celecoxib, Celebrex
Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis.

Kawamori T, Rao CV, Seibert K, Reddy BS.

Division of Nutritional Carcinogenesis, American Health Foundation, Valhalla, New York 10595, USA.

Epidemiological and laboratory studies suggest that nonsteroidal antiinflammatory drugs reduce the risk of colon cancer and that the inhibition of colon carcinogenesis is mediated through modulation of prostaglandin production by cyclooxygenase (COX) isozymes (COX-1 and -2). Overexpression of COX-2 has been observed in colon tumors; therefore, specific inhibitors of COX-2 activity could potentially serve as chemopreventive agents. Our recent study indicated that celecoxib (SC-58635), a specific COX-2 inhibitor, suppressed colonic aberrant crypt foci formation induced by azoxymethane in rats and led us to investigate more specifically the chemopreventive potential of this compound using colon tumors as end points. Five-week-old male F344 rats were fed the control diet (modified AIN-76A) or an experimental diet containing 1500 ppm celecoxib. Two weeks later, all animals except those in the saline-treated groups received s.c. injections of azoxymethane (15 mg/kg of body weight) once weekly for 2 weeks. All groups were kept on their regimen until the experiment was terminated, 50 weeks after carcinogen treatment. Colon tumors were evaluated histopathologically. Remarkably, dietary administration of celecoxib inhibited both incidence and multiplicity of colon tumors by about 93 and 97%, respectively. It also suppressed the overall colon tumor burden by more than 87%. The degree of tumor inhibition was more pronounced with celecoxib than it was with previously evaluated nonsteroidal anti-inflammatory drugs. The results of this study provide evidence, for the first time, that a specific COX-2 inhibitor, celecoxib, possesses strong chemopreventive activity against colon carcinogenesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9458081&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Interactions between inducible isoforms of nitric oxide synthase and cyclo-oxygenase in vivo: investigations using the selective inhibitors, 1400W and celecoxib.

Hamilton LC, Warner TD.

Vascular Inflammation, The William Harvey Research Institute, St. Bartholomew's and the Royal London School of Medicine and Dentistry.

1. Exposure of tissues to endotoxin (LPS) and/or cytokines leads to the induction of both inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2). It has previously been reported that there is 'cross-talk' between these two systems. However, such previous studies have been limited by the availability of highly selective inhibitors. Here we have investigated the interactions between iNOS and COX-2 in vivo using 1400W, an iNOS-selective inhibitor, and celecoxib, a COX-2-selective inhibitor. 2. Infusion of LPS to rats for 6 h caused a time-dependent increase in the plasma concentrations of 6 keto-prostaglandin F1alpha (6 keto-PGF1alpha) and nitrite/nitrate (NO2/NO3), consistent with the induction of iNOS and COX-2. Bolus injection of arachidonic acid (AA) at t=6 h resulted in a further increase of circulating levels of 6 keto-PGF1alpha in LPS-treated animals. 3. Treatment of rats with 1400W or the non-selective NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) inhibited the increase in plasma NO2/NO3 but were both without effect on the plasma concentration of 6 keto-PGF1alpha before or after AA. 4. Treatment with the non-steroidal anti-inflammatory drugs (NSAIDs), A771726 or diclofenac, or with celecoxib significantly reduced the increase in circulating 6 keto-PGF1alpha caused by LPS, and the large increase in 6 keto-PGF1alpha following injection of AA. None of the COX inhibitors affected the increase in plasma NO2/NO3. Dexamethasone, however, significantly inhibited both the increase in 6 keto-PGF1alpha and the increase in NO2/NO3. 5. In conclusion, the use of selective inhibitors does not support the concept of cross talk in vivo between iNOS and COX-2.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9786506&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Pharmacological analysis of cyclooxygenase-1 in inflammation.

Smith CJ, Zhang Y, Koboldt CM, Muhammad J, Zweifel BS, Shaffer A, Talley JJ, Masferrer JL, Seibert K, Isakson PC.

Searle Research and Development, 700 Chesterfield Parkway North, St. Louis, MO 63198, USA.

The enzymes cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. These lipid mediators play important roles in inflammation and pain and in normal physiological functions. While there are abundant data indicating that the inducible isoform, COX-2, is important in inflammation and pain, the constitutively expressed isoform, COX-1, has also been suggested to play a role in inflammatory processes. To address the latter question pharmacologically, we used a highly selective COX-1 inhibitor, SC-560 (COX-1 IC50 = 0.009 microM; COX-2 IC50 = 6.3 microM). SC-560 inhibited COX-1-derived platelet thromboxane B2, gastric PGE2, and dermal PGE2 production, indicating that it was orally active, but did not inhibit COX-2-derived PGs in the lipopolysaccharide-induced rat air pouch. Therapeutic or prophylactic administration of SC-560 in the rat carrageenan footpad model did not affect acute inflammation or hyperalgesia at doses that markedly inhibited in vivo COX-1 activity. By contrast, celecoxib, a selective COX-2 inhibitor, was anti-inflammatory and analgesic in this model. Paradoxically, both SC-560 and celecoxib reduced paw PGs to equivalent levels. Increased levels of PGs were found in the cerebrospinal fluid after carrageenan injection and were markedly reduced by celecoxib, but were not affected by SC-560. These results suggest that, in addition to the role of peripherally produced PGs, there is a critical, centrally mediated neurological component to inflammatory pain that is mediated at least in part by COX-2.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9789085&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2.

McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA.

EUPENN Group of Investigators, Center For Experimental Therapeutics, University Of Pennsylvania, Philadelphia, PA 19104, USA.

Prostaglandins (PG) are synthesized by two isoforms of the enzyme PG G/H synthase [cyclooxygenase (COX)]. To examine selectivity of tolerated doses of an inhibitor of the inducible COX-2 in humans, we examined the effects of celecoxib on indices of COX-1-dependent platelet thromboxane (Tx) A2 and on systemic biosynthesis of prostacyclin in vivo. Volunteers received doses of 100, 400, or 800 mg of celecoxib or 800 mg of a nonselective inhibitor, ibuprofen. Ibuprofen, but not celecoxib, significantly inhibited TxA2-dependent aggregation, induced ex vivo by arachidonic acid (83 +/- 11% vs. 11. 9 +/- 2.2%; P < 0.005) and by collagen. Neither agent altered aggregation induced by thromboxane mimetic, U46619. Ibuprofen reduced serum TxB2 (-95 +/- 2% vs. -6.9 +/- 4.2%; P < 0.001) and urinary excretion of the major Tx metabolite, 11-dehydro TxB2 (-70 +/- 9.9% vs. -20.3 +/- 5.3%; P < 0.05) when compared with placebo. Despite a failure to suppress TxA2-dependant platelet aggregation, celecoxib had a modest but significant inhibitory effect on serum TxB2 4 hr after dosing. By contrast, both ibuprofen and celecoxib suppressed a biochemical index of COX-2 activity (endotoxin induced PGE2 in whole blood ex vivo) to a comparable degree (-93.3 +/- 2% vs. -83 +/- 6.1%). There was no significant difference between the doses of celecoxib on COX-2 inhibition. Celecoxib and ibuprofen suppressed urinary excretion of the prostacyclin metabolite 2,3 dinor 6-keto PGF1alpha. These data suggest that (i) platelet COX-1-dependent aggregation is not inhibited by up to 800 mg of celecoxib; (ii) comparable COX-2 inhibition is attained by celecoxib (100-800 mg) and ibuprofen (800 mg) after acute dosing; and (iii) COX-2 is a major source of systemic prostacyclin biosynthesis in healthy humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9874808&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Solubility enhancement of celecoxib using beta-cyclodextrin inclusion complexes.

Rawat S, Jain SK.

YB Chavan College of Pharmacy, Rouza Bagh, Aurangabad, MS, India. swati k.st

Celecoxib has very low water solubility. It forms a complex with beta-cyclodextrin (betaCD) both in aqueous and in solid state. It was observed that due to formation of the inclusion complex, the solubility and dissolution rate of celecoxib were enhanced. The formation of 1:1 complex with betaCD in solution was confirmed by phase solubility and spectral shift studies. The apparent stability constants calculated by these techniques were 881.5 and 341.5 M(-1), respectively. The solid inclusion complexes of celecoxib and betaCD were prepared by the kneading method using different molar proportions of betaCD, and formation of solid inclusion complexes of celecoxib and betaCD at different molar ratios were confirmed by differential scanning calorimetry. Enhancement of dissolution rates with increasing quantity of betaCD in the complex was observed. It was also observed that the complexes exhibit higher dissolution rates than the pure drug and physical mixture.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15018983&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Growth inhibition of breast epithelial cells by celecoxib is associated with upregulation of insulin-like growth factor binding protein-3 expression.

Levitt RJ, Buckley J, Blouin MJ, Schaub B, Triche TJ, Pollak M.

Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Que., Canada H3T 1E2.

Several experimental and epidemiological studies have suggested a role for the use of cyclooxygenase (COX)-2 inhibitors in the prevention of breast cancer. The relative lack of toxicity associated with these compounds favors their use as chemopreventive agents, but the underlying mechanism of their chemopreventive effect remains unclear. We have observed that the COX-2 inhibitor celecoxib inhibits growth and induces apoptosis in the immortalized breast epithelial cell line 184htert. Microarray gene expression analysis of 184htert cells treated with 50 microM celecoxib for 6h revealed the modulation of several genes of interest, including a significant induction of expression of the mRNA encoding insulin-like growth factor binding protein-3 (IGFBP-3). IGFBP-3 is a potent pro-apoptotic protein and growth inhibitor of breast cancer cells, which acts mainly by inhibiting the access of the mitogens IGF-I and IGF-II to their cell surface receptor, but also via IGF-independent effects. Quantitative real-time RT PCR demonstrated that 50 microM celecoxib induced a approximately 3-fold increase in expression of IGFBP-3 mRNA after 6h. Furthermore, ligand blot analysis revealed that celecoxib treatment was associated with the upregulation of IGFBP-3 at the protein level. IGFBP-3 (500 ng/ml) treatment of 184htert cells inhibited IGF-I and serum-induced proliferation, but had no effect on cell growth under serum-free conditions, indicating that IGF-independent effects of IGFBP-3 are not observed in this system. Our results suggest that celecoxib may decrease IGF-I-associated breast cancer risk by a mechanism involving induction of expression of IGFBP-3 and subsequent reduced proliferation of at-risk breast epithelial cells.

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celecoxib, Celebrex
Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity.

Wei D, Wang L, He Y, Xiong HQ, Abbruzzese JL, Xie K.

Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

The aggressive biology of human pancreatic adenocarcinoma has been linked with overexpression of vascular endothelial growth factor (VEGF). Constitutive activation of the transcription factor Sp1 plays a critical role in VEGF overexpression. Recent studies indicated that celecoxib, a selective cyclooxygenase-2 inhibitor, exhibits potent antitumor activity. However, the underlying molecular mechanisms of this activity remain unclear. In the present study, we used a pancreatic cancer model to determine the role of Sp1 in the antitumor activity of celecoxib. Treatment of various pancreatic cancer cells with celecoxib suppressed VEGF expression at both the mRNA and protein level in a dose-dependent manner. VEGF promoter deletion and point mutation analyses indicated that a region between nucleotide -109 and -61 and its intact Sp1-binding sites were required for the inhibition of VEGF promoter activity by celecoxib. Also, celecoxib treatment reduced both Sp1 DNA binding activity and transactivating activity. This decreased activity correlated with reduced Sp1 protein and its phosphorylation as determined using Western blot analysis. Furthermore, in an orthotopic pancreatic cancer animal model, celecoxib treatment inhibited tumor growth and metastasis. The antitumor activity was consistent with inhibition of angiogenesis as determined by evaluating tumor microvessel formation, which correlated with decreased Sp1 activity and VEGF expression. Collectively, our data provide a novel molecular mechanism for the antitumor activity of celecoxib and may help further improve its effectiveness in controlling pancreatic cancer growth and metastasis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15026340&dopt=Abstract celecoxib, Celebrex