Prostanoids, ornithine decarboxylase, and polyamines in primary chemoprevention of familial adenomatous polyposis - PubMed (original) (raw)

Clinical Trial

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

Francis M Giardiello et al. Gastroenterology. 2004 Feb.

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 prostaglandin 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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Figures

Figure 1

Figure 1

Serial mean prostaglandin levels (ng/mg/protein) in each of 4 patient groups: sulindac patients polyp free (◆), sulindac patients who developed polyps (■), placebo patients who are polyp free (▲), and placebo patients who developed polyps (●), for each of 5 prosglandin F2α [PGF2α], thromboxane B2 [TXB2], and 6 keto prostaglandin F1α [6KetoPGF1α]).

Figure 2

Figure 2

Individual patient prostaglandin levels (ng/mg protein) at baseline (time 0) and 1 year for patients in the sulindac group who were polyp free (−) and those who developed polyps (+) by study end for each of 5 prostaglandins (prostaglandin D2 [PGD2], prostaglandin E2 [PGE2], prostaglandin F2α [PGF2α], thromboxane B2 [TXB2], and 6 keto prostaglandin F1α [6KetoPGF1α]). *Indicates P < 0.005 and †indicates P < 0.05 when 1 year mean values are compared with baseline.

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