Prostanoids, Ornithine Decarboxylase, and Polyamines in Primary Chemoprevention of Familial Adenomatous Polyposis

Francis M Giardiello, Robert A Casero, Stanley R. Hamilton, Linda M. Hylind, Jill Brensinger Trimbath, Deborah E. Geiman, Katharine R. Judge, Walter Hubbard, G. Johan A Offerhaus, Vincent W. Yang

Research output: Contribution to journalArticle

Abstract

Background & Aims: Familial adenomatous polyposis because of germline mutation of the adenomatous polyposis coli gene is characterized by development of colorectal adenomas and, ultimately, colorectal cancer. The usefulness of colorectal mucosal compounds to predict the effect on adenoma development of primary chemoprevention with the nonsteroidal anti-inflammatory drug sulindac was evaluated. Methods: A randomized, double-blind, placebo-controlled study of 41 subjects genotypically affected with familial adenomatous polyposis but phenotypically unaffected was conducted. Patients received either sulindac or placebo for 48 months, and development of new adenomas was evaluated. The levels of 5 prostanoids, ornithine decarboxylase, and polyamines were measured serially in normal-appearing rectal mucosa. Results: There were no statistically significant differences between treatment groups in baseline levels of prostanoids, ornithine decarboxylase, or polyamines. At conclusion of the study, 4 of 5 prostaglandin levels were statistically significantly lower in the sulindac group than in the placebo group. Among the subset of patients taking sulindac, 3 of 5 prostaglaiidin levels were statistically significantly lower in patients who were polyp free than in those who developed polyps. By contrast, there were no statistically significant differences in ornithine decarboxylase or polyamines between treatment groups or in those on sulindac who were polyp free compared with those who developed polyps. Conclusions: Colorectal mucosal prostaglandin levels, but not ornithine decarboxylase or polyamines, may be valuable biomarkers to assess appropriate drug dosage and medication compliance in patients undergoing primary chemoprevention therapy with sulindac. Reduction of mucosal prostaglandin levels may be necessary to achieve chemopreventive benefit from this agent.

Original languageEnglish (US)
Pages (from-to)425-431
Number of pages7
JournalGastroenterology
Volume126
Issue number2
DOIs
StatePublished - Feb 2004

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Sulindac
Adenomatous Polyposis Coli
Ornithine Decarboxylase
Chemoprevention
Polyamines
Prostaglandins
Polyps
Adenoma
Placebos
APC Genes
Medication Adherence
Germ-Line Mutation
Pharmaceutical Preparations
Colorectal Neoplasms
Mucous Membrane
Anti-Inflammatory Agents
Therapeutics
Biomarkers

ASJC Scopus subject areas

  • Gastroenterology

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Prostanoids, Ornithine Decarboxylase, and Polyamines in Primary Chemoprevention of Familial Adenomatous Polyposis. / Giardiello, Francis M; Casero, Robert A; Hamilton, Stanley R.; Hylind, Linda M.; Brensinger Trimbath, Jill; Geiman, Deborah E.; Judge, Katharine R.; Hubbard, Walter; Offerhaus, G. Johan A; Yang, Vincent W.

In: Gastroenterology, Vol. 126, No. 2, 02.2004, p. 425-431.

Research output: Contribution to journalArticle

Giardiello, Francis M ; Casero, Robert A ; Hamilton, Stanley R. ; Hylind, Linda M. ; Brensinger Trimbath, Jill ; Geiman, Deborah E. ; Judge, Katharine R. ; Hubbard, Walter ; Offerhaus, G. Johan A ; Yang, Vincent W. / Prostanoids, Ornithine Decarboxylase, and Polyamines in Primary Chemoprevention of Familial Adenomatous Polyposis. In: Gastroenterology. 2004 ; Vol. 126, No. 2. pp. 425-431.
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abstract = "Background & Aims: Familial adenomatous polyposis because of germline mutation of the adenomatous polyposis coli gene is characterized by development of colorectal adenomas and, ultimately, colorectal cancer. The usefulness of colorectal mucosal compounds to predict the effect on adenoma development of primary chemoprevention with the nonsteroidal anti-inflammatory drug sulindac was evaluated. Methods: A randomized, double-blind, placebo-controlled study of 41 subjects genotypically affected with familial adenomatous polyposis but phenotypically unaffected was conducted. Patients received either sulindac or placebo for 48 months, and development of new adenomas was evaluated. The levels of 5 prostanoids, ornithine decarboxylase, and polyamines were measured serially in normal-appearing rectal mucosa. Results: There were no statistically significant differences between treatment groups in baseline levels of prostanoids, ornithine decarboxylase, or polyamines. At conclusion of the study, 4 of 5 prostaglandin levels were statistically significantly lower in the sulindac group than in the placebo group. Among the subset of patients taking sulindac, 3 of 5 prostaglaiidin levels were statistically significantly lower in patients who were polyp free than in those who developed polyps. By contrast, there were no statistically significant differences in ornithine decarboxylase or polyamines between treatment groups or in those on sulindac who were polyp free compared with those who developed polyps. Conclusions: Colorectal mucosal prostaglandin levels, but not ornithine decarboxylase or polyamines, may be valuable biomarkers to assess appropriate drug dosage and medication compliance in patients undergoing primary chemoprevention therapy with sulindac. Reduction of mucosal prostaglandin levels may be necessary to achieve chemopreventive benefit from this agent.",
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AU - Giardiello, Francis M

AU - Casero, Robert A

AU - Hamilton, Stanley R.

AU - Hylind, Linda M.

AU - Brensinger Trimbath, Jill

AU - Geiman, Deborah E.

AU - Judge, Katharine R.

AU - Hubbard, Walter

AU - Offerhaus, G. Johan A

AU - Yang, Vincent W.

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N2 - Background & Aims: Familial adenomatous polyposis because of germline mutation of the adenomatous polyposis coli gene is characterized by development of colorectal adenomas and, ultimately, colorectal cancer. The usefulness of colorectal mucosal compounds to predict the effect on adenoma development of primary chemoprevention with the nonsteroidal anti-inflammatory drug sulindac was evaluated. Methods: A randomized, double-blind, placebo-controlled study of 41 subjects genotypically affected with familial adenomatous polyposis but phenotypically unaffected was conducted. Patients received either sulindac or placebo for 48 months, and development of new adenomas was evaluated. The levels of 5 prostanoids, ornithine decarboxylase, and polyamines were measured serially in normal-appearing rectal mucosa. Results: There were no statistically significant differences between treatment groups in baseline levels of prostanoids, ornithine decarboxylase, or polyamines. At conclusion of the study, 4 of 5 prostaglandin levels were statistically significantly lower in the sulindac group than in the placebo group. Among the subset of patients taking sulindac, 3 of 5 prostaglaiidin levels were statistically significantly lower in patients who were polyp free than in those who developed polyps. By contrast, there were no statistically significant differences in ornithine decarboxylase or polyamines between treatment groups or in those on sulindac who were polyp free compared with those who developed polyps. Conclusions: Colorectal mucosal prostaglandin levels, but not ornithine decarboxylase or polyamines, may be valuable biomarkers to assess appropriate drug dosage and medication compliance in patients undergoing primary chemoprevention therapy with sulindac. Reduction of mucosal prostaglandin levels may be necessary to achieve chemopreventive benefit from this agent.

AB - Background & Aims: Familial adenomatous polyposis because of germline mutation of the adenomatous polyposis coli gene is characterized by development of colorectal adenomas and, ultimately, colorectal cancer. The usefulness of colorectal mucosal compounds to predict the effect on adenoma development of primary chemoprevention with the nonsteroidal anti-inflammatory drug sulindac was evaluated. Methods: A randomized, double-blind, placebo-controlled study of 41 subjects genotypically affected with familial adenomatous polyposis but phenotypically unaffected was conducted. Patients received either sulindac or placebo for 48 months, and development of new adenomas was evaluated. The levels of 5 prostanoids, ornithine decarboxylase, and polyamines were measured serially in normal-appearing rectal mucosa. Results: There were no statistically significant differences between treatment groups in baseline levels of prostanoids, ornithine decarboxylase, or polyamines. At conclusion of the study, 4 of 5 prostaglandin levels were statistically significantly lower in the sulindac group than in the placebo group. Among the subset of patients taking sulindac, 3 of 5 prostaglaiidin levels were statistically significantly lower in patients who were polyp free than in those who developed polyps. By contrast, there were no statistically significant differences in ornithine decarboxylase or polyamines between treatment groups or in those on sulindac who were polyp free compared with those who developed polyps. Conclusions: Colorectal mucosal prostaglandin levels, but not ornithine decarboxylase or polyamines, may be valuable biomarkers to assess appropriate drug dosage and medication compliance in patients undergoing primary chemoprevention therapy with sulindac. Reduction of mucosal prostaglandin levels may be necessary to achieve chemopreventive benefit from this agent.

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