Levels of rectal mucosal polyamines and prostaglandin E2 predict ability of DFMO and sulindac to prevent colorectal adenoma

Abstract

Background & aims: Combination of polyamine and prostaglandin E2 (PGE2)-synthesis inhibitors reduced the risk of colorectal adenoma (CRA) by 70% in patients who received polypectomies. We studied effects of the combination of difluoromethylornithine (DFMO) and sulindac on biomarkers and investigated factors that modify their efficacy.

Methods: We analyzed rectal mucosal levels of polyamines (spermidine, spermine, and putrescine) and PGE2, treatment regimens, and risk of CRA in 267 participants of a phase IIb/III chemoprevention trial of DFMO/sulindac.

Results: In the group that received DFMO/sulindac, spermidine-to-spermine ratio (Spd:Spm) in rectal mucosa decreased between baseline and 12- and 36-month follow-up examinations (0.30, 0.23, and 0.24, respectively; P < .001 for both comparisons to baseline). Putrescine levels decreased between baseline and 12 months (0.46 vs 0.15 nmol/mg protein; P < .001) but rebounded between 12 and 36 months (0.15 vs 0.36 nmol/mg protein; P = .001). PGE2 levels did not change, although aspirin use was significantly associated with lower baseline levels of PGE2. No significant associations were observed between changes in biomarker levels and efficacy. However, drug efficacy was greatest in subjects with low Spd:Spm and high PGE2 at baseline; none of these subjects, versus 39% of those given placebo, developed CRA (P < .001). Efficacy was lowest in subjects with high Spd:Spm and low PGE2 at baseline; 28% developed CRA, compared with 36% of patients given placebo (P = .563).

Conclusions: A combination of DFMO and sulindac significantly suppressed production of rectal mucosal polyamines but not PGE2. No relationship was found between changes in biomarker levels and response. However, baseline biomarker levels modified the effect of DFMO/sulindac for CRA prevention.

Trial registration: ClinicalTrials.gov NCT00005882 NCT00118365.

Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Study schema

Figure 2. Biomarker levels over time, by treatment group

Box plots are shown at three time points for normal rectal mucosal levels of (A) prostaglandin E2 (PGE2), (B) spermidine-to-spermine ratio (Spd:Spm), and (C) putrescine. Y-axes are drawn on a logarithmic scale because the distributions of these variables are right-skewed. A closed star indicates a significant difference in the median between paired values from baseline, and an open star indicates a significant difference in the median between paired values from 12 months.

Figure 3. DFMO/sulindac efficacy, by biomarker levels

Participants were categorized according to their baseline levels of prostaglandin E2 (PGE2) and the spermidine-to-spermine ratio (Spd:Spm). Low versus high cut points were defined by the median biomarker levels in the study population. The table below the figure includes the number (and percent) of participants with metachronous adenoma in each stratum. A Fisher’s exact test was conducted to test for a significant difference between the two groups in the proportion of individuals with metachronous adenoma.