A Randomized, Placebo-Controlled, Preoperative Trial of Allopurinol in Subjects with Colorectal Adenoma

Abstract

Inflammation and oxidative stress play a crucial role in the development of colorectal cancer (CRC) and interference with these mechanisms represents a strategy in CRC chemoprevention. Allopurinol, a safe molecular scavenger largely used as antigout agent, has been shown to increase survival of patients with advanced CRC and to reduce CRC incidence in long-term gout users in epidemiologic studies. We conducted a randomized, double-blind, placebo-controlled preoperative trial in subjects with colorectal adenomatous polyps to assess the activity of allopurinol on biomarkers of colorectal carcinogenesis.After complete colonoscopy and biopsy of the index polyp, 73 subjects with colorectal adenomas were assigned to either placebo or one of two doses of allopurinol (100 mg or 300 mg) and treated for four weeks before polyp removal. Change of Ki-67 labeling index in adenomatous tissue was the primary endpoint. Secondary endpoints were the immunohistochemical (IHC) expression of NF-kB, b-catenin, topoisomerase-II-a, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in adenomatous polyps and normal adjacent colonic tissue.Compared with placebo, Ki-67 levels were not significantly modulated by allopurinol, whereas b-catenin and NF-kB expression levels decreased significantly in adenomatous tissue, with a mean change from baseline of À10.6%, 95% confidence interval (CI), À20.5 to À0.7, and À8.1%, 95% CI, À22.7 to 6.5, respectively. NF-kB also decreased significantly in normal adjacent tissue (À16.4%; 95% CI, À29.0 to À3.8).No dose-response relationship was noted, except for NF-kB expression in normal tissue.Allopurinol can inhibit biomarkers of oxidative activation in colon adenomatous polyps and normal adjacent tissue. Further studies should define its potential chemopreventive activity. Cancer Prev Res; 6(2); 74-81. Ó2012 AACR.

S100A4 and Uric Acid Promote Mesenchymal Stromal Cell Induction of IL-10+/IDO+ Lymphocytes

“…The clinically approved agent allopurinol decreases the plasma concentration of UA and could be considered as a component of cancer therapy. Interestingly, a population-based case control study demonstrated that the use of allopurinol for at least 5 y was associated with a diminished risk of dying from colorectal cancer (odds ratio, 0.33; 95% confidence interval, 0.16-0.71) when adjusted for other known risk factors (44). Allopurinol administration also increases the survival of patients with advanced colorectal cancer (44).…”

“…Interestingly, a population-based case control study demonstrated that the use of allopurinol for at least 5 y was associated with a diminished risk of dying from colorectal cancer (odds ratio, 0.33; 95% confidence interval, 0.16-0.71) when adjusted for other known risk factors (44). Allopurinol administration also increases the survival of patients with advanced colorectal cancer (44). Recently, simple stressful conditions have been suggested to promote reprogramming of otherwise normal cells to acquire pluripotency (45,46), although these results have recently been called into question.…”

Toward an Understanding of Structural Insights of Xanthine and Aldehyde Oxidases: An Overview of their Inhibitors and Role in Various Diseases

“…Circulating XO is an indicator of hepatic and intestinal damage, and can also acts as a circulating mediator that is accountable for remote organ injury in a variety of pathophysiological conditions. 42 The higher expression of XO also leads to inflammation, [70][71][72] metabolic disorder, 59 diabetes, 73 chronic heart failure, [74][75][76] hypertension, 77,78 cardiovascular diseases, 77,79,80 renal disease, 81 ischemia-reperfusion damage, 70,82 atherosclerosis, 83 dementia, 84 schizophrenia, 85 carcinogenesis, 14,15 endothelial dysfunction, 71,86 tumor lysis syndrome, 87,88 atrial fibrillation, 89 and circulatory shock. XO abets the oxidation/hydroxylation of numerous purines, pterins, aromatic heterocycles, aliphatic and aromatic aldehydes, thereby assist in the detoxification or activation of endogenous compounds and it also plays a vital role in the drug metabolism.…”

“…8,9 XO is well known to catalyze the key steps of the purine metabolism, that is, oxidation of hypoxanthine to xanthine and then to uric acid; however, the physiological functions of AOX1 are still unknown. [10][11][12][13] The high expression of XO is associated with overproduction of uric acid that leads to hyperuricemia, gout, cancer, 14,15 and other diseases. 16,17 Various purine-and nonpurine-based XO inhibitors are being developed and allopurinol, febuxostat, 18 and topiroxostat (Japan, 2013) are clinically approved as antihyperuricemic/gout agents.…”

Trials and Tribulations of Interrogating Biomarkers to Define Efficacy of Cancer Risk Reductive Interventions

“…The manuscript from Puntoni et al (11) in this issue of Cancer Prevention Research highlights both the strengths and challenges of employing tissue-based biomarkers for cancer risk reductive efficacy. The design of the Phase IIa colon cancer risk reductive preoperative window of opportunity trial of Puntoni et al exploits the requirement for repetitive colonoscopic procedures for some patients who have colonic adenomas of ≥1 cm.…”