|
1
|
Xiu MX, Liu YM, Chen GY, Hu C, Kuang BH. Identifying Hub Genes, Key Pathways and Immune Cell Infiltration Characteristics in Pediatric and Adult Ulcerative Colitis by Integrated Bioinformatic Analysis. Dig Dis Sci 2021; 66:3002-3014. [PMID: 32974809 DOI: 10.1007/s10620-020-06611-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 09/10/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS In the present study, we investigated the differentially expressed genes (DEGs), pathways and immune cell infiltration characteristics of pediatric and adult ulcerative colitis (UC). METHODS We conducted DEG analysis using the microarray dataset GSE87473 containing 19 pediatric and 87 adult UC samples downloaded from the Gene Expression Omnibus. Gene ontology and pathway enrichment analyses were conducted using Metascape. We constructed the protein-protein interaction (PPI) network and the drug-target interaction network of DEGs and identified hub modules and genes using Cytoscape and analyzed immune cell infiltration in pediatric and adult UC using CIBERSORT. RESULTS In total, 1700 DEGs were screened from the dataset. These genes were enriched mainly in inter-cellular items relating to cell junctions, cell adhesion, actin cytoskeleton and transmembrane receptor signaling pathways and intra-cellular items relating to the splicing, metabolism and localization of RNA. CDC42, POLR2A, RAC1, PIK3R1, MAPK1 and SRC were identified as hub DEGs. Immune cell infiltration analysis revealed higher proportions of naive B cells, resting memory T helper cells, regulatory T cells, monocytes, M0 macrophages and activated mast cells in pediatric UC, along with lower proportions of memory B cells, follicular helper T cells, γδ T cells, M2 macrophages, and activated dendritic cells. CONCLUSIONS Our study suggested that hub genes CDC42, POLR2A, RAC1, PIK3R1, MAPK1 and SRC and immune cells including B cells, T cells, monocytes, macrophages and mast cells play vital roles in the pathological differences between pediatric and adult UC and may serve as potential biomarkers in the diagnosis and treatment of UC.
Collapse
Affiliation(s)
- Meng-Xi Xiu
- Medical School of Nanchang University, 603 Bayi Road, Nanchang, 330006, Jiangxi, China
| | - Yuan-Meng Liu
- Medical School of Nanchang University, 603 Bayi Road, Nanchang, 330006, Jiangxi, China
| | - Guang-Yuan Chen
- Medical School of Nanchang University, 603 Bayi Road, Nanchang, 330006, Jiangxi, China
| | - Cong Hu
- Medical School of Nanchang University, 603 Bayi Road, Nanchang, 330006, Jiangxi, China
| | - Bo-Hai Kuang
- Medical School of Nanchang University, 603 Bayi Road, Nanchang, 330006, Jiangxi, China.
| |
Collapse
|
|
2
|
Rabbenou W, Ullman TA. Risk of Colon Cancer and Recommended Surveillance Strategies in Patients with Ulcerative Colitis. Gastroenterol Clin North Am 2020; 49:791-807. [PMID: 33121696 DOI: 10.1016/j.gtc.2020.08.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Longstanding and extensive ulcerative colitis (UC) are associated with the subsequent development of colorectal cancer (CRC). This article summarizes key strategies for colonoscopic surveillance, the most widely used and evidence-based method of CRC prevention. As currently constituted and practiced, surveillance examinations every 1 to 3 years with lesion detection and removal using high-definition endoscopic systems with or without pancolonic spray-dye chromoendoscopy is the best method for mitigating the development of CRC morbidity and mortality. For patients with primary sclerosing cholangitis with UC, surveillance should begin at the time of diagnosis and colonoscopy should be performed annually.
Collapse
Affiliation(s)
- Wendy Rabbenou
- Division of Gastroenterology, Montefiore Medical Center, Albert Einstein College of Medicine, 33030 Rochambeau Avenue, Bronx, NY 10461, USA
| | - Thomas A Ullman
- Division of Gastroenterology, Montefiore Medical Center, Albert Einstein College of Medicine, 33030 Rochambeau Avenue, Bronx, NY 10461, USA.
| |
Collapse
|
|
3
|
DUOX2 and DUOXA2 form the predominant enzyme system capable of producing the reactive oxygen species H2O2 in active ulcerative colitis and are modulated by 5-aminosalicylic acid. Inflamm Bowel Dis 2014; 20:514-24. [PMID: 24492313 DOI: 10.1097/01.mib.0000442012.45038.0e] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND NADPH oxidase-derived reactive oxygen species, such as H2O2, are part of the intestinal innate immune system but may drive carcinogenesis through DNA damage. We sought to identify the predominant enzyme system capable of producing H2O2 in active ulcerative colitis and assess whether it is affected by 5-aminosalicylic acid (5-ASA). METHODS We studied human mucosal biopsies by expression arrays, quantitative real-time polymerase chain reaction for NADPH oxidase family members, in situ hybridization (DUOX2 and DUOXA2) and immunofluorescence for DUOX, 8-OHdG (DNA damage), and γH2AX (DNA damage response) and sought effects of 5-ASA on ex vivo cultured biopsies and cultured rectal cancer cells. RESULTS DUOX2 with maturation partner DUOXA2 forms the predominant system for H2O2 production in human colon and is upregulated in active colitis. DUOX2 in situ is exclusively epithelial, varies between and within individual crypts, and increases near inflammation. 8-OHdG and γH2AX were observed in damaged crypt epithelium. 5-ASA upregulated DUOX2 and DUOXA2 levels in the setting of active versus quiescent disease and altered DUOX2 expression in cultured biopsies. Ingenuity pathway analysis confirmed that inflammation status and 5-ASA increase expression of DUOX2 and DUOXA2. An epithelial cell model confirmed that cultured cancer cells expressed DUOX protein and produced H2O2 in response to hypoxia and 5-ASA exposure. CONCLUSIONS Both DUOX2 and DUOXA2 expression are involved specifically in inflammation and are regulated on a crypt-by-crypt basis in ulcerative colitis tissues. Synergy between inflammation, hypoxia, and 5-ASA to increase H2O2 production could explain how 5-ASA supports innate defense, although potentially increasing the burden of DNA damage.
Collapse
|
|
4
|
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease
(IBD) associated with multiple colonic and extraintestinal
complications, the most severe being the development of colorectal
cancer (CRC). Compared to the general population, there is an
increased risk of CRC associated with UC. Although the
pathogenesis of CRC in UC is unknown, most studies have linked it
to long-standing inflammation as well as other risk factors such
as duration of disease, extent of inflammation, family history of
CRC, and coexisting conditions such as primary sclerosing
cholangitis (PSC). UC is a life-long disease for which patients
enter a vigilant screening program which includes surveillance
colonoscopy to promote early detection of CRC yet some
controversies exist regarding the cost effectiveness of
surveillance colonoscopy and improving survival. Newer modalities
such as chromoendoscopy, narrow band imaging, high definition
colonoscopy, and confocal microscopy have aided in developing a
more targeted approach for early detection of dysplasia in
surveillance colonoscopy. This review focuses on the role of
chronic colonic inflammation and dysplasia in development of
UC-associated CRC and current methods of screening, detection,
chemoprevention, and treatment of UC-associated CRC.
Collapse
|
|
5
|
Takagi T, Naito Y, Uchiyama K, Yoshikawa T. The role of heme oxygenase and carbon monoxide in inflammatory bowel disease. Redox Rep 2011; 15:193-201. [PMID: 21062534 DOI: 10.1179/174329210x12650506623889] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease, is a chronic and recurrent inflammatory disorder of the intestinal tract. Since the precise pathogenesis of IBD remains unclear, it is important to investigate the pathogenesis of IBD and to evaluate new anti-inflammatory strategies. Recent evidence suggests that heme oxygenase-1 (HO-1) plays a critical protective role during the development of intestinal inflammation. In fact, it has been demonstrated that the activation of HO-1 may act as an endogenous defensive mechanism to reduce inflammation and tissue injury in various animal intestinal injury models induced by ischemia-reperfusion, indomethacin, lipopolysaccharide-associated sepsis, trinitrobenzene sulfonic acid or dextran sulfate sodium. In addition, carbon monoxide (CO) derived from HO-1 has been shown to be involved in the regulation of intestinal inflammation. Furthermore, administration of a low concentration of exogenous CO has a protective effect against intestinal inflammation. These data suggest that HO-1 and CO may be novel therapeutic molecules for patients with gastrointestinal inflammatory diseases. In this review, we present what is currently known regarding the role of HO-1 and CO in intestinal inflammation.
Collapse
Affiliation(s)
- Tomohisa Takagi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | | | | | | |
Collapse
|
|
6
|
Hurley JJ, Turner J, Berrill J, Swift G, Dolwani S, Green J. Surveillance for colorectal cancer in patients with inflammatory bowel disease. Br J Hosp Med (Lond) 2010; 71:562-7. [DOI: 10.12968/hmed.2010.71.10.78939] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Joanna J Hurley
- Department of Gastroenterology, University Hospital Llandough, Cardiff CF64 2XX
| | - Jeff Turner
- Department of Gastroenterology, University Hospital Llandough, Cardiff CF64 2XX
| | - James Berrill
- Department of Gastroenterology, University Hospital Llandough, Cardiff CF64 2XX
| | - Gillian Swift
- Department of Gastroenterology, University Hospital Llandough, Cardiff CF64 2XX
| | - Sunil Dolwani
- Department of Gastroenterology, University Hospital Llandough, Cardiff CF64 2XX
| | - John Green
- Department of Gastroenterology, University Hospital Llandough, Cardiff CF64 2XX
| |
Collapse
|
|
7
|
Mesalamine protects against colorectal cancer in inflammatory bowel disease. Dig Dis Sci 2010; 55:1696-703. [PMID: 19705280 DOI: 10.1007/s10620-009-0942-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2009] [Accepted: 08/06/2009] [Indexed: 12/15/2022]
Abstract
BACKGROUND Individuals with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC) compared with the general population. Previous studies show this risk is strongly associated with dysplasia, extent of disease, duration of disease, and degree of inflammation, while chemoprevention of CRC has less support. AIM Evaluate factors influencing risk of colorectal cancer development in inflammatory bowel disease patients. METHODS IBD patients with CRC were matched to controls by IBD type, age at diagnosis, sex, race, extent of disease, and disease duration. We compared body mass index, family history of IBD, family history of CRC, tobacco use, and cumulative and daily use of aminosalicylates, immunomodulators, folic acid, steroids, and nonsteroidal anti-inflammatory drugs. Statistical analysis was performed with logistic regression and receiver operating characteristic (ROC) curves. RESULTS Of 1,594 IBD patients, 30 CRC patients were identified. Of these, 18 CRC patients were matched to 30 controls. More control patients used a cumulative aminosalicylate dose of >or=4,500 g (46.6% versus 5.6%; P = 0.047), folic acid (40.0% versus 16.7%; P = 0.002), cumulative folic acid dose of >or=1,400 mg (30.0% versus 11.1%; P = 0.014), and average daily folic acid dose of >or=1 mg (30.0% versus 16.7%; P = 0.002) compared with CRC patients. Multivariate analysis showed that a cumulative aminosalicylate dose of >or=4,500 g reduced the risk of CRC by 97.6% (P = 0.047). Folic acid reduced CRC risk by 89% (P = 0.002). CONCLUSIONS Aminosalicylate and folic acid use may decrease the risk of CRC among IBD patients.
Collapse
|
|
8
|
Campregher C, Honeder C, Chung H, Carethers JM, Gasche C. Mesalazine reduces mutations in transforming growth factor beta receptor II and activin type II receptor by improvement of replication fidelity in mononucleotide repeats. Clin Cancer Res 2010; 16:1950-6. [PMID: 20197483 DOI: 10.1158/1078-0432.ccr-09-2854] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
PURPOSE Mesalazine (5-aminosalicylic acid, 5-ASA) has chemopreventive properties in colitis-associated cancer. In vitro, it improves replication fidelity at (CA)13 microsatellites independent of mismatch repair proficiency. Therefore, 5-ASA might be advantageous in patients with hereditary nonpolyposis colorectal cancer. At this point, however, it is uncertain whether this improvement of replication fidelity is specific for (CA)13 repetitive sequences. Here, we tested the effect of 5-ASA on replication fidelity in mononucleotide, dinucleotide, and tetranucleotide repeats. EXPERIMENTAL DESIGN HCT116 and HCT116+chr3 cells were transfected with pIREShyg2-EGFP reporter plasmids harboring the following microsatellites: A10, G10, (CA)13, (CA)26, (AAAG)17, poly-A tracts, and their flanking sequences of transforming growth factor beta receptor II (TGFBR2; A10) and activin type II receptor (ACVR2; A8). Stably transfected single-cell clones were selected, characterized by Southern blotting, sorted into six-well plates, and cultured with or without 5-ASA. Frameshift mutations that shift the enhanced green fluorescence protein into its proper reading frame were quantified by flow cytometry. RESULTS In HCT116, 5-ASA reduced the mutant fraction at (CA)13 by 48.3%, at A10 by 35.6-43.6%, at G10 by 74.9-83.6%, and at (AAAG)17 by 37.6-44.4%. Similar results were observed in hMLH1-proficient HCT116+chr3 cells. Moreover, the presence of 5-ASA significantly reduced mutations in TGFBR2 (A10) and ACVR2 (A8) by 39.9% and 46.2%, respectively. CONCLUSIONS 5-ASA increases replication fidelity in mononucleotide, dinucleotide, and tetranucleotide repeats and reduces mutations in tumor suppressor genes TGFBR2 and ACVR2, a finding that may provoke in vivo studies for the prevention of colorectal cancer in hereditary nonpolyposis colorectal cancer.
Collapse
Affiliation(s)
- Christoph Campregher
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria
| | | | | | | | | |
Collapse
|
|
9
|
Das KK, Bajpai M, Kong Y, Liu J, Geng X, Das KM. Mesalamine suppresses the expression of TC22, a novel tropomyosin isoform associated with colonic neoplasia. Mol Pharmacol 2009; 76:183-91. [PMID: 19369484 PMCID: PMC2701462 DOI: 10.1124/mol.109.056028] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2009] [Accepted: 04/07/2009] [Indexed: 01/06/2023] Open
Abstract
Although a protective role for mesalamine against colon cancer in ulcerative colitis has been shown epidemiologically, its molecular mechanism is unknown. We cloned and sequenced a novel human tropomyosin (hTM) isoform, TC22, which is an alternatively spliced variant of normal epithelial hTM isoform 5 (hTM5), identical apart from 25 C-terminal amino acids. TC22 is expressed in 100% of colorectal carcinoma but is not expressed in normal colon epithelial cells. To explore a molecular mechanism of chemoprevention, we examined the effect of mesalamine on TC22 expression using LS180 colon cancer cells. Expression of hTM5 and TC22 was investigated at the protein and gene levels by fluorescence-activated cell sorting and real-time reverse transcription-polymerase chain reaction. Small interference RNA (siRNA) against the TC22 variant were transfected into LS180 colon cancer cells, reducing protein and transcript levels by 45 to 50%. Mesalamine or sulfasalazine (2 mM), but not sulfapyridine, significantly (p < 0.02-0.006) reduced the expression of the TC22 transcript and significantly (p < 0.05 to <0.0002) reduced the expression of TC22 protein in a dose-dependent and reversible manner. Rosiglitazone, a specific peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist, similarly and significantly (p < 0.002) reduced TC22 protein expression. A polymerase chain reaction array of 84 cancer-related genes performed on TC22 siRNA-transfected cells demonstrated a significant (more than two times) change in targets involved in apoptosis, adhesion, angiogenesis, and tissue remodeling. We conclude that mesalamine, sulfasalazine, and rosiglitazone significantly reduced the cellular expression of TC22, implicating PPARgamma in this modulation. Similar suppression of TC22 by siRNA produced gene level changes on several critical carcinogenic pathways. These findings suggest a novel antineoplastic molecular effect of mesalamine.
Collapse
Affiliation(s)
- Koushik K Das
- Crohn's and Colitis Center of New Jersey, Division of Gastroenterology and Hepatology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA
| | | | | | | | | | | |
Collapse
|
|
10
|
Yang GY, Taboada S, Liao J. Inflammatory bowel disease: a model of chronic inflammation-induced cancer. Methods Mol Biol 2009; 511:193-233. [PMID: 19347299 DOI: 10.1007/978-1-59745-447-6_9] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Chronic inflammation is a well-recognized risk factor for the development of human cancer. Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a typical longstanding inflammatory disease of the colon with increased risk for the development of colorectal carcinoma. Several molecular events involved in chronic inflammatory process may contribute to multistage progression of human cancer development, including the overproduction of reactive oxygen and nitrogen species, overproduction/activation of key arachidonic acid metabolites and cytokines/growth factors, and immunity system dysfunction. Multiple animal models of IBD have been established, and in general, these models can be mainly categorized into chemically induced, genetically engineered (transgenic or gene knock-out), spontaneous, and adoptive transferring animal models. This chapter mainly focuses on (1) epidemiologic and molecular evidence on IBD and risk of colorectal cancer, (2) molecular pathogenesis of IBD-induced carcinogenesis, and (3) modeling of IBD-induced carcinogenesis in rodents and its application.
Collapse
Affiliation(s)
- Guang-Yu Yang
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | | | | |
Collapse
|
|
11
|
Tanaka T, Yasui Y, Ishigamori-Suzuki R, Oyama T. Citrus compounds inhibit inflammation- and obesity-related colon carcinogenesis in mice. Nutr Cancer 2009; 60 Suppl 1:70-80. [PMID: 19003583 DOI: 10.1080/01635580802381253] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Dietary polyphenols are important potential chemopreventive natural agents. Other agents, such as citrus compounds, are also candidates for cancer chemopreventives. They act on multiple key elements in signal transduction pathways related to cellular proliferation, differentiation, apoptosis, inflammation, and obesity. This short review article provides our findings of preclinical studies on potential chemopreventive activities of dietary citrus compounds, auraptene, collinin, and citrus unshiu segment membrane (CUSM), using clitis- and obesity-related colon tumorigenesis models. Dietary feeding with auraptene and collinin at dose levels of 0.01% and 0.05% significantly lowered the incidence (50-60% reduction) and multiplicity (67-80% reduction) of colonic adenocarcinomas induced by azoxymetahene [AOM, single intraperitoneal injection of 10 mg/kg body weight (bw)] and dextran sodium sulfate (1% in drinking water). Anti-inflammatory potency of aurapene and collinin may contribute to the effects. Administration with CUSM at 3 doses in diet significantly inhibited development of aberrant crypts foci induced by 5 weekly subcutaneous injections of AOM (15 mg/kg bw) in male db/db mice: 53% inhibition by 0.02% CUSM, 54% inhibition by 0.1% CUSM, and 59% inhibition by 0.5% CUSM. CUSM treatment also decreased serum level of triglycerides. Our findings suggest that certain citrus materials are capable of inhibiting clitis- and obesity-related colon carcinogenesis.
Collapse
Affiliation(s)
- Takuji Tanaka
- Kanazawa Medical University, Daigaku, Uchinada, Ishikawa, Japan.
| | | | | | | |
Collapse
|
|
12
|
Abstract
With few exceptions, epidemiological studies have found that individuals who take nonsteroidal antiinflammatory drugs (NSAIDs) have a reduced risk of colorectal adenomas and carcinoma. Similarly, randomized studies in patients with familial adenomatous polyposis have uniformly found that NSAIDs can lead to polyp regression and prevention of new polyps, and trials in patients with sporadic adenomas document that aspirin reduces the risk of adenoma recurrence. Together these data provide convincing evidence for the chemopreventive efficacy ofNSAIDs in the large bowel.
Collapse
Affiliation(s)
- John A Baron
- Evergreen Center, Biostatistics and Epidemiology, Lebanon, NH 03756, USA.
| |
Collapse
|
|
13
|
Abstract
Oxidative stress is defined as an imbalance between generation of reactive oxygen species (ROS) and decreased antioxidant defense systems. Oxidative stress develops particularly in inflammatory reactions because the inflammatory cells, neutrophils, and macrophages produce large amounts of ROS. It has been known for a long time that oxidative stress in inflamed tissue can pave the way for malignant tumors, and that it is a major pathogenetic factor for the well-established correlation between inflammatory diseases and cancer. Oxidative stress has long been associated with the pathogenesis of chronic inflammatory bowel disease (IBD)-related colorectal cancer. This article provides an overview of the pathology of ROS and presents recent advances concerning the role of ROS in IBD-related colorectal carcinogenesis (Fig. 1).
Collapse
|
|
14
|
Harpaz N. Neoplastic precursor lesions related to the development of cancer in inflammatory bowel disease. Gastroenterol Clin North Am 2007; 36:901-26, vii-viii. [PMID: 17996797 DOI: 10.1016/j.gtc.2007.08.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Dysplasia is an intermediate stage in the progression from inflammation to cancer in patients with inflammatory bowel disease. Clinically, dysplasia is used to define appropriate endpoints for colectomy in high-risk patients undergoing endoscopic surveillance. Surveillance is currently the only credible alternative to prophylactic colectomy for high-risk patients. The success of surveillance can be maximized by adherence of gastroenterologists to recommended procedural guidelines, adherence of pathologists to standardized histological criteria and nomenclature, and a joint commitment to close clinical-pathological communication. Technical enhancements to conventional endoscopy hold promise of improved efficiency and accuracy. Molecular-based testing may have a future role for risk stratification and early detection of neoplasia in inflammatory bowel disease.
Collapse
Affiliation(s)
- Noam Harpaz
- Division of Gastrointestinal Pathology, Department of Pathology, The Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029, USA.
| |
Collapse
|
|
15
|
Karvellas CJ, Fedorak RN, Hanson J, Wong CKW. Increased risk of colorectal cancer in ulcerative colitis patients diagnosed after 40 years of age. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2007; 21:443-6. [PMID: 17637947 PMCID: PMC2657965 DOI: 10.1155/2007/136406] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The association between ulcerative colitis (UC) and colorectal cancer (CRC) is well established. Retrospective data show a 5.4% CRC incidence rate among patients with pancolitis and suggest that cancer surveillance should be provided to patients following eight to 10 years of extensive UC. AIM To identify premalignant risk factors for UC patients and to determine whether current recommendations for cancer surveillance need reviewing. PATIENTS AND METHODS A retrospective audit was conducted of adult patients with UC who were diagnosed with CRC between 1991 and 2002 in five hospitals in Edmonton, Alberta. RESULTS Thirty-one cases of CRC (68% male) were identified. In this group, the mean ages at diagnosis were 44.4 years for UC patients and 60.1 years for CRC patients. For patients in whom the initial data of diagnosis of UC could be determined (n=29), the median duration of UC at the time of CRC diagnosis was 16 years. Patients diagnosed with UC after 40 years of age (n=15, mean age 64 years) progressed more rapidly to CRC than patients diagnosed before 40 years of age (n=14, mean age 23 years). The median durations of UC before development of CRC were 22 years and 10 years, respectively, for patients with a diagnosis of UC before and after 40 years of age (OR 11.5, 95% CI 2.41 to 20.16; P=0.00029). Only four patients (13%) were enrolled in an appropriate cancer-screening program. Nine of these UC patients (29%) who were older than 40 years of age developed CRC before the 10-year point. CONCLUSIONS In the present study, patients diagnosed with UC after 40 years of age developed CRC more rapidly than those diagnosed before 40 years of age. This finding suggests that patients who are diagnosed with UC after 40 years of age should undergo CRC surveillance earlier than current recommendations.
Collapse
Affiliation(s)
| | | | | | - Clarence KW Wong
- Correspondence: Dr Clarence KW Wong, Division of Gastroenterology, University of Alberta, #331 Community Services Centre, Royal Alexandra Hospital, 10240 Kingsway Avenue, Edmonton, Alberta T5H 3V9. Telephone 780-735-6838, fax 780-735-5650, e-mail
| |
Collapse
|
|
16
|
Verma M, Seminara D, Arena FJ, John C, Iwamoto K, Hartmuller V. Genetic and epigenetic biomarkers in cancer : improving diagnosis, risk assessment, and disease stratification. Mol Diagn Ther 2007; 10:1-15. [PMID: 16646573 DOI: 10.1007/bf03256438] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gene expression patterns change during the initiation, progression, and development of cancer, as a result of both genetic and epigenetic mechanisms. Genetic changes arise due to irreversible changes in the nucleotide sequence, whereas epigenetic changes occur due to changes in chromatin conformation, histone acetylation, and methylation of the CpG islands located primarily in the promoter region of a gene. Both genetic and epigenetic markers can potentially be utilized to identify different stages of tumor development. Several such markers exhibit high sensitivity and specificity for different tumor types and can be assayed in biofluids and other specimens collected by noninvasive technologies. In spite of the availability of large numbers of diagnostic markers, only a few have been clinically validated so far. The current status and the challenges in the field of genetic and epigenetic markers in cancer diagnosis, risk assessment, and disease stratification are discussed.
Collapse
Affiliation(s)
- Mukesh Verma
- Analytic Epidemiology Research Branch, Epidemiology and Genetics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, Maryland 20852, USA.
| | | | | | | | | | | |
Collapse
|
|
17
|
Englund G, Jacobson A, Rorsman F, Artursson P, Kindmark A, Rönnblom A. Efflux transporters in ulcerative colitis: decreased expression of BCRP (ABCG2) and Pgp (ABCB1). Inflamm Bowel Dis 2007; 13:291-7. [PMID: 17206689 DOI: 10.1002/ibd.20030] [Citation(s) in RCA: 103] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Efflux transport proteins are important components of the intestinal barrier against bacterial toxins, carcinogens, and drugs. This investigation was conducted to determine the expression of Breast Cancer Resistance Protein (BCRP/ABCG2), P-glycoprotein (Pgp/MDR1/ABCB1), and Multidrug Resistance Protein 2 (MRP2/ABCC2) in the gut mucosa of patients with ulcerative colitis (UC). METHODS Patients were thoroughly diagnosed according to well-established clinical, endoscopic, and histologic criteria to be included in the group of patients with active UC (n = 16) or UC in remission (n = 17). Colonic and rectal mucosa from patients with UC were compared with tissues from control subjects (n = 15). The mRNA expression (TaqMan) of the efflux transporters and the proinflammatory cytokines interleukin (IL)-1beta and IL-6 was determined. Western blot was used in the analysis of protein expression and the tissue localization of BCRP was determined with confocal microscopy. RESULTS BCRP and Pgp expression was strongly reduced in individuals with active inflammation compared with controls and was negatively correlated with the levels of IL-6 mRNA. The BCRP staining of colonic epithelium seen in healthy mucosa was diminished in inflamed tissues, with concurrent disruption of epithelial F-actin structure. CONCLUSIONS Two of the efflux transporters of importance for the barrier function of the gut mucosa, Pgp and BCRP, are expressed at strongly reduced levels during active inflammation in patients with UC. Investigations are warranted to determine whether the low levels of efflux transporters during active UC contribute to altered transport and tissue exposure of carcinogens, bacterial toxins, and drugs.
Collapse
|
|
18
|
Luciani MG, Campregher C, Fortune JM, Kunkel TA, Gasche C. 5-ASA affects cell cycle progression in colorectal cells by reversibly activating a replication checkpoint. Gastroenterology 2007; 132:221-35. [PMID: 17241873 PMCID: PMC1839818 DOI: 10.1053/j.gastro.2006.10.016] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2006] [Accepted: 09/21/2006] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Individuals with inflammatory bowel disease are at risk of developing colorectal cancer (CRC). Epidemiologic, animal, and laboratory studies suggest that 5-amino-salicylic acid (5-ASA) protects from the development of CRC by altering cell cycle progression and by inducing apoptosis. Our previous results indicate that 5-ASA improves replication fidelity in colorectal cells, an effect that is active in reducing mutations. In this study, we hypothesized that 5-ASA restrains cell cycle progression by activating checkpoint pathways in colorectal cell lines, which would prevent tumor development and improve genomic stability. METHODS CRC cells with different genetic backgrounds such as HT29, HCT116, HCT116(p53-/-), HCT116+chr3, and LoVo were treated with 5-ASA for 2-96 hours. Cell cycle progression, phosphorylation, and DNA binding of cell cycle checkpoint proteins were analyzed. RESULTS We found that 5-ASA at concentrations between 10 and 40 mmol/L affects cell cycle progression by inducing cells to accumulate in the S phase. This effect was independent of the hMLH1, hMSH2, and p53 status because it was observed to a similar extent in all cell lines under investigation. Moreover, wash-out experiments demonstrated reversibility within 48 hours. Although p53 did not have a causative role, p53 Ser15 was strongly phosphorylated. Proteins involved in the ATM-and-Rad3-related kinase (ATR)-dependent S-phase checkpoint response (Chk1 and Rad17) were also phosphorylated but not ataxia telengectasia mutated kinase. CONCLUSIONS Our data demonstrate that 5-ASA causes cells to reversibly accumulate in S phase and activate an ATR-dependent checkpoint. The activation of replication checkpoint may slow down DNA replication and improve DNA replication fidelity, which increases the maintenance of genomic stability and counteracts carcinogenesis.
Collapse
Affiliation(s)
- M Gloria Luciani
- Medical University of Vienna, Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Währinger Gürtel 18, A-1090 Vienna, Austria
| | | | | | | | | |
Collapse
|
|
19
|
Fei SJ, Xiao SD, Peng YS, Chen XY, Shi Y. Chemopreventive effects of rofecoxib and folic acid on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats. ACTA ACUST UNITED AC 2006; 7:134-40. [PMID: 16808793 DOI: 10.1111/j.1443-9573.2006.00258.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Epidemiological and experimental studies indicate that non-steroidal anti-inflammatory drugs (NSAIDs) are chemopreventive agents of gastrointestinal cancers, but few studies on gastric cancer have been carried out. A decrease in folic acid supplement and subsequent DNA hypomethylation are related to gastrointestinal cancers, and it has been shown that high-dose folic acid may interfere with gastric carcinogenesis in dogs. The objective of this study was to investigate the effects of rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, and folic acid on the chemoprevention of gastric cancer induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Wistar rats, and to evaluate the cell proliferation of gastric mucosa in different experimental groups. METHODS Eighty male Wistar rats were randomly divided into five groups (16 rats in each group). In the control group, the rats were given pure water and basal diet. In the MNNG group, the rats received MNNG in drinking water (100 mg/L) and basal diet. In the MNNG + low-dose rofecoxib group, the rats were given MNNG and rofecoxib 5 mg/kg per day with basal diet. In the MNNG + high-dose rofecoxib group, the rats were given MNNG and rofecoxib 15 mg/kg per day with basal diet. In the MNNG + folic acid group, the rats were given MNNG and folic acid 5 mg/kg per day with basal diet. The experiment was terminated at 50 weeks, and all rats were killed. Blood samples of 3 mL were obtained for measurement of serum folic acid concentrations in the control group, the MNNG group and the MNNG + folic acid group by using chemiluminescent method. The stomach was removed from all rats for histopathological examination and immunohistochemical study. Proliferating cell nuclear antigen (PCNA) expression in gastric epithelial cells was also determined. RESULTS In the MNNG group, five of 11 rats (45.5%) developed gastric cancer, while in all other four groups no gastric cancer was found (P < 0.05). The positivity rate of PCNA expression in the cancerous tissues was significantly higher than that in the non-cancerous tissues (80.0%vs 14.1%, P < 0.05). The positivity rate of PCNA expression in the gastric mucosal cells of the MNNG group was significantly higher than that in the other four groups. The mean serum folic acid concentration of rats was significantly higher in the MNNG + folic acid group (193.70 +/- 60.73 ng/mL) than those in the control group (84.21 +/- 25.26 ng/mL) and the MNNG group (72.27 +/- 16.70 ng/mL, P < 0.05). It was shown that both low- and high-dose rofecoxib as well as folic acid interfered with the development of gastric cancer induced by MNNG in Wistar rats. CONCLUSIONS The results indicate that rofecoxib as well as folic acid interferes with gastric carcinogenesis induced by MNNG in Wistar rats, and the suppression of gastric cell proliferation may play a crucial role in the chemoprevention of gastric cancer by rofecoxib and folic acid. The higher serum folic acid concentration of rats may play an important role in the prevention of gastric cancer.
Collapse
Affiliation(s)
- Su Juan Fei
- Department of Gastroenterology, Affiliated Hospital of Xuzhou Medical College, Jiangsu Province, China.
| | | | | | | | | |
Collapse
|
|
20
|
Thomson A. Chemoprevention of colorectal cancer in ulcerative colitis. Intern Med J 2006; 36:540; author reply 541. [PMID: 16866668 DOI: 10.1111/j.1445-5994.2006.01107.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
|
|
21
|
Picco MF, Krishna M, Cangemi JR, Shelton D. Oral mesalamine and clinical remission are associated with a decrease in the extent of long-standing ulcerative colitis. Inflamm Bowel Dis 2006; 12:537-42. [PMID: 16804389 DOI: 10.1097/01.ibd.0000225345.29603.7d] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
OBJECTIVE To compare colonoscopy alone with surveillance biopsy for the determination of anatomic extent in long-standing ulcerative colitis (UC). To assess the influences of mesalamine use and clinical disease activity on the change of histologic extent with time. MATERIALS AND METHODS Disease extent (proctosigmoiditis, left-sided colitis, or pancolitis) measured by colonoscopy and surveillance biopsy was compared among 212 consecutive patients with long-standing UC. Among the 102 patients who had 2 consecutive colonoscopies with surveillance biopsies, the following influences on change in histologic extent were determined: disease activity, mesalamine use, age at disease onset, folic acid, corticosteroid and azathioprine/6-mercaptopurine use, and time between colonoscopies. RESULTS Agreement between gross and microscopic findings was poor (kappa = 0.39). Colonoscopy underestimated and overestimated extent in 25.9% and 8.5%, respectively. Microscopic distribution between consecutive colonoscopies remained the same in 60.8%. Where distribution changed, an increase was twice as common as a decrease in extent. There was no difference in age at onset, time between colonoscopies, or disease duration among those with an increase, decrease, or no change in extent. Clinical remission and oral mesalamine were independently associated with 10.7 and 5.8 times the odds of a decrease in disease extent, respectively. Folic acid, topical mesalamine, corticosteroids, and immunomodulators did not influence change in extent. CONCLUSIONS UC extent is best determined by surveillance biopsy. Among patients with long-standing UC, histologic extent fluctuates with time. Disease remission and oral mesalamine were independently associated with decreases in disease extent.
Collapse
|
|
22
|
Kohno H, Suzuki R, Curini M, Epifano F, Maltese F, Gonzales SP, Tanaka T. Dietary administration with prenyloxycoumarins, auraptene and collinin, inhibits colitis-related colon carcinogenesis in mice. Int J Cancer 2006; 118:2936-42. [PMID: 16395701 DOI: 10.1002/ijc.21719] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
We previously reported the chemopreventive ability of a prenyloxycoumarin auraptene in chemically induced carcinogenesis in digestive tract, liver and urinary bladder of rodents. The current study was designed to determine whether dietary feeding of auraptene and its related prenyloxycoumarin collinin can inhibit colitis-related mouse colon carcinogenesis. The experimental diets, containing the compounds at 2 dose levels (0.01 and 0.05%), were fed for 17 weeks to male CD-1 (ICR) mice that were initiated with a single intraperitoneal injection of azoxymethane (AOM, 10 mg/kg body weight) and promoted by 1% (w/v) DSS in drinking water for 7 days. Their tumor inhibitory effects were assessed at week 20 by counting the incidence and multiplicity of colonic neoplasms and the immunohistochemical expression of proliferating cell nuclear antigen (PCNA)-labeling index, apoptotic index, cyclooxygenase (COX)-2, inducible nitric oxide (iNOS) and nitrotyrosine in colonic epithelial malignancy. Feeding with auraptene or collinin, at both doses, significantly inhibited the occurrence of colonic adenocarcinoma. In addition, feeding with auraptene or collinin significantly lowered the positive rates of PCNA, COX-2, iNOS and nitrotyrosine in adenocarcinomas, while the treatment increased the apoptotic index in colonic malignancies. Our findings may suggest that certain prenyloxycoumarins, such as auraptene and collinin, could serve as an effective agent against colitis-related colon cancer development in rodents.
Collapse
Affiliation(s)
- Hiroyuki Kohno
- Department of Oncologic Pathology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
| | | | | | | | | | | | | |
Collapse
|
|
23
|
Yeo M, Kim DK, Park HJ, Oh TY, Kim JH, Cho SW, Paik YK, Hahm KB. Loss of transgelin in repeated bouts of ulcerative colitis-induced colon carcinogenesis. Proteomics 2006; 6:1158-65. [PMID: 16402363 DOI: 10.1002/pmic.200500390] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Though ulcerative colitis (UC)-associated colon cancer develops from dysplastic lesions caused by chronic inflammation, the specific mechanistic link between chronic inflammation and carcinogenesis in colon has not been integrated into molecular understanding. We therefore established an experimental animal model for colitic cancer, and used proteomic analysis, based on 2-DE and MALDI-TOF MS, to identify proteins involved in colitic cancer. In our model, 6-week-old C57BL/6J mice were exposed to 15 cycles of dextran sodium sulfate (DSS), with each cycle consisting of 0.7% DSS for 1 week followed by distilled water for 10 days. Colorectal tumors developed in 22 of 24 mice (91.6%), with a tumor multiplicity of 1.727 per tumor-bearing mouse. Comparative 2-DE analysis showed that 38 protein spots were differentially expressed in colon tumors and normal colon. We identified 27 of these proteins, including GRP94, HSC70, enolase, prohibitin, and transgelin. The reduction of transgelin expression in mouse colon tumors was confirmed by Western blotting and immunohistochemistry. We also found that transgelin expression was significantly reduced in human colon tumors compared with adjacent nontumorous tissues. In conclusion, these results suggest that loss of transgelin could be a candidate for biomarker of repeated colitis-associated colon cancer.
Collapse
Affiliation(s)
- Marie Yeo
- Genome Research Center for Gastroenterology, Ajou University School of Medicine, Paldal-gu, Suwon, Korea
| | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Abstract
Patients with inflammatory bowel disease (IBD) are subject to increased risks for the development of colorectal cancer (CRC), risks that are attributed to the duration and anatomic extent of disease in patients with ulcerative colitis and Crohn's disease. Although IBD contributes only 1%-2% to all cases of CRC, the mortality rate in patients with a diagnosis of CRC in the setting of IBD is higher than for those afflicted with sporadic cases of CRC. Given the length of time from IBD onset to the development of CRC, surveillance continues to be widely practiced. Although still under development, novel techniques for the earlier detection of dysplastic lesions have moved to the forefront in an attempt to optimize surveillance strategies and decrease the risk of CRC development.
Collapse
Affiliation(s)
- Parsia A Vagefi
- Department of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA
| | | |
Collapse
|
|
25
|
Abstract
Both genetics and epigenetics regulate gene expression in cancer. Regulation by genetics involves a change in the DNA sequence, whereas epigenetic regulation involves alteration in chromatin structure and methylation of the promoter region. During the initiation, development, and progression of cancer, a number of genes undergo epigenetic changes. Some of these changes can be used as biomarkers for early detection of cancer as well as to follow treatment. A panel of epigenetic biomarkers is preferred to a single biomarker in clinical assays. Changes in gene expression due to epigenetic regulation can be reversed by chemicals, and this approach opens up a novel approach in cancer prevention and treatment.
Collapse
Affiliation(s)
- Mukesh Verma
- Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892-7324, USA.
| | | | | |
Collapse
|
|
26
|
Cheng Y, Desreumaux P. 5-aminosalicylic acid is an attractive candidate agent for chemoprevention of colon cancer in patients with inflammatory bowel disease. World J Gastroenterol 2005; 11:309-14. [PMID: 15637733 PMCID: PMC4205326 DOI: 10.3748/wjg.v11.i3.309] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is classically subdivided into ulcerative colitis (UC) and Crohn’s disease (CD). Patients with IBD have increased risk for colorectal cancer. Because the pathogenesis of colorectal carcinoma has not been entirely defined yet and there is no ideal treatment for colon cancer, cancer prevention has become increasingly important in patients with IBD. The two adopted methods to prevent the development of colon cancer in clinical practice include the prophylactic colectomy and colonoscopic surveillance. But patients and physicians seldom accept colectomy as a routine preventive method and most patients do not undergo appropriate colonoscopic surveillance. Chemoprevention refers to the use of natural or synthetic chemical agents to reverse, suppress, or to delay the process of carcinogenesis. Chemoprevention is a particularly useful method in the management of patients at high risk for the development of specific cancers based on inborn genetic susceptibility, the presence of cancer-associated disease, or other known risk factors. Prevention of colorectal cancer by administration of chemopreventive agents is one of the most promising options for IBD patients who are at increased risks of the disease. The chemopreventive efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against intestinal tumors has been well established. But with reports that NSAIDs aggravated the symptoms of colitis, their sustained use for the purpose of cancer chemoprevention has been relatively contraindicated in IBD patients. Another hopeful candidate chemoprevention drug for IBD patients is 5-aminosalicylic acid (5-ASA), which is well tolerated by most patients and has limited systemic adverse effects, and no gastrointestinal toxicity. 5-ASA lacks the well-known side effects of long-term NSAIDs use. Retrospective correlative studies have suggested that the long-term use of 5-ASA in IBD patients may significantly reduce the risk of development of colorectal cancer. According to the literature, this agent might well satisfy clinical expectations with respect to a safe and effective chemopreventive agent.
Collapse
Affiliation(s)
- Yang Cheng
- Institute of Liver Disease, Shanghai University of Traditional Chinese Medicine, No.1200 Cailun Road, Pudong District, Shanghai 201203, China.
| | | |
Collapse
|
|
27
|
Raedler A, Behrens C, Bias P. Mesalazine (5-aminosalicylic acid) micropellets show similar efficacy and tolerability to mesalazine tablets in patients with ulcerative colitis--results from a randomized-controlled trial. Aliment Pharmacol Ther 2004; 20:1353-63. [PMID: 15606398 DOI: 10.1111/j.1365-2036.2004.02282.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Formulations containing 5-aminosalicylic acid, such as mesalazine, are the gold standard of treatment for mild-to-moderate ulcerative colitis. Current oral regimens require the use of large tablets and frequent dosing to reach the recommended treatment dose. Mesalazine micropellets were designed to allow less frequent dosing in an easier to swallow formulation. AIM To compare the efficacy of mesalazine micropellets with the tablet formulation in patients with mild-to-moderate ulcerative colitis. METHODS This phase 2, double-blind, active-controlled, parallel-group, multiple dose clinical trial randomized 362 patients to either mesalazine micropellets or tablets, at a dosage of 3 g/day. The primary efficacy end-point was the incidence of clinical remission within 8 weeks, defined as the sum of clinical activity index components 1-4 (CAI(C1-4)) < or = 2. RESULTS CAI(C1-4) decreased significantly in both treatment groups within 8 weeks. The micropellet formulation showed confirmatory non-inferiority with statistical significance compared with the tablet formulation, with regard to the incidence of clinical remission (odds ratio in according-to-protocol population 1.008; 95% CI: 0.623-1.632). There was no significant difference in the incidence of adverse events. CONCLUSIONS The mesalazine micropellet formulation is as effective as tablets in patients with mild-to-moderate ulcerative colitis, enabling a larger dose to be taken comfortably and conveniently, thereby potentially improving patient compliance, treatment response and quality of life.
Collapse
Affiliation(s)
- A Raedler
- Department of Internal Medicine II--Gastroenterology, Asklepios Westklinikum Hamburg, Teaching Hospital of the University of Hamburg, Hamburg, Germany
| | | | | |
Collapse
|
|
28
|
Flourié B, Abitbol V, Lavergne-Slove A, Tennenbaum R, Tiret E. Situations particulières au cours du traitement de la rectocolite ulcéro-hémorragique. ACTA ACUST UNITED AC 2004; 28:1031-8. [PMID: 15672573 DOI: 10.1016/s0399-8320(04)95179-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Bernard Flourié
- Service d'hépato-gastroentérologie, CH Lyon SUD, 69495 Pierre Bénite
| | | | | | | | | |
Collapse
|
|
29
|
Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol 2004; 287:G7-17. [PMID: 15194558 DOI: 10.1152/ajpgi.00079.2004] [Citation(s) in RCA: 884] [Impact Index Per Article: 42.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Patients with ulcerative colitis and Crohn's disease are at increased risk for developing colorectal cancer. To date, no known genetic basis has been identified to explain colorectal cancer predisposition in these inflammatory bowel diseases. Instead, it is assumed that chronic inflammation is what causes cancer. This is supported by the fact that colon cancer risk increases with longer duration of colitis, greater anatomic extent of colitis, the concomitant presence of other inflammatory manifestations such as primary sclerosing cholangitis, and the fact that certain drugs used to treat inflammation, such as 5-aminosalicylates and steroids, may prevent the development of colorectal cancer. The major carcinogenic pathways that lead to sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also occur in colitis-associated colorectal cancers. Unlike normal colonic mucosa, however, inflamed colonic mucosa demonstrates abnormalities in these molecular pathways even before any histological evidence of dysplasia or cancer. Whereas the reasons for this are unknown, oxidative stress likely plays a role. Reactive oxygen and nitrogen species produced by inflammatory cells can interact with key genes involved in carcinogenic pathways such as p53, DNA mismatch repair genes, and even DNA base excision-repair genes. Other factors such as NF-kappaB and cyclooxygenases may also contribute. Administering agents that cause colitis in healthy rodents or genetically engineered cancer-prone mice accelerates the development of colorectal cancer. Mice genetically prone to inflammatory bowel disease also develop colorectal cancer especially in the presence of bacterial colonization. These observations offer compelling support for the role of inflammation in colon carcinogenesis.
Collapse
Affiliation(s)
- Steven H Itzkowitz
- Gastrointestinal Division, Box 1069, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA.
| | | |
Collapse
|
|
30
|
Abstract
There continue to be evolutionary changes in the management of ulcerative colitis despite the fact that, aside from a variety of aminosalicylate formulations, no new therapies have been approved over the past few decades. Nevertheless, debates continue regarding the optimization of treatment with aminosalicylates and the short- and long-term benefits of immunomodulation in ulcerative colitis. This article focuses on the most recent clinical studies pertaining to the management of ulcerative colitis and explores both the advances and controversies pertaining to aminosalicylate therapy, corticosteroids, cyclosporine, and the purine antimetabolites. Novel therapeutic approaches--including preliminary experience with biological therapies directed at tumor necrosis factor and other cytokines, adhesion molecules, growth factors, and probiotics--will be reviewed. Recent data regarding potential chemoprevention in long-standing ulcerative colitis and management of postoperative complications and pouchitis will also be discussed.
Collapse
Affiliation(s)
- Stephen B Hanauer
- Department of Medicine and Clinical Pharmacology, Section of Gastroenterology and Nutrition, University of Chicago, Illinois 60637, USA.
| |
Collapse
|
|
31
|
Abstract
During a 13-year period, 213 patients with ulcerative colitis who had no clinical or endoscopic evidence of colonic carcinoma were enrolled in a biopsy surveillance program for dysplasia and carcinoma. The aims of the study were to determine whether such a program could decrease the cancer risk in this group of patients, to determine whether patients with a low risk of carcinoma could be identified, thus enabling them to retain their colon, and to accomplish these goals with a reasonable expenditure of resources. Eighteen patients had dysplasia detected in the initial biopsy specimens; 15 of these patients underwent colectomy, and 7 had unsuspected carcinoma (1 Dukes' stage A, 2 stage B, and 4 stage C). Eleven patients had dysplasia detected during follow-up; 7 of these patients had colectomy, and only 1 patient had carcinoma (Dukes' B). Dysplasia developed in 5 of 20 patients with indefinite changes on initial biopsy samples; 3 of these patients underwent colectomy, and 1 patient had carcinoma (Dukes' B). There was no difference in the prevalence of dysplasia between patients with left-sided disease and patients with extensive disease. With the exception of 2 patients with inadequate surveillance, there has been no clinical evidence of carcinoma in any of the 148 patients whose biopsy results remained negative throughout the study; carcinoma has not developed in any of 175 patients without dysplasia on initial biopsy sample. All 4 patients who died of carcinoma had high-grade dysplasia in their initial colonoscopic biopsy samples. It is concluded that a biopsy surveillance program can be an effective aid in helping control the risk of carcinoma in patients with long-standing ulcerative colitis, that the short-term risk of carcinoma for patients with negative biopsy results is low and colectomy for risk of carcinoma can be deferred in this group, and that patients with extensive and left-sided disease share the same risk of the development of dysplasia.
Collapse
Affiliation(s)
- W M Chambers
- Department of Colorectal Surgery, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
| | | | | | | |
Collapse
|