Chemoprevention of Green Tea Polyphenol on Liver Cancer

描述(申请人提供)：这项修订申请的长期目标是设计有效的预防策略，以减少高危人群中肝癌的发病率。原发性肝癌，主要是肝细胞癌，是亚洲和非洲最常见的癌症之一。这种恶性肿瘤预后不佳，是世界上导致癌症死亡的第三大常见原因。慢性乙肝病毒感染和饮食中黄曲霉毒素暴露是高危地区肝细胞癌的两个主要病因危险因素。预防和控制癌症的巨大挑战是如何管理那些已经接触致癌物的人，例如乙肝表面抗原携带者和长期接触黄曲霉毒素的人。化学预防已被认为是针对这些高危人群的良好工具。在各种已鉴定的化学预防药物中，绿茶多酚(GTP)在不同靶器官部位(包括黄曲霉毒素诱导的肝肿瘤)的生物测试和动物模型中被证明是安全和高效的抑制致癌物诱导的突变和肿瘤发生。本研究的具体目的是(1)将黄曲霉毒素暴露、乙肝病毒感染和DNA氧化损伤的分子生物标记物分析纳入正在进行的随机、双盲、安慰剂对照的GTP干预试验，该试验在中国共和国广西壮族自治区扶绥县1,800名乙肝表面抗原和黄曲霉毒素-白蛋白加合物双阳性居民中进行；通过监测研究人群中危险因素特异性分子标志物水平的变化和肝癌的实际发病率来确定化学预防试验的有效性。(2)通过检测300名受试者不同时间的血清黄曲霉毒素-白蛋白加合物和尿液黄曲霉毒素生物标志物，观察和评价GTP降低黄曲霉毒素生物标志物的效果。将确定代谢表型/基因类型的差异，因为它们与黄曲霉毒素生物标志物水平有关。(3)观察GTP对血清中HBVDNA复制及免疫功能变化的抑制作用。(4)确定GTP在抑制研究参与者尿样中8-羟基-2‘-脱氧鸟苷水平方面的抗氧化作用；(5)确定和评估GTP的长期生物利用度和生物转化以及GTP对研究参与者的长期毒理学影响。本研究的结果将有助于评价GTP对人肝癌的化学保护作用，并有助于了解GTP在明确主要危险因素引起的人肝癌化学预防中的分子机制。

DESCRIPTION (provided by applicant): The long-term goal of this revised application is to design effective prevention strategies for reducing the incidence of liver cancer in high-risk populations. Primary liver cancer, mainly hepatocellular carcinoma (HCC), is one of the most common cancers in Asia and Africa. The poor prognosis of this malignancy results in it being the third most common cause of cancer deaths in the world. Chronic infection with hepatitis B viruses (HBV) and dietary aflatoxin exposure are two major etiologic risk factors for HCC in high-risk areas. The great challenge in cancer prevention and control is how to manage those who have already been exposed to carcinogens, such as individuals who are HBsAg carriers and have long-term aflatoxin exposure. Chemoprevention has been proposed as the good tool to target these high-risk populations. Among various identified chemopreventive agents, green tea polyphenols (GTP) have been shown to be safe and high effective in inhibition of carcinogen-induced mutagenesis and tumorigenesis in bioassays and animal models for different target organ sites, including aflatoxin-induced liver tumors. The specific aims for this study are (1) to incorporate molecular biomarkers analysis for aflatoxin exposure, HBV infection, and oxidative DNA damage into an on-going randomized, double blinded, and placebo-controlled intervention trial of GTP in 1,800 residents who are double seropositive of HBsAg and aflatoxin-albumin adduct in Fusui County, Guangxi Zhuang Autonomous Region, People's Republic of China; efficacy of the chemopreventive trial will be determined by monitoring changes of levels of risk-factor specific molecular biomarkers and the actual incidence of HCC in the studied population. (2) to examine and assess the efficacy of GTP in reducing aflatoxin biomarkers by measuring aflatoxin-albumin adducts in serum and various aflatoxin biomarkers in urine collected from 300 participants in different time of the study. Difference in metabolic phenotypes/genotypes as they related to aflatoxin biomarker levels will be determined. (3) to evaluate the inhibitory effect of GTP on HBV-associated markers including HBV-DNA replication and HBV-induced immunologic changes in serum samples. (4) to determine antioxidative role of GTP in inhibition of the level of 8-hydroxy-2'-deoxyguanosine in urine samples collected from the study participants and (5) to determine and assess long-term bioavailability and biotransformation of GTP and the long-term toxicological effect of GTP on study participants. The results of this study would help to evaluate the chemoprotective effect of GTP against human HCC and to understand the molecular mechanisms of GTP in chemoprevention of human HCC caused by well-defined major risk factors.