Polyphenon E for the Chemoprevention of Colorectal Cancer

摘要 绿色茶成分，包括多酚已令人信服地显示，赋予癌症预防 动物模型系统中的特性。此外，流行病学研究表明，绿色 喝茶可以降低患结直肠癌的风险。主要的和最活跃的绿色茶多酚是 （-）-表没食子儿茶素-3-没食子酸酯（EGCG）。Polyphenon E（PPE），一种确定的绿色茶多酚制剂 含有约65%的表没食子儿茶素没食子酸酯和少于0.1%的咖啡因，目前正在评估的化学预防 人类癌症的研究。如初步结果所述，膳食PPE减少了 结肠直肠异常隐窝病灶（ACF），并降低ACF的百分比与高度异型增生， 氧化偶氮甲烷（AOM）啮齿动物模型的结肠癌发生。这些和其他引人注目的临床前数据 支持PPE对结肠癌预防的评估。我们建议进行一项随机的II期 PPE与安慰剂在复发性前列腺增生高危受试者中消退直肠ACF的化学预防试验 结直肠肿瘤主要研究终点将是在6时直肠中ACF数量的百分比变化。 与基线相比，使用放大色素内镜连续PPE治疗10个月。ACF 还将研究特征（大小、形态、组织病理学）。药物水平和组织生物标志物 根据啮齿动物致癌模型的机理见解选择，将在ACF中进行评价， 正常粘膜。临床前和人体研究支持ACF的效用，推定的人类前体， 腺瘤性息肉，作为化学预防试验的替代终点生物标志物（SEB）。在致癌物质中- 在啮齿类动物中，ACF作为腺瘤和癌的SEB。观察性 研究发现，ACF的数量、异型增生的存在和大小之间存在显著相关性。 病灶和腺瘤或先前结肠直肠癌的数量。重要的是， 非选择性考克斯抑制剂舒林酸在一个小的，开放的， 日本的标签试验。ACF由增大和增厚的隐窝组成，可以在人类结直肠中检测到 使用放大色素内镜检查粘膜。在拟议的研究中，我们检查了化学预防 PPE的有效性，并特别测试PPE可以预防/消退受试者的直肠ACF的假设， 增加CRC风险。叙事 绿色茶多酚是结肠癌动物模型中有效的化学预防剂 癌我们将确定多酚E对结直肠癌前病变的影响， 结直肠癌高风险患者的腺瘤。

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.