Polyphenon E for the Chemoprevention of Colorectal Cancer

描述（由申请人提供）：在动物模型系统中，已经令人信服地显示包括多酚的绿色茶成分赋予癌症预防特性。此外，流行病学研究表明，饮用绿色茶与降低结直肠癌风险有关。主要且最具活性的绿色茶多酚是（-）-表没食子儿茶素-3-没食子酸酯（EGCG）。Polyphenon E（PPE）是一种含有约65%表没食子儿茶素没食子酸酯（EGCG）和低于0.1%咖啡因的确定的绿色茶多酚制剂，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，在氧化偶氮甲烷（AOM）啮齿动物结肠癌发生模型中，饮食PPE减少了结直肠异常隐窝病灶（ACF）的总数，并降低了具有高度异型增生的ACF百分比。这些和其他令人信服的临床前数据支持PPE预防结肠癌的评价。我们建议进行一项随机的II期化学预防试验，比较PPE与安慰剂对复发性结直肠肿瘤高风险受试者的直肠ACF的消退。主要研究终点将是使用放大色素内镜检查，连续PPE治疗6个月时直肠中ACF数量与基线相比的百分比变化。还将研究ACF特性（大小、形态、组织病理学）。将在ACF和正常粘膜中评价基于来自啮齿动物致癌模型的机理见解选择的药物水平和组织生物标志物。临床前和人体研究支持ACF（人类腺瘤性息肉的推定前体）作为化学预防试验的替代终点生物标志物（SEB）的效用。在致癌物诱发的啮齿类动物结肠癌中，ACF充当腺瘤和癌的SEB。在观察性研究中，发现ACF数量、异型增生病灶的存在和大小与腺瘤数量或既往结直肠癌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，短期给予非选择性考克斯抑制剂舒林酸可使高危患者的直肠ACF消退。ACF由增大和增厚的隐窝组成，可以使用放大色素内镜在人结直肠粘膜中检测到。在拟议的研究中，我们检查了PPE的化学预防功效，并特别检验了PPE可以预防/消退CRC风险增加的受试者的直肠ACF的假设。公共卫生相关性：绿色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.