Primary Chemoprevention of Familial Adenomatous Polyposis with Sulindac

Giardiello, Francis M.; Yang, Vincent W.; Hylind, Linda M.; Krush, Anne J.; Petersen, Gloria M.; Trimbath, Jill D.; Piantadosi, Steven; Garrett, Elizabeth; Geiman, Deborah E.; Hubbard, Walter C.; Offerhaus, G. J. A.; Hamilton, Stanley R.

doi:10.1056/nejmoa012015

Cited by 365 publications

(217 citation statements)

References 21 publications

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“…Observations that the selective COX-2 inhibitor celecoxib, as well as other non-steroidal anti-inflammatory drugs such as sulindac, induce regression of existing adenomas, as well as prevent polyposis in FAP patients (Giardiello et al, 1993(Giardiello et al, , 2002Steinbach et al, 2000) and murine models of FAP (Jacoby et al, 2000), concurs with our finding that the intestinal epithelial cell phenotype induced by macrophages in our model, was reversible. If an initiation-promotion-progression paradigm is applied to human colorectal carcinogenesis (Pitot et al, 2000), reversibility in vitro implies a role for COX-2 during reversible tumour promotion and emphasises the importance of COX-2 as a chemoprevention target for a potentially reversible stage of colorectal carcinogenesis.…”

Section: Discussionsupporting

confidence: 92%

Paracrine cyclooxygenase-2-mediated signalling by macrophages promotes tumorigenic progression of intestinal epithelial cells

Chapple

Hawcroft

et al. 2002

Oncogene

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In human colorectal adenomas or polyps, cyclooxygenase-2 is expressed predominantly by stromal (or interstitial) macrophages. Therefore, we tested the hypothesis that macrophage cyclooxygenase-2 has paracrine pro-tumorigenic activity using in vitro models of macrophage-epithelial cell interactions. We report that macrophages can promote tumorigenic progression of intestinal epithelial cells (evidenced by decreased cellcell contact inhibition, increased proliferation and apoptosis, gain of anchorage-independent growth capability, decreased membranous E-cadherin expression, up-regulation of cyclooxygenase-2 expression, down-regulation of transforming growth factor-b type II receptor expression and resistance to the antiproliferative activity of transforming growth factor-b 1 ) in a paracrine, cyclooxygenase-2-dependent manner. Pharmacologically relevant concentrations (1 -2 mM) of a selective cyclooxygenase-2 inhibitor had no detectable, direct effect on intestinal epithelial cells but inhibited the macrophage-epithelial cell signal mediating tumorigenic progression. Cyclooxygenase-2-mediated stromal-epithelial cell signalling during the early stages of intestinal tumorigenesis provides a novel target for chemoprevention of colorectal cancer (and other gastro-intestinal epithelial malignancies, which arise on a background of chronic inflammation, such as gastric cancer) and may explain the discrepancy between the concentrations of cyclooxygenase inhibitors required to produce antineoplastic effects in vitro and in vivo.

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Section: Discussionsupporting

confidence: 92%

Paracrine cyclooxygenase-2-mediated signalling by macrophages promotes tumorigenic progression of intestinal epithelial cells

Chapple

Hawcroft

et al. 2002

Oncogene

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“…34 The incidence of any adverse event did not differ significantly between the sulindac and placebo group. Sulindac had no effect on adenoma development or characteristics.…”

Section: Efficacymentioning

confidence: 85%

Prostanoids, ornithine decarboxylase, and polyamines in primary chemoprevention of familial adenomatous polyposis

et al. 2004

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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%