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.
|Huang, Shengbing; Okamoto, Koichi; Yu, Chunrong et al. (2013) p62/sequestosome-1 up-regulation promotes ABT-263-induced caspase-8 aggregation/activation on the autophagosome. J Biol Chem 288:33654-66|