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Newman P, Muscat J. Potential Role of Non-Steroidal Anti-Inflammatory Drugs in Colorectal Cancer Chemoprevention for Inflammatory Bowel Disease: An Umbrella Review. Cancers (Basel) 2023; 15:cancers15041102. [PMID: 36831446 PMCID: PMC9954537 DOI: 10.3390/cancers15041102] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/31/2023] [Accepted: 02/02/2023] [Indexed: 02/11/2023] Open
Abstract
Inflammatory Bowel Disease (IBD) is a category of autoimmune diseases that targets the destruction of the gastrointestinal system and includes both Crohn's Disease and Ulcerative Colitis (UC). Patients with IBD are at a higher risk of developing colorectal cancer (CRC) throughout their lives due to chronically increased inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are potential chemopreventative agents that can inhibit the development of CRC in persons without IBD. However, the use of NSAIDs for CRC chemoprevention in IBD patients is further complicated by NSAIDs' induction of damage to the bowel mucosal layer and ulcer formation. There has been a push in new research on chemopreventative properties of certain NSAIDs for IBD. The purpose of this umbrella review is to investigate the potential of low-dose NSAID compounds as chemopreventative agents for patients with IBD. This paper will also suggest future areas of research in the prevention of CRC for patients with IBD.
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Wang D, Li Y, Zhang C, Li X, Yu J. MiR‐216a‐3p inhibits colorectal cancer cell proliferation through direct targeting COX‐2 and ALOX5. J Cell Biochem 2017; 119:1755-1766. [DOI: 10.1002/jcb.26336] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 08/07/2017] [Indexed: 12/19/2022]
Affiliation(s)
- Dongxia Wang
- Department of Radiation OncologyShandong Cancer Hospital Affiliated to Shandong UniversityJinanChina
- Department of Radiation OncologyDongguan People's HospitalDongguanChina
| | - Yuechun Li
- Department of Gastrointestinal SurgeryDongguan People's HospitalDongguanChina
| | - Chun Zhang
- Department of Radiation OncologyDongguan People's HospitalDongguanChina
| | - Xianming Li
- Department of Radiation OncologyShenzhen People's HospitalShenzhenChina
| | - Jinming Yu
- Department of Radiation OncologyShandong Cancer Hospital Affiliated to Shandong UniversityJinanChina
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Folic Acid Supplementation May Reduce Colorectal Cancer Risk in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. J Clin Gastroenterol 2017; 51:247-253. [PMID: 26905603 DOI: 10.1097/mcg.0000000000000498] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
GOALS To evaluate the role of folic acid supplementation in colorectal cancer (CRC) chemoprevention in patients with inflammatory bowel disease (IBD). BACKGROUND CRC is a serious complication of IBD. Folic acid supplementation has been shown to be chemopreventative in sporadic CRC. Patients with IBD are at risk of folate deficiency though intestinal malabsorption and also competitive inhibition by concurrent sulfasalazine use. To date, there have been several studies reporting on folic acid supplementation in patients with IBD and CRC. STUDY We searched electronic databases for studies reporting folic acid use and CRC incidence in patients with IBD. We produced a pooled hazard ratio with 95% confidence intervals using a random-effects model. Preplanned subgroup analyses were performed to explore for any potential sources of heterogeneity. RESULTS Ten studies reporting on 4517 patients were included. We found an overall protective effect for folic acid supplementation on the development of CRC, pooled hazard ratio=0.58 (95% confidence interval, 0.37-0.80). There was low to moderate heterogeneity among studies, I=29.7%. Subgroup analyses suggested that folic acid use was protective in hospital-based studies, studies from North America and those that were performed before folate fortification of foods in 1998. CONCLUSIONS CRC remains an important complication of IBD. Chemoprevention is an attractive strategy and folic acid as a cheap, safe, and well-tolerated supplement may have a role. Focused prospective studies are required to precisely define any potential effect.
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Burr NE, Hull MA, Subramanian V. Does aspirin or non-aspirin non-steroidal anti-inflammatory drug use prevent colorectal cancer in inflammatory bowel disease? World J Gastroenterol 2016; 22:3679-3686. [PMID: 27053860 PMCID: PMC4814654 DOI: 10.3748/wjg.v22.i13.3679] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 02/09/2016] [Accepted: 03/02/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether aspirin or non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAIDs) prevent colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD).
METHODS: We performed a systematic review and meta-analysis. We searched for articles reporting the risk of CRC in patients with IBD related to aspirin or NA-NSAID use. Pooled odds ratios (OR) and 95%CIs were determined using a random-effects model. Publication bias was assessed using Funnel plots and Egger’s test. Heterogeneity was assessed using Cochran’s Q and the I2 statistic.
RESULTS: Eight studies involving 14917 patients and 3 studies involving 1282 patients provided data on the risk of CRC in patients with IBD taking NA-NSAIDs and aspirin respectively. The pooled OR of developing CRC after exposure to NA-NSAIDs in patients with IBD was 0.80 (95%CI: 0.39-1.21) and after exposure to aspirin it was 0.66 (95%CI: 0.06-1.39). There was significant heterogeneity (I2 > 50%) between the studies. There was no change in the effect estimates on subgroup analyses of the population studied or whether adjustment or matching was performed.
CONCLUSION: There is a lack of high quality evidence on this important clinical topic. From the available evidence NA-NSAID or aspirin use does not appear to be chemopreventative for CRC in patients with IBD.
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Tanaka T, Kochi T, Shirakami Y, Mori T, Kurata A, Watanabe N, Moriwaki H, Shimizu M. Cimetidine and Clobenpropit Attenuate Inflammation-Associated Colorectal Carcinogenesis in Male ICR Mice. Cancers (Basel) 2016; 8:cancers8020025. [PMID: 26907350 PMCID: PMC4773748 DOI: 10.3390/cancers8020025] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Revised: 02/01/2016] [Accepted: 02/16/2016] [Indexed: 01/17/2023] Open
Abstract
Histamine and histamine receptors (Hrhs) have been identified as critical molecules during inflammation and carcinogenesis. This study was conducted to determine the effects of Hrh1-Hrh3 antagonists on inflammation-associated colorectal carcinogenesis. Male ICR mice were treated with azoxymethane (AOM, 10 mg/kg bw, i.p.) and 1.5% dextran sodium sulfate (DSS, drinking water for 7 days) to induce colorectal carcinogenesis. The mice were then fed diets containing test chemical (500 ppm terfenadine, 500 ppm cimetidine or 10 ppm clobenpropit) for 15 weeks. At week 18, feeding with the diets containing cimetidine (Hrh2 antagonist) and clobenpropit (Hrh3 antagonist/inverse agonist) significantly lowered the multiplicity of colonic adenocarcinoma. Terfenadine (Hrh1 antagonist) did not affect AOM-DSS-induced colorectal carcinogenesis. Adenocarcinoma cells immunohistochemically expressed Hrh1, Hrh2, Hrh3 and Hrh4 with varied intensities. Because clobenpropit is also known to be a Hrh4 receptor agonist, Hrh2, Hrh3 and Hrh4 may be involved in inflammation-related colorectal carcinogenesis. Additional data, including the mRNA expression of pro-inflammatory cytokines and inducible inflammatory enzymes in the colonic mucosa, are also presented.
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Affiliation(s)
- Takuji Tanaka
- Department of Diagnostic Pathology (DDP) and Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu City, Gifu 500-8513, Japan.
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
| | - Takahiro Kochi
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
| | - Yohei Shirakami
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
| | - Takayuki Mori
- Department of Pharmacy, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki 503-8502, Japan.
| | - Ayumi Kurata
- Department of Diagnostic Pathology (DDP) and Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu City, Gifu 500-8513, Japan.
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
| | - Naoki Watanabe
- Department of Diagnostic Pathology (DDP) and Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu City, Gifu 500-8513, Japan.
| | - Hisataka Moriwaki
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
| | - Masahito Shimizu
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan.
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Han YM, Park JM, Lee HJ, Kim EH, Hahm KB. Short-term Intervention to Revert Premalignant Lesions as Strategy to Prevent Gastrointestinal Cancers. J Cancer Prev 2014; 18:289-97. [PMID: 25337558 PMCID: PMC4189441 DOI: 10.15430/jcp.2013.18.4.289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 09/11/2013] [Accepted: 09/12/2013] [Indexed: 12/20/2022] Open
Abstract
"Prevention might be better than treatment in cancer treatment" is brief conclusion drawn from war on cancer through National Cancer Act of 1971 by U.S. President Richard Nixon. However, the clinical practice of chemoprevention is still in its infancy in spite of a wealth of data showing its effectiveness in experimental animals as well as in vitro mechanism research. Recent advances in either high throughput analysis including cancer genomes and tailored medicine or molecular targeted therapeutics, preventive strategies also should be changes as previous preventive strategies including phytoceuticals, life-style modification, and some empirical agents. Furthermore, molecular targeted therapeutics achieved high goal of effectiveness under the concept of therapeutic or preventive "synthetic lethality", of which extended application can be included within the scope of chemoprevention. Here, we will summarize several recent advances in chemopreventive strategy objected to justify optimism that chemoprevention will be an effective approach for the control of human cancer. siTRP (short-term intervention to revert premalignancy) strategy will be introduced for cancers in gastroenterology.
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Affiliation(s)
- Young-Min Han
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul ; College of Pharmacy, CHA University, Pocheon
| | - Jong-Min Park
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul
| | - Ho-Jae Lee
- Lee Gil Ya Cancer and Diabetes Research Institute, Gachon University, Incheon
| | - Eun-Hee Kim
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul ; Lee Gil Ya Cancer and Diabetes Research Institute, Gachon University, Incheon
| | - Ki Baik Hahm
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul ; Department of Gastroenterology, CHA Bundang Medical Center, Seongnam, Korea
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Shimizu M, Kochi T, Shirakami Y, Genovese S, Epifano F, Fiorito S, Mori T, Tanaka T, Moriwaki H. A newly synthesized compound, 4'-geranyloxyferulic acid-N(omega)-nitro-L-arginine methyl ester suppresses inflammation-associated colorectal carcinogenesis in male mice. Int J Cancer 2014; 135:774-84. [PMID: 24474144 DOI: 10.1002/ijc.28718] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 12/07/2013] [Accepted: 12/30/2013] [Indexed: 12/25/2022]
Abstract
We previously reported the cancer chemopreventive activity of 4'-geranyloxyferulic acid (GOFA, Miyamoto et al., Nutr Cancer 2008; 60:675-84) and a β-cyclodextrin inclusion compound of GOFA (Tanaka et al., Int J Cancer 2010; 126:830-40) in colitis-related colorectal carcinogenesis. In our study, the chemopreventive effects of a newly synthesized GOFA-containing compound, GOFA-N(omega)-nitro-L-arginine methyl ester (L-NAME), which inhibits inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX) enzymes, were investigated using a colitis-associated mouse colorectal carcinogenesis model with azoxymethane (AOM) and dextran sodium sulfate (DSS). The dietary administration of GOFA-L-NAME after the AOM and DSS treatments significantly reduced the multiplicity of adenocarcinomas (inhibition rates: 100 ppm, 84%, p < 0.001; 500 ppm, 94%, p < 0.001) compared with the AOM + DSS group. Dietary GOFA-L-NAME significantly decreased the proliferation (p < 0.001) and increased the apoptosis (p < 0.001) of colonic adenocarcinoma cells. A subsequent short-term experiment revealed that dietary GOFA-L-NAME decreased the mRNA expression of inflammatory enzymes, such as iNOS and COX-2, and proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and macrophage inflammatory protein (MIP)-2 in the colonic mucosa of mice that received 1.5% DSS in their drinking water for 7 days. Our findings indicate that GOFA-L-NAME is able to inhibit colitis-associated colon carcinogenesis by modulating inflammation, proliferation, apoptosis and the expression of proinflammatory cytokines in mice.
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Affiliation(s)
- Masahito Shimizu
- Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan
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Ganesh R, Marks DJB, Sales K, Winslet MC, Seifalian AM. Cyclooxygenase/lipoxygenase shunting lowers the anti-cancer effect of cyclooxygenase-2 inhibition in colorectal cancer cells. World J Surg Oncol 2012; 10:200. [PMID: 23013454 PMCID: PMC3527267 DOI: 10.1186/1477-7819-10-200] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2012] [Accepted: 09/10/2012] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Arachidonic acid metabolite, generated by cyclooxygenase (COX), is implicated in the colorectal cancer (CRC) pathogenesis. Inhibiting COX may therefore have anti-carcinogenic effects. Results from use of non-steroidal anti-inflammatory drugs inhibiting only COX have been conflicting. It has been postulated that this might result from the shunting of arachidonic acid metabolism to the 5-lipoxygenase (5-LOX) pathway. Cancer cell viability is promoted by 5-LOX through several mechanisms that are similar to those of cyclooxygenase-2 (COX-2). Expression of 5-LOX is upregulated in colorectal adenoma and cancer. The aim of this study was to investigate the shunting of arachidonic acid metabolism to the 5-LOX pathway by cyclooxygenase inhibition and to determine if this process antagonizes the anti-cancer effect in colorectal cancer cells. METHODS Three colorectal cancer cell lines (HCA7, HT-29 & LoVo) expressing 5-LOX and different levels of COX-2 expression were used. The effects of aspirin (a non-selective COX inhibitor) and rofecoxib (COX-2 selective) on prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) secretion were quantified by ELISA. Proliferation and viability were studied by quantifying double-stranded DNA (dsDNA) content and metabolic activity. Apoptosis was determined by annexin V and propidium iodide staining using confocal microscopy, and caspase-3/7 activity by fluorescent substrate assay. RESULTS COX inhibitors suppressed PGE2 production but enhanced LTB4 secretion in COX-2 expressing cell lines (P <0.001). The level of COX-2 expression in colorectal cancer cells did not significantly influence the anti-proliferative and pro-apoptotic effects of COX inhibitors due to the shunting mechanism. CONCLUSIONS This study provides evidence of shunting between COX and 5-LOX pathways in the presence of unilateral inhibition, and may explain the conflicting anti-carcinogenic effects reported with use of COX inhibitors.
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Affiliation(s)
- Radhakrishnan Ganesh
- Division of Surgery and Interventional Science, University College London, Rowland Hill Street, London NW3 2PF, UK.
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Bohn T, Blackwood M, Francis D, Tian Q, Schwartz SJ, Clinton SK. Bioavailability of phytochemical constituents from a novel soy fortified lycopene rich tomato juice developed for targeted cancer prevention trials. Nutr Cancer 2011; 65:919-29. [PMID: 22098224 DOI: 10.1080/01635581.2011.630156] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Studies suggest that tomato and soy foods may contribute to a lower risk of certain cancers. We developed a novel soy germ tomato juice to be used in controlled cancer prevention trials. This study describes an initial test of compliance, phytochemical bioavailability, and effects on biomarkers of blood lipids. Healthy men and women (n = 18) consumed a soy germ-fortified juice daily (300 mL supplying 66 mg isoflavones and 22 mg lycopene) for 8 wk. A single-dose bioavailability study was completed on day 1 and isoflavones in plasma and urine, and lycopene in the plasma, were measured. All subjects completed the trial, with 97.7% ± 3.5% (mean ± SD) of the scheduled juice consumed. No adverse effects were documented. The postprandial study indicated that 3.1% ± 2.3% of lycopene was absorbed and that 49.3% ± 12.1% isoflavones ingested were recovered in 24-h urines. Lycopene plasma concentration changed from 0.60 ± 0.22 to 1.24 ± 0.30 μmol/L during 8 wk of consumption. Juice consumption significantly improved resistance of LDL+VLDL-C to Cu(2+)-mediated oxidation (P = 0.039), HDL-C (47.3 ± 15.8 to 51.7 ± 14.8 mg/dL, P < 0.001), and the ratio of total-C/HDL-C (4.25 ± 1.59 to 3.63 ± 1.16, P < 0.001) at 8 wk. A well-characterized soy-fortified tomato juice can be produced in large scale for multiinstitutional long-term cancer prevention trials and showed excellent compliance with no toxicity, while demonstrating absorption of biologically active phytochemicals.
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Affiliation(s)
- Torsten Bohn
- Department of Food Science and Technology, The Ohio State University, Columbus, Ohio, USA.
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Kefalakes H, Stylianides TJ, Amanakis G, Kolios G. Exacerbation of inflammatory bowel diseases associated with the use of nonsteroidal anti-inflammatory drugs: myth or reality? Eur J Clin Pharmacol 2009; 65:963-70. [PMID: 19711064 DOI: 10.1007/s00228-009-0719-3] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2009] [Accepted: 08/05/2009] [Indexed: 02/06/2023]
Abstract
BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs), conventional and selective cyclooxygenase-2 (COX-2) inhibitors, are among the most widely used medications for the treatment of various inflammatory conditions. There is strong evidence of a possible association between the use of these drugs and the relapse of inflammatory bowel diseases (IBD). OBJECTIVE Our objective was to examine the literature regarding the exacerbation of IBD associated with the use of conventional NSAIDs and selective COX-2 inhibitors and the underlying pathogenetic mechanisms. STUDY DESIGN We reviewed articles, including original papers, controlled trials, case reports, reviews, and editorials published in English at the PubMed, Scopus Database, and Science Direct database, searching with the following keywords: nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, Coxibs, inflammatory bowel diseases (IBD), ulcerative colitis (UC), Crohn's disease (CD). RESULTS There is substantial evidence that exacerbation of IBD happens after treatment with NSAIDs, but the available data remain conflicting, and it is not clear whether selective COX-2 inhibitors are safer than traditional NSAIDs. However, there is some evidence that selective COX-2 inhibition and COX-1 inhibition (with low-dose aspirin) appear to be well-tolerated in the short term. Regarding the mechanisms of relapse, the reduction of prostaglandins appears to be the hallmark of the NSAIDs adverse effects. CONCLUSIONS Further randomized, double-blind, controlled trials should be performed to address this issue, and more in vitro studies to identify the pathways involved are required.
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Affiliation(s)
- Helenie Kefalakes
- Clinical Pharmacology, Faculty of Medicine, University of Crete, Crete, Greece
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Abstract
Chemoprevention means the use of agents to prevent, delay, or reverse carcinogenesis. This review was designed to critically discuss the most promising agents in colorectal cancer (CRC) chemoprevention. Aspirin is the best studied chemopreventive agent for CRC. Optimal chemoprevention requires long-term use and high dose of aspirin that may increase the risk of gastrointestinal bleeding. Nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors may also be candidates for chemoprevention. The regular use of nonsteroidal anti-inflammatory drugs, however, causes adverse effects including gastrointestinal bleeding, and cyclooxygenase-2 inhibitors may increase the risk of cardiovascular events. In patients with ulcerative colitis 5-aminosalicylates reduce the risk of CRC and dysplasia. Ursodeoxycholic acid can reduce the risk of dysplasia or CRC in patients with primary sclerosing cholangitis and ulcerative colitis. Current data are insufficient to support the use of hormone replacement therapy to reduce the risk of CRC. Statins may have chemopreventive effects, but further investigation of their overall benefits in preventing CRC is warranted. Antioxidant supplements cannot prevent CRC. The usefulness of selenium, folate, calcium, and vitamin D awaits further evaluation. Chemoprevention cannot yet be accepted as standard medical practice. Use of chemopreventive agents cannot be a substitute for colorectal surveillance.
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