炎症性肠病的癌变预防及氨基水杨酸类制剂的潜在化学预防作用

虽然炎症性肠病(IBD)最终发展为结直肠癌的概率较低,但IBD相关性结直肠癌一直被认为是最令人担忧的并发症.近年来,该领域进展颇多,如确定了癌变的危险因素,癌症预防相关研究的证据日益增多.目前认为IBD发展为结直肠癌的最大危险因素是疾病持续时间,成功的预防策略应包括对这些远期结局进行早期干预.本文旨在综述该领域的最新进展,包括IBD相关性结直肠癌的流行病学特征、发病机制和化学预防,特别强调5-氨基水杨酸盐(5-ASA)疗法.     

5-氨基水杨酸在炎症性肠病及其相关性结直肠癌中的作用新机制

炎症性肠病（IBD）包括溃疡性结肠炎（UC）和克罗恩病（CD）,5-氨基水杨酸（5-ASA）是IBD治疗中最经典的抗炎剂。IBD患者结直肠癌（CRC）的发病率较正常人群明显增高,长期使用5-ASA可减少IBD患者发生CRC的风险。5-ASA传统的抗炎机制是通过影响抑制前列腺素合成、调节各种细胞因子的产生而发挥抗炎作用的,新近研究发现5-ASA可能通过氧化物酶体增殖物激活受体（PPAR）-γ途径发挥抗炎和抗瘤作用。本文就5-ASA的作用新机制作一简要概述。     

5-氨基水杨酸对炎症性肠病相关性结肠癌和上皮内瘤变化学预防:Meta分析

目的 探讨5-氨基水杨酸(5-ASA)对炎症性肠病(IBD)相关性结肠癌(IBDACa)和上皮内瘤变(IBDADys)发生率的影响,评估5-ASA对IBDACa/Dys的化学预防作用.方法 检索正式发表的关于5-ASA对IBDACa/Dys化学预防的临床研究.外文数据库包括PubMed (Medline)、EMCC、OVID、the Cochrane Library;中文数据库包括万方、维普、CNKI、谷歌学术搜索.将符合要求的文献利用统计软件RevMan统计OR值和95％ CI.对研究设计类型、IBD类型进行亚组分析.结果 共纳入14篇文献,其中10篇为病例对照研究,4篇为队列研究.结果显示:与未使用5-ASA相比,使用5-ASA患者的IBDACa和IBDADys发生率为50％,OR=0.50(95％ CI:0.34 ～0.73),其中病例对照研究Meta分析结果示OR =0.30(95％ CI:0.10 ～0.92),队列研究示OR =0.56(95％ CI:0.37～0.85);使用5-ASA的溃疡性结肠炎(UC)患者发生UCCa/Dys的OR=0.45 (95％ CI:0.27～0.77),使用5-ASA的克罗恩病(CD)患者发生CDCa/Dys的OR =0.39(95％ CI:0.16～0.97).结论 5-ASA对IBDACa/Dys有化学预防作用.     

溃疡性结肠炎癌变和丁酸的预防作用

溃疡性结肠炎(UC)是一种病因不明,主要累及直肠、乙状结肠黏膜甚至全结肠和末端回肠黏膜的慢性非特异性炎症。UC患者发生结直肠癌的风险增加,但其癌变机制尚不清楚。近年来,体外研究和动物实验均证实丁酸对结直肠癌具有化学预防作用。本文就UC的癌变机制、丁酸对结直肠癌的预防作用及其与UC相关结直肠癌的关系作一综述。     

美沙拉嗪对实验性结肠炎大鼠内毒素-Toll样受体4-细胞核因子-кB信号通路的影响

越来越多的细胞核因子-кB(NF-кB)与炎症性肠病(inflammatory bowel disease,IBD)相关性证据表明,调节NF-кB通路可能是IBD治疗的主要靶点[1].而5-氨基水杨酸制剂(5-aminosalicylic acid,5-ASA)如美沙拉嗪是治疗IBD的主要药物,研究表明5-ASA作用机制广泛.如诱导中性粒细胞凋亡等[2].本研究观察美沙拉嗪对结肠炎大鼠内毒素(LPS)-Toll样受体4(TLR4)-NF-кB信号通路的影响,探讨5-ASA治疗IBD其他可能的作用机制.     

5-ASA不同药物制剂在溃疡性结肠炎患者肠黏膜中浓度的对比研究

目的比较5-ASA不同药物制剂治疗溃疡性结肠炎(ulcerative colitis,UC)患者肠黏膜中浓度的差异。方法纳入我院133例UC患者,按治疗分为四组:A组(pH依赖的5-ASA)68例,B组(时间依赖的5-ASA)14例,C组(5-ASA前体)30例,D组(pH依赖的5-ASA,口服联合局部用药)21例,常规行肠镜检查并于乙状结肠区取组织活检,采用高压液相色谱法分析比较肠黏膜中5-ASA药物浓度。结果①A组肠黏膜5-ASA浓度明显高于B组及C组(P0.05);②内镜下缓解期的UC患者肠黏膜5-ASA浓度明显高于活动期患者[(61.02±7.11)ng/mg vs(36.16±6.28)ng/mg,P=0.03],组织学炎症缓解的UC患者肠黏膜5-ASA浓度明显高于炎症活动的患者[(66.68±8.95)ng/mg vs(34.98±5.61)ng/mg,P0.001];③口服联合局部用药(灌肠)的UC患者肠黏膜5-ASA浓度明显高于单独口服用药的患者[(72.55±10.89)ng/mg vs(52.21±6.78)ng/mg,P=0.03]。结论 5-ASA治疗UC患者,pH依赖性的5-ASA易获得较高的药物浓度,且口服联合局部用药效果更佳。     

MicroRNA在溃疡性结肠炎活动度和癌变监测中的应用

炎症性肠病(inflammatory bowel disease,IBD)在我国将成为常见病,溃疡性结肠炎(ulcerative colitis,UC)是其主要类型之一。目前UC病情活动度评估和癌变监测主要依赖内镜检查,尚缺乏较理想的实验室指标。MicroRNA(miRNA)是近年发现的非编码小分子RNA,调控炎症、肿瘤等多种生命活动。在UC患者肠组织和外周血中已发现多种与炎症和癌变相关的miRNA,部分机制得到阐明,提示其作为UC相关生物标记(Biomarker)有很好的应用前景。本文就miRNA和UC研究现状作一概述,为寻找UC活动度评估和癌变监测相关miRNA Biomarker提供依据。     

柳氮磺胺吡啶Sulfasalazine及其新同类药

Sulfasalazine(SAS)用于防治炎症性肠病(IBD)将近40年.一些文献复习表明口服SAS2-4g/d对轻、中型溃疡性结肠炎有效,且能预防复发,对结肠及回肠结肠部的克隆氏病(CD)也有作用,但不能预防复发,对局限于小肠的CD则效果不佳.SAS是磺胺吡啶与5-氨基水杨酸(5-ASA)由偶氮基连接而成,5-ASA是SAS的主要具活性的代谢产物,而磺胺吡啶则与大部分毒性作用有关.口服SAS后约75%到结肠,在该处释出5-ASA与磺胺吡啶.5-     

5-氨基水杨酸在炎症性肠病中的研究进展及化学预防作用

正炎症性肠病(IBD)是病因尚未明确的慢性非特异性肠道炎症性疾病,主要包括溃疡性结肠炎(UC)和克罗恩病(CD)。自从20世纪40年代瑞典Nana Svartz发现柳氮磺嘧啶(SASP)在治疗类风湿性关节炎的同时还可以改善伴发的结肠炎症状,1952年首次报道SASP用于治疗UC,至1977年英国牛津大学Hanauer发现SASP活性成分是5-氨基水杨酸(5-aminosalicylic acid,5-ASA),近年来对5-ASA的认识和研究逐渐增多,综述如下。     

甘草酸二铵对溃疡性结肠炎大鼠的治疗作用

目的:观察甘草酸二铵(DG)对溃疡性结肠炎(UC)大鼠的治疗作用并探讨其可能的作用机制.方法:50只♂清洁级健康Wistar大鼠分为正常对照组,模型对照组,5-氨基水杨酸(5-ASA)组,DG组,5-ASA+DG组,每组10只.用2,4-二硝基氯苯+乙酸联合建模法制备UC大鼠模型.观察疾病活动指数(DAI)、结肠黏膜组织学变化、髓过氧化物酶(MPO)及超氧化物歧化酶(SOD)活性,免疫组织化学法检测核因子-κB(NF-κB)及诱生型一氧化氮合酶(iNOS)表达.结果:与模型对照组相比,DG组和5-ASA组大鼠的DAI(3.30±1.34,3.20±1.14 vs 7.80±1.62,均P<0.01)、组织学损伤评分(1.88±0.34,1.84±0.21 vs 3.09±0.22,均P<0.01)、MPO活性(0.46±0.07,0.47±0.04 vs 0.61±0.04,均P<0.01)和结肠黏膜NF-κB(0.373±0.031,0.368±0.028 vs 0.517±0.028,均P<0.01)、iNOS(0.350±0.015,0.365±0.025 vs0.487±0.021,均P<0.01)表达显著降低,SOD活性(19.83±3.36,20.27±2.44 vs 13.09±3.24,均P<0.01)显著增高;DG联合5-ASA治疗组以上指标改善更明显(均P<0.01),且与正常对照组相比各指标间差异无统计学意义.DG组和5-ASA组相比上述各指标间差异也无统计学意义.结论:DG可有效治疗UC,其作用机制可能与抑制NF-κB活化、清除氧自由基、抗氧化损伤等有关.与5-ASA联用其治疗效果优于两者单独用药.     

5-aminosalicylic acid is an attractive candidate agent for chemoprevention of colon cancer in patients with inflammatory bowel disease

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 longterm 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.     

Will a 5-ASA a day keep the cancer (and dysplasia) away?

Prevention strategies for colorectal cancer in chronic ulcerative colitis (UC) are currently based on the identification of neoplasia by surveillance colonoscopy, but there is a great interest in the possibility of primary chemoprevention. 5-aminosalicylic acid (5-ASA) therapy is an attractive option for chemoprevention in UC due to the fact that it is a derivative of aspirin and has been shown to have a variety of other molecular and genetic targets of cancer prevention, but human studies in UC have been limited by observational design and limited data collection or follow-up. The recently performed metaanalysis of 5-ASA chemoprevention trials shows a favorable role of 5-ASA in the prevention of cancer and dysplasia in patients with UC, and adds to the available evidence favoring its use. This editorial discusses the substantial logistical and ethical challenges in designing a randomized double-blind trial to measure the effect of 5-ASA on cancer risk in UC. The authors conclude that the safety and current maintenance use of 5-ASA warrant its acceptance as a probable chemopreventive agent at this time.     

Colorectal cancer in inflammatory bowel disease: Molecular and clinical considerations

Opinion statement Adenocarcinoma of the colon is an accepted and feared complication of chronic ulcerative colitis (UC) and colonic Crohn’s disease (CD). When cancer is identified, surgery is necessary, and unlike with sporadic colorectal cancer (CRC), in which partial colectomy is effective, proctocolectomy is required. As CRC is a rare complication of these diseases, studies of the pathogenesis are limited primarily to observational studies; thus, the mechanism and molecular events that lead to neoplastic change are not fully understood or well known. Precancerous dysplasia has been associated with concurrent or future CRC in UC and, although less studied, in CD, and is therefore considered a marker of cancer risk in inflammatory bowel disease (IBD). Risk factors for dysplasia and CRC in IBD include longer duration of disease, greater extent of disease, younger age at diagnosis, diagnosis with primary sclerosing cholangitis (PSC), family history of CRC, and possibly backwash ileitis and degree of inflammation of the bowel over time. Prevention of cancer in IBD has been focused on secondary measures of identifying dysplasia in flat mucosa or protruding lesions during surveillance colonoscopy with random biopsies and, when confirmed, performing proctocolectomy. Studies of primary prevention of dysplasia and CRC using chemopreventive agents have suggested a possible benefit with a number of agents. These include ursodeoxycholic acid (in patients with PSC and UC), aminosalicylates, and possibly statins.     

Microproteinuria in patients with inflammatory bowel disease： Is it associated with the disease activity or the treatment with 5-aminosalicylic acid？

AIM: To investigate whether microproteinuria in patients with inflammatory bowel disease (IBD) is associated with the disease activity or the treatment with 5-aminosalicylic acid (5-ASA). METHODS: We prospectively studied microproteinuria in 86 consecutive patients with IBD, 61 with ulcerative colitis (UC) and 25 with Crohn's disease (CD), before as well as 2 and 6 months after their inclusion in the study. Forty-six patients received 5-ASA for a period of 28.8 months (range 1-168 mo). Microalbuminuria (mALB) and urine levels of the renal tubular proteins beta2-microglobulin (beta2mGLB) and beta-N-acetyl-D-glucosamidase (beta-NAG) as well as the creatinine clearance were determined in a 12-h overnight urine collection. Tumor necrosis factor-alpha (TNF-alpha) serum levels were also measured. RESULTS: A total of 277 measurements (194 in UC patients and 83 in CD patients) were performed. The prevalence of abnormal microproteinuria in UC and CD patients was 12.9% and 6.0% for mALB, 22.7% and 27.7% for beta2mGLB, and 11.3% and 8.4% for beta-NAG, respectively. mALB was not associated with IBD activity. Beta2mGLB and beta-NAG urine levels were correlated to UC activity (UCAI: P<0.01; UCEI: P<0.005). mALB in UC patients and beta-NAG urine levels in CD patients were related to TNF-alpha serum levels. An association was noticed between microproteinuria and smoking habit. Treatment with 5-ASA was not correlated to the severity of microproteinuria or to the changes of creatinine clearance. CONCLUSION: Microproteinuria is mainly associated with UC and its activity but not affected by 5-ASA.     

Chemoprevention of colorectal cancer in ulcerative colitis: digging deep in current evidence

Introduction: Patients with ulcerative colitis (UC) have an increased risk of developing colorectal cancer (CRC). Surveillance colonoscopy is currently recommended for patients with long-standing extensive colitis for reducing CRC risk. Chemoprevention is an attractive complementary strategy.

Areas covered: Inflammation is a major determinant of CRC risk and is potentially modifiable. Reducing inflammation is supposed to reduce CRC risk. Several medications have been evaluated in this setting: 5-ASA, thiopurines, anti-TNFα agents and ursodeoxycholic acid (UCDA) in patients with associated primary sclerosing cholangitis (PSC). This review offers a critical evaluation of current evidence of the potential chemopreventive effect of such medications.

Expert commentary: No randomized controlled trials have been performed and the available evidence come from observational studies. Although biological plausibility supports a chemopreventive role of the aforementioned agents, the overall evidence of efficacy is weak because of several methodological limitations of the studies. Indirect epidemiological evidence, biologic plausibility and results of meta-analyses reasonably support a potential chemopreventive effect of 5-ASA. Available evidence does not support a specific chemopreventive effect of purine analogues and anti-TNFα medications, despite their efficacy in the management of inflammatory bowel disease. Data addressing UDCA and folate supplementation are inconclusive. Limited data are available for statins.     

Microproteinuria in patients with inflammatory bowel disease:TS it associated with the disease activity or the treatment with 5-aminosalicylic acid?

AIM: To investigate whether microproteinuria in patients with inflammatory bowel disease (IBD) is associated with the disease activity or the treatment with 5-aminosalicylic acid (5-ASA).METHODS: We prospectively studied microproteinuria in 86 consecutive patients with IBD, 61 with ulcerative colitis (UC) and 25 with Crohn's disease (CD), before as well as 2 and 6 months after their inclusion in the study.Forty-six patients received 5-ASA for a period of 28.8months (range 1-168 mo). Microalbuminuria (mALB) and urine levels of the renal tubular proteins β2-microglobulin (β2mGLB) and β-N-acetyl-D-glucosamidase (β-NAG) as well as the creatinine clearance were determined in a 12-h overnight urine collection. Tumor necrosis factor-α(TNF-α) serum levels were also measured.RESULTS: A totalof 277 measurements (194 in UC patients and 83 in CD patients) were performed. The prevalence of abnormal microproteinuria in UC and CD patients was 12.9% and 6.0% for mALB, 22.7% and 27.7% for β2mGLB, and 11.3% and 8.4% for β-NAG,respectively. mALB was not associated with IBD activity.β2mGLB and β-NAG urine levels were correlated to UC activity (UCAI:P＜0.01; UCEI: P＜0.005). mALB in UC patients and β-NAG urine levels in CD patients were related to TNF-a serum levels. An association was noticed between microproteinuria and smoking habit.Treatment with 5-ASA was not correlated to the severity of microproteinuria or to the changes of creatinine clearance.CONCLUSION: Microproteinuria is mainly associated with UC and its activity but not affected by 5-ASA.     

Chemoprevention: risk reduction with medical therapy of inflammatory bowel disease

The ideal chemopreventative agent, in addition to being efficacious in the prevention of cancer, must be easily administered, affordable, safe, and well tolerated, with minimal side effects. In the past decade, a growing body of literature has emerged on the prevention of CRC in patients with long-standing CD and UC. The data are not definitive and consist almost exclusively of retrospective case-control and cohort studies rather than the more rigorous prospective RCTs. 5-ASA compounds have been most thoroughly studied, and most of the existing data support the use of 5-ASA in the prevention of CRC. Although the precise dose and duration are unclear, studies suggest that chronic systemic administration of 5-ASA at a dose of at least 1.2 g/d is most likely to be effective. A beneficial effect of folate, albeit not statistically significant, has been consistently shown in every study performed for this purpose. Folate supplementation, which is safe and affordable, should also be recommended for all patients with IBD, especially those taking sulfasalazine. UDCA has been shown to exert a protective effect in most studies on patients with UC and concomitant PSC. Because this patient population is at particularly high risk for CRC, it is advisable to consider UDCA in all patients with colitis complicated by PSC. For patients without PSC, sufficient data do not exist to recommend it for the purpose of cancer prevention.Five of the six corticosteroid studies have found a beneficial effect of systemic steroids, although most did not reach statistical significance. Regardless, given the frequent and serious adverse effects associated with chronic steroid use, systemic corticosteroids should not be prescribed for this indication. Budesonide, an oral corticosteroid with minimal systemic absorption, is a potential alternative, although it has not yet been studied as a chemopreventative agent. Similarly, until the long-term safety of chronic NSAID use can be demonstrated in patients with IBD, the role of NSAIDs in chemoprevention remains undefined. Although the data are conflicting, immune-modulating medications, such as AZA, do not seem to confer any reduction in the risk of dysplasia or CRC. The data on calcium supplementation and statin use are still too limited to endorse their use for the prevention of colitis-related CRC.Chemoprevention is an area that holds great promise in the reduction of morbidity and mortality associated with IBD. Further studies, including prospective trials when possible and cost-effectiveness analyses, need to be performed to develop an optimal strategy for the reduction of cancer risk in patients with IBD.