NSAIDs, gastroprotection and cyclo‐oxygenase‐II‐selective inhibitors*

Micklewright, Ruth; Lane, Stephen; Linley, W.; McQuade, Colin; Thompson, Fiona; Maskrey, Neal

doi:10.1046/j.1365-2036.2003.01454.x

Cited by 74 publications

(40 citation statements)

References 46 publications

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“…Inhibition of cell division and alteration of the cell cycle distribution were observed in cultured colon cancer cells, tumor cells were arrested in G 0 /G 1 phase, and finally undergoing apoptosis. Furthermore, etodolac was found to inhibit COX-2 associated PGE 2 synthesis in HT-29/Inv3 cell lines (26,27). In this study, the effect of the NSAID, etodolac, a 1,8-diethyl-1,3,4,9-tetrahydro-pyrano (3,4-ß) indole-1-acetic acid (Fig.…”

Section: Introductionmentioning

confidence: 60%

Profiling of cell cycle genes of breast cells exposed to etodolac

Roy

Arason²,

Chowdhury³

et al. 2010

Oncol Rep

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Abstract. Breast cancer represents the second leading cause of cancer-related deaths in the world. There is increasing evidence that perturbation of cell cycle regulation is an important contributing factor to various cancer progression stages. There are key checkpoints in the cell cycle involving various regulatory proteins. The relationship between these cell cycle regulatory proteins and cell cycle arrest by cyclooxygenase (COX) inhibitors during neoplastic progression remains largely unknown. Preclinical studies and epidemiological investigations have consistently shown that nonsteroidal anti-inflammatory drugs have some anti-proliferative and anti-oxidative stress response on various tumors. In this study, the effect of etodolac, a 1,8-diethyl-1,3,4,9-tetrahydropyrano (3,4-ß) indole-1-acetic acid on signaling pathways was investigated by examining the differential expression of various cell cycle regulatory protein genes. A human cell cycle gene array was used to profile the expression of 96 genes involved in the cell cycle regulation. Differentially expressed genes were highly altered by etodolac treatment. Twenty-six genes were up-and 20 down-regulated with 0.5 and 2 mM etodolac treatment, respectively. Seven genes (ATM, BAX, CCNA2, CDC27, RAD50 and p21) were prominently altered, and six (ATM, CCND2, CCNF, CDC20, CDK1A and RAD50) were commonly altered with both concentrations. This finding indicated that etodolac could play a critical role on cancer cells by inducing cell death. IntroductionBreast cancer represents the second leading cause of cancerrelated deaths in the United States and other Western countries; accounting for about 30-40% of all newly diagnosed cancers (1,2). Hereditary breast cancer accounts for just 5-10% of cases. It is generally believed that a family history of breast cancer and hormonal imbalances also contributes to the development of breast cancer (3,4). The etiology of breast cancer remains unknown, however, a profound and diverse number of factors including developmental, genetic, nutrition, chemotherapy, hormones, the environment and other yet undetermined factors have been implicated as risk factors for mammary tumorigenesis (5-8).The malignant breast cell phenotype develops as a result of a multi-step process, requiring multiple genetic mutations (9-12). These mutations contribute to a cell that is increasingly characterized by uncontrolled proliferation, deregulated production of growth factors, non-responsiveness to extracellular anti-proliferative signals, anchorage independence, metastatic potential and resistance to antineoplastic agents. Recent advances in the molecular biology of breast cancer have identified various genes associated with tumorigenesis (13,14). The development and progression of neoplastic transformation and the experimental reversal of tumorigenicity are accompanied by complex changes in patterns of gene expression. Complicated events are required for normal cells to change their behavior and these events involve the interaction between genes and pos...

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Section: Introductionmentioning

confidence: 60%

Profiling of cell cycle genes of breast cells exposed to etodolac

Roy

Arason²,

Chowdhury³

et al. 2010

Oncol Rep

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“…Gastrointestinal toxicity of NSAIDs has been alleviated by developing molecules that are selective for the inducible isoform (COX-2) over the constitutive form (COX-1) (Laine, 2002;Pronai et al, 2003, Laporte et al, 2004Micklewright et al, 2003). It has been suggested that GI toxicity arises when both COX-1 and COX-2 enzymes are inhibited, and that inhibiting either one alone does not cause injury to the gastrointestinal mucosa (Takeuchi et al, 2003;Tanaka et al, 2002aTanaka et al, , 2002b.…”

Section: Drug Signatures For the Acute Phase Responsementioning

confidence: 99%

NSAID-Induced Acute Phase Response is Due to Increased Intestinal Permeability and Characterized by Early and Consistent Alterations in Hepatic Gene Expression

Tugendreich

Pearson

Sagartz³

et al. 2006

Toxicol Pathol

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Toxicogenomics using a reference database can provide a better understanding and prediction of toxicity, largely by creating biomarkers that tie gene expression to actual pathology events. During the course of building a toxicogenomic database, an observation was made that a number of non-steroidal anti-inflammatory compounds (NSAIDs) at supra-pharmacologic doses induced an acute phase response (APR) and displayed hepatic gene expression patterns similar to that of intravenous lipopolysaccharide (LPS). Since NSAIDs are known to cause injury along the gastrointestinal tract, it has been suggested that NSAIDs increase intestinal permeability, allowing LPS and/or bacteria into the systemic circulation and stimulating an APR detectable in the liver. A short term study was subsequently conducted examining the effects of aspirin, indomethacin, ibuprofen, and rofecoxib to rats and a variety of endpoints were examined that included serum levels of inflammatory cytokines, histologic evaluation, and hepatic gene expression. Both indomethacin and ibuprofen injured the gastrointestinal tract, induced an APR, and increased serum levels of LPS, while rofecoxib and aspirin did not affect the GI tract or induce an APR. In treatments that eventually showed a systemic inflammatory response, hepatic expression of many inflammatory genes was noted as early as 6 hours after treatment well before alterations in traditional clinical pathology markers were detected. This finding led to the creation of a hepatic gene expression biomarker of APR that was effectively shown to be an early identifier of imminent inflammatory injury. In terms of the relative gastrointestinal safety and the NSAIDs studied, an important safety distinction can be made between the presumptive efficacious dose and the APR-inducing dose for indomethacin (1-2-fold), ibuprofen (5-fold), and rofecoxib (∼250-fold). Our data support the notion that NSAID-induced intestinal injury results in leakage of commensural bacteria and/or LPS into the circulation, provoking a systemic inflammatory response and that hepatic gene expression-based biomarkers can be used as early and sensitive biomarkers of APR onset.[The table referenced in this paper is not printed in this issue of Toxicologic Pathology. It is available as a downloadable text file in the online edition of Toxicologic Pathology, 34(2). In order to access the full article online, you must have either an individual subscription or a member subscription accessed through www.toxpath.org.]

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“…Recent studies suggest that coxibs (cyclooxygenase-2-selective inhibitors) have a favorable safety profi le regarding the gastrointestinal tract [10][11][12] . However, longerterm gastrointestinal data from the celecoxib study (CLASS) have questioned the risk-benefi t profi le of these drugs [13] .…”

mentioning

confidence: 99%

NSAID-Associated Dyspepsia and Ulcers: A Prospective Cohort Study in Primary Care

Hollenz

Stolte²,

Leodolter³

et al. 2006

Dig Dis

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Background and Aim: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause dyspeptic complaints and lesions in the upper gastrointestinal tract. The true incidence of these side effects in the everyday situation remains uncertain. We therefore investigated as to how often patients on NSAIDs in the primary care setting must be expected to develop troublesome dyspepsia and/or ulcers in the upper gastrointestinal tract. Patients and Methods: Admitted to the study were consecutive patients requiring NSAID treatment for at least 2 weeks, who were free of treatment-requiring dyspeptic symptoms, and who were not receiving any prophylactic co-medication. After a minimum of 2 weeks of treatment with a NSAID, a standardized questionnaire and endoscopy of the upper gastrointestinal tract were obtained. Results: 104 patients (median age 53 years, 91 women) were recruited to the study. Four patients had to be excluded for protocol violations. NSAID treatment was applied mainly with diclofenac (n = 67), followed by ibuprofen (n = 22) and rofecoxib (n = 9). The main indication was degenerative complaints affecting the vertebral column and joints. Under treatment, 35% of the patients developed troublesome dyspepsia that required treatment. The frequency of dyspepsia was independent of the duration of NSAID use. Ulcer prevalence was 16% (duodenal ulcer: n = 5; gastric ulcer: n = 11; cardiac ulcer: n = 1). Relevant epigastric pain was experienced more frequently by ulcer patients than those with no ulcer (35 vs. 18%, p = n.s.), but their overall symptom frequency was no higher than in the latter. Predictors for the development of ulcer were smoking (odds ratio 5.11 [1.59–16.48]), regular use of alcohol (odds ratio 4.49 [1.34–15.07]) and duration of treatment less than 1 month (odds ratio 4.95 [1.06–23.09]). No ulcer complications occurred during the period under observation. Overall, 44% of the patients developed troublesome dyspepsia and/or ulcer. Conclusion: Primary care patients with an average risk profile frequently develop dyspeptic symptoms requiring treatment, and ulcers while on NSAIDs. Patients who developed an ulcer were not identifiable on the basis of symptoms or risk factors.

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NSAIDs, gastroprotection and cyclo‐oxygenase‐II‐selective inhibitors*

Cited by 74 publications

References 46 publications

Profiling of cell cycle genes of breast cells exposed to etodolac

Profiling of cell cycle genes of breast cells exposed to etodolac

NSAID-Induced Acute Phase Response is Due to Increased Intestinal Permeability and Characterized by Early and Consistent Alterations in Hepatic Gene Expression

NSAID-Associated Dyspepsia and Ulcers: A Prospective Cohort Study in Primary Care

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