesis in the stroma. CONCLUSIONS: The COX-2 expression was increased during hamster cheek pouch chemical carcinogenesis. Administration of celecoxib demonstrated the chemopreventive potential against the carcinogenesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15482328&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Interactions between aspirin and COX-2 inhibitors or NSAIDs in a rat thrombosis model.

Umar A, Boisseau M, Yusup A, Upur H, Begaud B, Moore N.

Department of Pharmacology, Universite Victor Segalen, 33076 Bordeaux, France.

Recent in vitro studies, clinical trials and epidemiological studies have suggested possible interactions between aspirin and other cyclo-oxygenase (COX) inhibitors, such as ibuprofen of the COX-2 inhibitors celecoxib and rofecoxib. The objective of this study was to test the effects of aspirin (1, 2.5 and 5 mg/kg), and ibuprofen (4 and 15 mg/kg), diclofenac (2.5 mg/kg), flurbiprofen (2 mg/kg), celecoxib (7.5 mg/kg), and rofecoxib (1 mg/kg), alone or combined on a rat model of arterial thrombosis. Drugs were given orally daily for 7 days, before insertion of an arterio-venous shunt thrombosis system, left in place for 15 min. Main parameter was thrombus weight. Five to 12 rats were used per experiment, and 35 controls overall. Aspirin inhibited thrombus formation in a dose-dependent manner. All NSAIDS given alone also inhibited thrombus formation to approximately the same level as aspirin 1 mg/kg/day. Ibuprofen, celecoxib and rofecoxib inhibited the effects of aspirin, but not diclofenac or flurbiprofen. The interactions with aspirin do not seem to affect all NSAIDs to equal levels. The clinical impact of this needs to be confirmed in adequately powered clinical trials or pharmaco-epidemiological studies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15482377&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Heterotropic modulation of sulfotransferase 2A1 activity by celecoxib: product ratio switching of ethynylestradiol sulfation.

Cui D, Booth-Genthe CL, Carlini E, Carr B, Schrag ML.

Drug Metabolism Department, Merck Research Laboratories, West Point, Pennsylvania, USA.

The major sulfated product of 17alpha-ethynylestradiol (EE) after incubations with 3'-phosphoadenosine-5'-phosphosulfate and recombinant human sulfotransferase 2A1 (SULT2A1), or liver cytosol, is the 3-O-sulfate of EE. However, when celecoxib is also present in the incubation, sulfation is switched (in a concentration-dependent manner) from the 3-O-position to the 17beta-O-position of ethynylestradiol. In incubations with recombinant SULT2A1, increasing concentrations of celecoxib decreased the Vmax of 3-O-sulfate product formation by 3- to 4-fold, with no major change in the Km value. For 17beta-O-sulfate formation, increasing concentrations of celecoxib resulted in an 8-fold decrease in the Km and a 7-fold increase in Vmax. Celecoxib not only modulated the regioselectivity of the enzyme, but also activated the enzyme such that total sulfated product exceeded product formation by the native enzyme, 3- to 4-fold (at 250 microM celecoxib). Finally, IC50 values obtained by varying celecoxib concentrations (0-250 microM) at fixed concentrations of EE showed that 3-O-sulfation was inhibited by celecoxib to the same extent, independent of the concentration of EE. In addition, the apparent kinetic constant for celecoxib (as measured by EE 17beta-O-sulfation) decreased 2-fold in the presence of high concentrations of EE, consistent with the potential for celecoxib to bind to either the enzyme-EE complex or to free enzyme. Taken as a whole, these data suggest that celecoxib is acting as a heterotropic modulator of SULT2A1 activity, most likely involving a separate noncompetitive binding site. Copyright 2004 The American Society for Pharmacology and Experimental Therapeutics

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15483193&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Celecoxib: a novel treatment for lung cancer.

Abou-Issa H, Alshafie G.

Ohio State University, Division of Surgical Oncology, Department of Surgery, College of Medicine & Public Health, M-260 Starling-Loving Hall, 320 W 10th Ave, Columbus, OH 43210, USA. abou-issa.1 osu.edu.

Lung cancer is by far the leading cause of cancer-related deaths. Overall survival is poor and has not improved substantially over the last 50 years. Therefore, it is clear that novel and more effective treatments are needed to improve the outcome of therapy. Recent attention has been drawn to the role of cyclooxygenase (COX)-2 in the pathogenesis of cancer, and it has been considered as an attractive target for therapeutic and chemopreventive strategies in lung cancer patients. Celecoxib (Celebrex((R)), Pfizer), a selective COX-2 inhibitor and potent anti-inflammatory agent, has been approved for the treatment of osteoarthritis and rheumatoid arthritis. This orally administered agent is generally well tolerated and has almost no gastrointestinal or renal toxicity. Phase II clinical trials suggest that COX-2 inhibition by celecoxib would enhance response to cytotoxic chemotherapy or radiation therapy through interference with cellular proliferation and tumor angiogenic processes, promotion of apoptosis and immune surveillance, or other possible mechanisms. Celecoxib has shown promising antitumor efficacy in lung cancer and a large variety of solid tumors that rely on COX-2-related mechanisms for growth and survival. This article reviews the profile of celecoxib and evidence supporting its role in the therapy of lung cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15485309&dopt=Abstract celecoxib, Celebrex