Effect of Long-Term Mesalamine Therapy on Cancer-Associated Gene Expression in Colonic Mucosa of Patients with Ulcerative Colitis
The role of 5-aminosalicylic acid (5-ASA or mesalamine) in the prevention of colorectal cancer in ulcerative colitis (UC) patients was reported, but the effect on molecular targets in UC colon mucosa is unknown.
This observational study evaluates gene expression levels of 5-ASA targets using serial colon biopsy specimens from UC patients undergoing long-term 5-ASA therapy.
Transcript levels were compared between colonoscopic biopsy specimens collected from 62 patients at initial and final follow-up colonoscopy at 2–6 years. All patients had mild-to-moderate UC and were undergoing long-term 5-ASA maintenance. Stepwise multiple linear regression analyses were performed to correlate changes in transcript levels with therapeutic response (Mayo clinical score endoscopy and DAI and/or Nancy histopathology score) and nonclinical variables.
The transcript levels of colorectal carcinogenesis-associated known 5-ASA target genes were significantly reduced after prolonged 5-ASA therapy (P < 0.005–0.03). Multiple linear regression models predicted significant association between transcript levels of Ki-67, NF-kB (p65), PPARγ, COX-2 and IL-8, CDC25A, and CXCL10 with duration of drug (5-ASA) exposure (P ≤ 0.05). Ki-67, NF-kB (p65), and CXCL10 transcripts were also correlated with reduced endoscopy sub-score (P ≤ 0.05). COX-2, IL-8, CDC25A, and TNF transcripts strongly correlated with DAI sub-scores (P ≤ 0.05). Only COX-2 and IL-8 transcript levels correlated (P ≤ 0.05) with Nancy histological score.
This study provides molecular evidence of changes in carcinogenesis-related targets/pathways in colon tissue during long-term 5-ASA maintenance therapy that may contribute to the observed chemopreventive effects of 5-ASA in UC patients.
Keywords5-aminosalicylic acid (5-ASA) Chemoprevention Ulcerative colitis (UC)
MB participated in study design, data acquisition, data analysis, writing the first draft, and coordinating the subsequent revisions of the manuscript with coauthors. DS, KMD, and EP participated in patient recruitment; MB, DS, JG, XG, JA, CM, KD, and PA assisted in data collection from experiments and patient charts; SG and JC assisted in statistical analysis; MB, DS, and KMD contributed to critical review of the draft, and all authors reviewed and approved the final manuscript.
The clinical component of this study was supported in part by an Investigator-Initiated Research Grant to KD by Proctor and Gamble Pharmaceuticals. The in vitro studies molecular assays and statistical analyses were supported by a Regional Grant-In-Aid by Proctor and Gamble Pharmaceuticals to MB.
Compliance with ethical standards
Conflict of interest
KD, XG and MB received funding for this study from Proctor and Gamble. Other authors have no conflicts to disclose.
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