Abstract A69: Randomized, presurgical study of allopurinol vs. placebo in subjects with colorectal adenomas
Authors: Puntoni Matteo , Branchi Daniela , Argusti Alessandra , Zanardi Silvia , Crosta Cristiano , Meroni Emanuele , Munizzi Francesco , Michetti Paolo , Coccia Gianni , Roberto Giuseppe De , Bandelloni Roberto , Turbino Laura , Minetti Egle , Mori Marco , Gatteschi Beatrice , Salvi Sandra , DeCensi Andrea 
Published: January 2011

Abstract
Rationale: Colorectal adenomas are well recognized colorectal cancer (CRC) risk markers, and regression of adenomas through chemopreventive strategies may reduce the incidence of CRC. Inflammation and oxidative stress appear to play a crucial role in the development of CRC, and interference with the mechanisms inducing oxidative stress and possibly cancer progression may represent a new strategy in CRC chemoprevention. Colonic cancerous tissue contains high levels of reactive oxygen metabolites (ROM), which may play an important role in the pathogenesis of CRC, and the effects of ROM scavengers are presently being tested for CRC chemoprevention.
Allopurinol, a structural analogue of hypoxanthine inhibiting the action of xantine oxidase (XO), is a ROM scavenger largely employed as an anti-gout agent in clinical practice. Allopurinol use is highly safe, with very uncommon adverse events. Allopurinol was shown to increase survival of patients with advanced CRC, and a recent population-based case-control study showed that its use for at least 5 years was correlated with a diminished risk of developing CRC (Odds Ratio=0.33; 95% CI=0.16-0.71, Rennert G et al. AACR 3rd International Conference on Frontiers in Cancer Prevention Research 2004, Abstract #C88) after adjustment for other known risk factors.
Design: To assess the effects of allopurinol on cell proliferation in both adenomatous and unaffected colonic tissue, we designed a randomized phase I/II, double blind, placebo-controlled, multicenter trial in patients with colorectal adenomatous polyps. After a complete colonoscopy and biopsy of the index polyp, subjects with histologically confirmed adenomas were assigned to either placebo or two doses of allopurinol (100mg or 300mg) and treated for 4-6 weeks before polyp removal. Samples of normal colonic tissue were also collected on both baseline and end-of-study colonoscopy. Treatment effect on cell proliferation was assessed by measuring changes of Ki-67 labeling index (primary endpoint: Ki-67 %change) on both adenomatous and normal colonic tissue. We calculated a total of 75 subjects (25 per arm), required (α = 0.05, 1-β = 0.85, one-sided test) to show a 27% to 40% reduction in Ki-67 LI depending on standard deviation of Ki-67. Secondary endpoints included treatment modulation of biomarkers of oxidative activation (NF-Kb and β-catenin), apoptosis (topoisomerase-II-α, Cox-3, Bcl-2), inflammation (u-CRP) and of circulating IGFs (IGF-1, IGFBP-3).
Preliminary results: The first patient entered the study on May 13th 2006 and the last on May 31th, 2010, for a total study enrolment duration of about 4 years. Enrolment stopped on July 1, 2010, with a total of 73 subjects enrolled.
An interim analysis performed on November 2008 (48 patients enrolled, mean age 62 yrs, mean BMI 25kg/m2) showed a 98% treatment compliance, with only 3 G1 adverse events (1 leg cramps, 1 erythema and 1 skin rush), confirming the high safety of allopurinol. Ki-67 analysis on the first 13 subjects enrolled showed a favourable trend: median Ki-67 expression in normal tissue doubled on placebo compared with a 5% increase in both treatments arms; in adenomas, it increased by 70% on placebo compared with 6% and 12% in the 100 mg and 300 mg allopurinol arm, respectively.
Tissue and serum biomarker analyses on all subjects enrolled are underway and further results will be presented at the conference.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A69.