celecoxib, Celebrex
Effect of combined cyclooxygenase-2 and matrix metalloproteinase inhibition on human sarcoma xenografts.

Dickens DS, Cripe TP.

Division of Pediatric Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Ohio 45229, USA.

PURPOSE: Sarcomas express cyclooxygenase (COX)-2, an inducible enzyme with known tumor-promoting activity. COX-2 inhibition is efficacious against many cancer types but has not been tested for human sarcomas. Matrix metalloproteinase (MMP) inhibitors also possess antiproliferative activity. Because MMP inhibitor therapy induces COX-2 expression, the authors hypothesized that the combination of COX-2 and MMP inhibitors results in a synergistic antitumor effect. METHODS: Human osteosarcoma or rhabdomyosarcoma cells were injected into athymic mice. Tumor development and growth were measured following treatment with a COX-2 inhibitor (celecoxib), an MMP inhibitor (doxycycline), or both. The tumors were analyzed for necrosis, apoptosis, cyclooxygenase activity (PGE2 production), and MMP-2 levels. RESULTS: When treatment was started prior to tumor cell implantation, doxycycline inhibited osteosarcoma tumor growth alone and in combination with celecoxib (30% and 33% reduction, respectively). An effect on osteosarcoma tumor implantation rates was noted in mice receiving doxycycline alone and in combination with celecoxib (12.5% and 6.25% reduction, respectively). Established osteosarcoma and rhabdomyosarcoma tumors were inhibited only by combination therapy (36% and 55%, respectively). A higher proportion of osteosarcoma tumors in the combination therapy group had more than 50% necrosis (3/7) when compared with control tumors (0/8). Antitumor effects did not correlate with PGE2 levels, suggesting the observed interaction with doxycycline was due to previously described non-enzymatic effects of celecoxib. CONCLUSIONS: The authors' preclinical data suggest that the combination of inexpensive, nontoxic, oral COX-2 and MMP inhibitors may be useful for the treatment of some types of solid tumors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12972806&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
A retrospective review of the effect of COX-2 inhibitors on blood pressure change.

Cho J, Cooke CE, Proveaux W.

Global Health Outcomes, Pharmacia Corporation, Peapack, NJ, USA. mjeanniecho hotmail.com

The objective of this study was to compare the difference between celecoxib and rofecoxib on blood pressure change. A retrospective review of medical records where the mean blood pressure in a 90-day period before and after start of the cyclooxygenase (COX)-2 inhibitors, celecoxib, and rofecoxib was compared. Data were abstracted from 249 patient records, of which 109 were included. The mean systolic blood pressures at baseline were comparable at 134.14 mm Hg and 134.05 mm Hg for the celecoxib (n = 52) and rofecoxib groups (n = 57), respectively (P = NS). A nonsignificant decrease in systolic blood pressure was observed for the celecoxib group (-1.15 mm Hg), while a statistically significant increase in systolic blood pressure was seen in the rofecoxib group (4.76 mm Hg, P = 0.044). The mean diastolic blood pressures at baseline were not significantly different between the two groups, and changes in the postperiod were also not statistically different compared with baseline values. The average total daily dose of COX-2 inhibitor was 219.2 mg for celecoxib and 25.23 mg for rofecoxib. A post hoc analysis of patients aged 65 years and older showed that the mean systolic blood pressure in the rofecoxib group increased by 7.37 mm Hg (P = 0.016), while there was an insignificant decrease for the celecoxib group (-1.94 mm Hg). This study showed that there were no significant changes in blood pressure after celecoxib initiation. While in the rofecoxib group, there was a significant increase in systolic blood pressure with an even greater increase for patients aged 65 years and older.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12975714&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
4-substituted 1,5-diarylpyrazole, analogues of celecoxib: synthesis and preliminary evaluation of biological properties.

Menozzi G, Merello L, Fossa P, Mosti L, Piana A, Mattioli F.

Dipartimento di Scienze Farmaceutiche, Universita di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy. menozzi unige.it

A number of 5-aryl-1-[4-(methylsulfonyl)-phenyl]-1H-pyrazoles and 4-(5-aryl-1H-pyrazol-1-yl)benzenesulfonamides 3, 4, 5, 6, analogues of the COX-2 selective inhibitor celecoxib (celebrex), were synthesized. In order to verify the effects on the biological properties of certain substituents put on position 4 of the pyrazole nucleus, some of these compounds were screened in vivo for their anti-inflammatory and analgesic activities. Moreover, sodium salts of carboxylic acids 4 were tested in vitro for their platelet anti-aggregating properties. The results of these preliminary biological assays showed that new derivatives are not endowed with improved anti-inflammatory and analgesic properties, in comparison with celecoxib. In addition, docking studies were carried out on the most significative compounds to evaluate their interaction mode at the active site of both COX-1 and COX-2. Some remarks about the SAR of this class of COX-inhibitors are drown out.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=13679172&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Inhibition of COX-2 in colon cancer cell lines by celecoxib increases the nuclear localization of active p53.

Swamy MV, Herzog CR, Rao CV.

Chemoprevention Program, Institute For Cancer Prevention, American Health Foundation Cancer Center, Valhalla, New York 10595, USA.

Inactivation of the p53 tumor suppressor gene usually involves somatic mutation or binding of viral oncoproteins to the p53 protein. However, several types of malignant and premalignant tissues harbor a genetically wild-type, but transcriptionally inactive, form of p53, often localized in the cytoplasm. Electrophilic prostaglandins (PGs) are known to sequester and inactivate p53 in the cytoplasm, an effect that is likely to occur when cyclooxygenase (COX)-2 levels become elevated during colon carcinogenesis. We determined the localization and expression of p53 in the presence of PGA(1) and celecoxib, a selective COX-2 inhibitor in human colon cell lines HCT-116 (wild-type p53) and HT-29 (mutant p53). In the absence of treatment, p53 protein accumulated preferentially in the nucleus in both cell lines. We observed that the total cellular levels of p53 protein increased with exposure time and concentration of PGA(1). By contrast, p21 protein levels remained unchanged as a function of time and concentration of PGA(1). In the presence of 20 micro M PGA(1), p53 accumulated preferentially in the cytosol. The nuclear:cytosol ratios of p53 were 31 and 2.1 in the controls and in the presence of PGA(1) in HCT-116 cells but were 22 and 4, respectively, in HT-29 cells. Treatment with 50 micro M celecoxib for 24 h did not significantly change p53 expression and localization. However, in the presence of 100 micro M celecoxib, p53 levels increased in the nucleus. The nuclear:cytosol ratios were then 31 (control) and 60 (100 micro M celecoxib) in HCT-116 cells and 22 (control) and 36 (100 micro M celecoxib) in HT-29 cells. These results indicate that electrophilic PGs cause wild-type p53 accumulation in the cytosol where it is inactive. Inhibition of COX-2 by celecoxib appears to alleviate this effect on p53 by reducing electrophilic PG synthesis. Thus, COX-2 inhibition of electrophilic PG formation appears to protect p53 tumor suppressor function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14500353&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Inhibition of cutaneous ultraviolet light B-mediated inflammation and tumor formation with topical celecoxib treatment.

Wilgus TA, Koki AT, Zweifel BS, Kusewitt DF, Rubal PA, Oberyszyn TM.

Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA.

Inflammation, which includes the release of growth factors, proinflammatory cytokines and prostaglandins, the infiltration and activation of inflammatory cells, and the induction of oxidative DNA damage, is known to play a role in cancer development. The combination of damage to the skin resulting from chronic ultraviolet light B (UVB) exposure itself and the inflammatory response it induces is a major source of skin cancer development. Cyclooxygenase-2 (COX-2), an inflammatory enzyme responsible for the production of prostaglandins, is now implicated in the development of epithelial cancers, including squamous cell carcinoma in the skin. Previous work conducted in our laboratory has shown that topical treatment with celecoxib following UVB irradiation inhibits several parameters of acute inflammation, including vascular permeability, the infiltration and activation of neutrophils, and the production of prostaglandin E(2) (PGE(2)). The present studies expanded these observations, demonstrating the ability of topical celecoxib to inhibit acute oxidative damage. In addition, long-term studies illustrate the effectiveness of topical treatment with this drug in reducing chronic inflammation and UVB-induced papilloma/carcinoma formation. This data provides compelling evidence to explore the clinical efficacy of topically applied COX-2 inhibitors for the prevention of human skin cancers. Copyright 2003 Wiley-Liss, Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14502644&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Indomethacin and celecoxib improve tendon healing in rats.

Forslund C, Bylander B, Aspenberg P.

Orthopedic Department, Lund University Hospital, Lund, Sweden.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of bone. However, they have been shown to increase tensile strength in healing tendons. Most NSAIDs inhibit two isoforms of cyclooxygenases called Cox-1 and Cox-2. Thanks to fewer side-effects, the recently introduced selective cyclooxygenase-2 (Cox-2) inhibitors will probably promote more widespread use of this kind of drug. To clarify the effects on tendon healing of a general Cox-inhibitor (indomethacin) as well as a selective Cox-2 inhibitor (celecoxib), we resected 3 mm of the Achilles tendon in rats and measured the strength of the tendon regenerate. Indomethacin given as daily injections in doses of 1.5, 3.0 and 5.0 mg/kg reduced the thickness (cross-sectional area) of the tendon regenerate at 14 days, as compared to controls, but there was no difference in the failure load or stiffness. In another series of measurements, indomethacin in a dose of 3.0 mg/kg reduced the cross-sectional area at 10, 14 and 18 days after transsection. Failure load was not affected, but tensile stress at failure was increased by indomethacin at 14 and 18 days. Indomethacin (3 mg/kg) was then compared to celecoxib (4.5 mg/kg) and controls 14 days after tendon transsection. No difference between the drugs was seen. Again, the transverse area was smaller in the treated tendons than in the controls. Failure load was unchanged and the tensile stress was higher in the treated tendons than in the controls. Because of the reduction in cross-sectional area without an effect on failure load, the use of Cox-inhibitors may be beneficial in clinical situations where thickening of a healing tendon is a problem--e.g., in the hand or shoulder.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14521300&dopt=Abstract celecoxib, Celebrex



celecoxib, Celebrex
Chronic inhibition of cyclooxygenase-2 does not alter plaque composition in a mouse model of advanced unstable atherosclerosis.

Bea F, Blessing E, Bennett BJ, Kuo CC, Campbell LA, Kreuzer J, Rosenfeld ME.

Department of Pathobiology and the Interdisciplinary Graduate Program in Nutritional Sciences, University of Washington, Seattle, WA 98195, USA.

OBJECTIVE: Inflammation contributes to atherosclerotic plaque initiation and progression. Recent studies suggest that anti-inflammatory drugs such as cyclooxygenase-2 (Cox-2) inhibitors have anti-atherogenic effects. The current study was designed to investigate whether administration of a Cox-2 inhibitor to older apolipoprotein E deficient (apo E-/-) mice with established lesions alters the composition and increases the stability of the lesions. METHODS AND RESULTS: The Cox-2 inhibitor Celecoxib was administered in chow to 26-week-old, male, apo E-/- mice exhibiting advanced, unstable atherosclerotic lesions within the innominate/brachiocephalic artery. Mice administered Celecoxib had no significant changes in serum cholesterol or the average cross sectional area of atherosclerotic lesion in the innominate artery after 15 weeks of treatment in comparison to non-treated control mice. Histological analyses of sections of the innominate artery demonstrated no significant changes in the frequency of markers of advanced and unstable atherosclerotic plaques, including intra-plaque hemorrhage, vascular calcification, thinning of the fibrous cap, size of the necrotic core and macrophage content. There were also no significant differences in the content of Cox-2 within the lesions. Quantitative real time polymerase chain reaction with mRNA isolated from the aorta of each mouse revealed no significant changes in the expression of tissue factor and inducible nitric oxide synthase. However, mRNA levels for MCP-1 were increased fivefold following 15 weeks of treatment with Celecoxib in comparison to non-treated control mice. CONCLUSIONS: These data suggest that Celecoxib has no effect on the composition of advanced atherosclerotic lesions in older apo E-/- mice.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14522423&dopt=Abstract celecoxib, Celebrex