Sulindac induced regression of colorectal adenomas in familial adenomatous polyposis: evaluation of predictive factors.

Giardiello, F. M.; Offerhaus, Johan; Tersmette, A. C.; Hylind, Linda M.; Krush, Anne J.; Brensinger, Jill D.; Booker, Susan V.; Hamilton, Stanley R.

doi:10.1136/gut.38.4.578

Cited by 79 publications

(59 citation statements)

References 15 publications

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“…In contrast, COX-2 knock-out mice are more resistant to tumorigenesis in various organs (Oshima et al, 1996;Tiano et al, 2002;Howe et al, 2005). A number of clinical studies were performed for colorectal cancer prevention by administration of Nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors including sulindac, aspirin, celecoxib, rofecoxib (Giardiello et al, 1996;Steinbach et al, 2000;Giardiello et al, 2002;Baron et al, 2003;Higuchi et al, 2003;Sandler et al, 2003;Bertagnolli et al, 2006). These COX-2 inhibitors reduced adenoma only at a high dose but significantly increased mortality from cardiovascular complication.…”

Section: Discussionmentioning

confidence: 99%

Eryngium foetidum Suppresses Inflammatory Mediators Produced by Macrophages

Mekhora

Muangnoi²,

Chingsuwanrote

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Section: Discussionmentioning

confidence: 99%

Eryngium foetidum Suppresses Inflammatory Mediators Produced by Macrophages

Mekhora

Muangnoi²,

Chingsuwanrote

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…twice a day as described previously (Giardiello et al, 1993(Giardiello et al, , 1996Cruz-Correa et al, 2002). All patients had adenomas at the initiation of treatment (baseline) and showed adenoma regression after 6 months treatment with sulindac.…”

Section: Patients and Adenoma Specimensmentioning

confidence: 99%

Sulindac targets nuclear β-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines

et al. 2004

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Nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive potential against colorectal carcinomas (CRCs). Inhibition of cyclooxygenase (COX)-2 underlies part of this effect, although COX-2-independent mechanisms may also exist. Nonsteroidal antiinflammatory drugs appear to inhibit the initial stages of the adenoma -carcinoma sequence, suggesting a link to the APC/b-catenin/ TCF pathway (Wnt-signalling pathway). Therefore, the effect of the NSAID sulindac on nuclear (nonphosphorylated) b-catenin and b-catenin/TCF-mediated transcription was investigated. Nuclear b-catenin expression was assessed in pretreatment colorectal adenomas and in adenomas after treatment with sulindac from five patients with familial adenomatous polyposis (FAP). Also, the effect of sulindac sulphide on b-catenin/TCF-mediated transcription was studied. Adenomas of FAP patients collected after treatment with sulindac for up to 6 months showed less nuclear b-catenin expression compared to pretreatment adenomas of the same patients. Sulindac sulphide abrogated b-catenin/TCF-mediated transcription in the CRC cell lines DLD1 and SW480, and decreased the levels of nonphosphorylated b-catenin. As a result, the protein levels of the positively regulated TCF targets Met and cyclin D1 were downregulated after sulindac treatment. This study provides in vivo and in vitro evidence that nuclear b-catenin localisation and b-catenin/TCF-regulated transcription of target genes can be inhibited by sulindac. The inhibition of Wnt-signalling provides an explanation for the COX-2-independent mechanism of chemoprevention by NSAIDs. . Also, in patients with familial adenomatous polyposis (FAP), an autosomal dominantly inherited disorder characterised by the development of numerous colorectal adenomas at a young age, the NSAIDs sulindac and indomethacin can cause regression of adenomas (Giardiello et al, 1993;Nugent et al, 1993;Spagnesi et al, 1994;Hirota et al, 1996;Winde et al, 1997;Picariello et al, 1998). The chemopreventive effect of NSAIDs appears mediated by the induction of apoptosis and cell cycle arrest (Pasricha et al, 1995;DuBois and Smalley, 1996;Piazza et al, 1997;Keller et al, 1999;Shiff and Rigas, 1999). The molecular mechanisms underlying these biological effects are not completely understood. Nonsteroidal anti-inflammatory drugs inhibit the enzymatic activity of cyclooxygenase (COX)-1 and -2, enzymes that convert arachidonic acid into prostaglandins (Shiff and Rigas, 1999). However, COX-independent mechanisms may also play a role, since NSAIDs inhibit the growth of colon cancer cell lines lacking COX-2 expression (Hanif et al, 1996;Zhang et al, 1999;Smith et al, 2000).Oncogenic activation of the Wnt-signalling pathway by mutations in Adenomatous polyposis coli (APC) or b-catenin, which results in the accumulation and nuclear translocation of b-catenin and in b-catenin/TCF4-regulated transcription of TCF target genes, is mandatory for the initial neoplastic transformation of intestinal epithelium (reviewed in Kinzler and Vogelstein, 1996...

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“…Similarly, Baron and colleagues demonstrated a moderate chemopreventive effect of aspirin in patients with a recent history of colorectal adenoma [58]. Sulindac has also been shown to reduce polyp burden in randomized control trials of patients with familial adenomatous polyposis (FAP) [59][60][61].…”

Section: Gastrointestinal Implications Of Fmo3 Polymorphismsmentioning

confidence: 99%

“…In the field of gastroenterology, the effect of FMO3 polymorphisms has been demonstrated in the metabolism of sulindac and H 2 blockers. Both medications have important roles in the management of common gastrointestinal diseases including colorectal adenoma and peptic ulcer disease [60,61,67]. Translational data is accumulating on the role of certain polymorphisms in in vivo human clinical settings [40,47,48,67], and the process of discovery and clinical utilization needs to be pursued.…”

Section: Expert Commentarymentioning

confidence: 99%

Genetic Polymorphisms of Human Flavin-Containing Monooxygenase 3: Implications for Drug Metabolism and Clinical Perspectives

Hisamuddin

Yang

2007

Pharmacogenomics

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Flavin-containing monooxygenase 3 (FMO3) is a hepatic microsomal enzyme that oxidizes a host of drugs, xenobiotics and other chemicals. Numerous variants in the gene encoding FMO3 have been identified, some of which result in altered enzymatic activity and, consequently, altered substrate metabolism. Studies also implicate individual and ethnic differences in the frequency of FMO3 polymorphisms. In addition, new variants continue to be identified with potentially important clinical implications. For example, the role of FMO3 variants in the pathophysiology of gastrointestinal diseases is an evolving area of research. Two commonly occurring polymorphisms of FMO3, E158K and E308G, have been associated with a reduction in polyp burden in patients with familial adenomatous polyposis who were treated with sulindac sulfide, an FMO3 substrate. These findings suggest a potential role for prospective genotyping of common FMO3 polymorphisms in the treatment of disease states that involve the use of drugs metabolized by FMO3. This review summarizes the current state of research on the genetic polymorphisms of FMO3, with a focus on their clinical implications in gastrointestinal diseases. Keywords chemoprevention; familial adenomatous polyposis; flavin-containing monooxygenase 3; gastrointestinal diseases; SNP; sulindac sulfide; trimethylaminuria Humans metabolize a vast array of endogenous and exogenous compounds, including drugs and xenobiotics. It has been observed that different individuals, genders and ethnicities respond differently to the same compounds. This has been attributed to multiple factors, one of which is SNPs. With the completion of the human genome sequence and the discovery of existing SNPs in the genome, interest has focused on the role of genetic polymorphisms of enzymeencoding genes involved in the metabolism of both endogenous and exogenous substances.The flavin-containing monooxygenases (FMOs) belong to a family of flavoprotein enzymes that catalyze the oxidation of a broad array of nucleophilic heteroatom-containing drugs, pesticides and chemicals [1][2][3][4]. There are six human isoforms of flavin-containing monooxygenases, of which five are functional. An additional gene cluster containing five pseudogenes has also been identified in both the human and mouse genome [5][6][7][8][9][10].

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Sulindac induced regression of colorectal adenomas in familial adenomatous polyposis: evaluation of predictive factors.

Abstract: Background-Sulindac, a non-steroidal anti-inflammatory drug, causes regression of colorectal adenomas in patients with familial adenomatous polyposis (FAP)

Cited by 79 publications

References 15 publications

Eryngium foetidum Suppresses Inflammatory Mediators Produced by Macrophages

Eryngium foetidum Suppresses Inflammatory Mediators Produced by Macrophages

Sulindac targets nuclear β-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines

Genetic Polymorphisms of Human Flavin-Containing Monooxygenase 3: Implications for Drug Metabolism and Clinical Perspectives

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