Polyphenon E for the Chemoprevention of Colorectal Cancer

摘要 包括多酚在内的绿茶成分已被令人信服地证明具有预防癌症的作用 动物模型系统中的属性。此外，流行病学研究表明，绿色食品与 饮茶和降低患结直肠癌的风险。最主要和最活跃的绿茶多酚是 表没食子儿茶素没食子酸酯(EGCG)。多酚E(PPE)，一种明确的绿茶多酚制剂 含有大约65%的EGCG和不到0.1%的咖啡因，目前正在进行化学预防的评估 针对人类癌症的研究。正如初步结果所概述的那样，饮食中的个人防护用品减少了 结直肠异位隐窝病灶(ACF)和ACF伴高度异型增生的百分比降低 偶氮甲烷(AOM)致结肠癌啮齿动物模型。这些和其他令人信服的临床前数据 支持PPE对结肠癌预防的评估。我们建议进行随机第二阶段 PPE与安慰剂对复发高危人群直肠ACF的化学预防试验 大肠肿瘤。主要研究终点将是直肠ACF数量在6时的百分比变化 使用放大色素内窥镜进行持续PPE治疗的月与基线的比较。ACF 特征(大小、形态、组织病理学)也将被研究。药物水平和组织生物标志物 根据啮齿动物致癌模型的机制见解选择的将在ACF和ACF中进行评估 正常的粘膜。临床前和人体研究支持ACF的用途，ACF是人类 腺瘤性息肉作为化学预防试验的替代终点生物标记物(SEB)。在致癌物质中- 在啮齿动物诱导的结肠癌中，ACF可作为腺瘤和癌的SEB。在观察性研究中 研究发现，ACF的数量、发育不良的存在和大小之间存在显著的相关性 病灶，以及腺瘤或结直肠癌病史。重要的是，短期内对 非选择性COX抑制剂舒林酸在一项小型、开放的临床试验中显示，在高危患者中，舒林酸可使直肠ACF消退。 来自日本的标签试验。ACF由可在人类结直肠中检测到的增大和增厚的隐窝组成 粘膜采用放大染色内窥镜检查。在拟议的研究中，我们检查了化学预防 PPE的有效性和特异性检验PPE可以预防/消退直肠ACF的假设 增加了CRC风险。叙事 绿茶多酚是结肠癌动物模型的有效化学预防药物 癌症。我们将确定多酚E对大肠前驱病变的影响 结直肠癌高危患者中的腺瘤。

ABSTRACT Green tea constituents including polyphenols have been convincingly shown to confer cancer preventive properties in animal model systems. Furthermore, epidemiologic studies have shown an association of green tea consumption and reduced risk of colorectal cancer. The major and most active green tea polyphenol is (-)-epigallocatechin-3-gallate (EGCG). Polyphenon E (PPE), a defined green tea polyphenol preparation containing about 65% EGCG and less than 0.1% caffeine, is currently being evaluated in the chemoprevention studies for human cancers. As outlined in Preliminary Results, dietary PPE reduced the total number of colorectal aberrant crypt foci (ACF) and decreased the percentage of ACF with high grade dysplasia in the azoxymethane (AOM) rodent model of colon carcinogenesis. These and other compelling preclinical data support the evaluation of PPE for colon cancer prevention. We propose to conduct a randomized phase II chemoprevention trial of PPE versus placebo to regress rectal ACF among subjects at high risk for recurrent colorectal neoplasia. The primary study endpoint will be the percent change in ACF number in the rectum at 6 months of continuous PPE treatment compared to baseline using magnifying chromoendoscopy. ACF characteristics (size, morphology, histopathology) will also be studied. Drug levels and tissue biomarkers selected based upon mechanistic insights from a rodent carcinogenesis model will be evaluated in ACF and normal mucosa. Preclinical and human studies support the utility of ACF, putative precursors of human adenomatous polyps, as a surrogate endpoint biomarker (SEB) for chemoprevention trials. In carcinogen- induced colon cancer in rodents, ACF serve as an SEB for adenomas and carcinomas. In observational studies, significant correlations were found between the number of ACF, the presence and size of dysplastic foci, and the number of adenomas or prior colorectal cancer. Importantly, short-term administration of the nonselective COX inhibitor sulindac was shown to regress rectal ACF in high risk patients in a small, open- label trial from Japan. ACF consist of enlarged and thickened crypts that can be detected in human colorectal mucosa using magnifying chromoendoscopy. In the proposed study, we examine the chemopreventive efficacy of PPE and specifically test the hypothesis that PPE can prevent/regress rectal ACF in subjects at increased CRC risk. NARRATIVE Green tea polyphenols are effective chemopreventive agents in animal models of colon cancer. We will determine the effect of polyphenon E on precursor lesions of colorectal adenomas in patients at high risk of colorectal cancer.