Polyphenon E for the Chemoprevention of Colorectal Cancer

描述（由申请人提供）：在动物模型系统中，包括多酚在内的绿茶成分已被令人信服地证明具有癌症预防特性。此外，流行病学研究表明，饮用绿茶与降低结直肠癌风险有关。主要和最活跃的绿茶多酚是(-)-表没食子儿茶素-3-没食子酸酯（EGCG）。多酚E （PPE）是一种确定的绿茶多酚制剂，含有约65%的EGCG和不到0.1%的咖啡因，目前正在人类癌症的化学预防研究中进行评估。如初步结果所述，在偶氮甲烷（AOM）结肠癌模型中，膳食PPE减少了结肠异常隐窝灶（ACF）的总数，并降低了高度发育不良的ACF的百分比。这些和其他令人信服的临床前数据支持PPE用于结肠癌预防的评估。我们建议进行一项随机II期化学预防试验，在复发性结直肠肿瘤高风险受试者中使用PPE和安慰剂来逆转直肠ACF。主要研究终点将是在连续PPE治疗6个月后，与使用放大色内窥镜检查的基线相比，直肠ACF数量的百分比变化。ACF的特征（大小、形态、组织病理学）也将被研究。根据啮齿动物癌变模型的机制见解选择的药物水平和组织生物标志物将在ACF和正常粘膜中进行评估。临床前和人体研究支持ACF作为人类腺瘤性息肉的假定前体作为化学预防试验的替代终点生物标志物（SEB）的效用。在啮齿动物致癌物诱导的结肠癌中，ACF作为腺瘤和癌的SEB。在观察性研究中，发现ACF的数量、发育不良灶的存在和大小与腺瘤或既往结直肠癌的数量之间存在显著相关性。重要的是，在日本的一项小型开放标签试验中，短期给予非选择性COX抑制剂舒林达克可使高危患者直肠ACF消退。ACF由增大和增厚的隐窝组成，可在人结肠粘膜中通过放大色内镜检测到。在本研究中，我们检验了PPE的化学预防效果，并专门检验了PPE可以预防/逆转CRC风险增加受试者直肠ACF的假设。公共卫生相关性：绿茶多酚在结肠癌动物模型中是有效的化学预防剂。我们将确定多酚E对结直肠癌高危患者结直肠腺瘤前体病变的影响。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.