Chemoprevention of Green Tea Polyphenol on Liver Cancer

描述（由申请人提供）：本次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（HCC），是亚洲和非洲最常见的癌症之一。这种恶性肿瘤的预后不良导致它成为世界上第三大癌症死亡原因。慢性乙型肝炎病毒（HBV）感染和饮食黄曲霉毒素暴露是高危地区HCC的两个主要病因危险因素。癌症预防和控制的巨大挑战是如何管理那些已经暴露于致癌物质的人，例如HBsAg携带者和长期暴露于黄曲霉毒素的人。化学预防被认为是针对这些高危人群的好工具。在众多已确定的化学预防剂中，绿茶多酚（GTP）在生物测定和动物模型中对不同靶器官部位（包括黄曲霉毒素诱导的肝脏肿瘤）的致癌诱变和肿瘤发生具有安全、高效的抑制作用。本研究的具体目的是：(1)将黄曲霉毒素暴露、HBV感染和氧化DNA损伤的分子生物标志物分析纳入正在进行的一项随机、双盲、安慰剂对照的GTP干预试验中，该试验对中华人民共和国广西壮族自治区阜阜县1800名HBsAg和黄曲霉毒素-白蛋白加合物双血清阳性的居民进行研究；化学预防试验的有效性将通过监测危险因素特异性分子生物标志物水平的变化和研究人群中HCC的实际发病率来确定。(2)通过测定300名受试者在不同时间采集的血清中黄曲霉毒素-白蛋白加合物和尿液中各种黄曲霉毒素生物标志物，来检验和评估GTP降低黄曲霉毒素生物标志物的效果。与黄曲霉毒素生物标志物水平相关的代谢表型/基因型差异将被确定。(3)评价GTP对血清样本中HBV-DNA复制和hbv诱导的免疫变化等hbv相关标志物的抑制作用。(4)确定GTP在抑制研究参与者尿液样本中8-羟基-2'-脱氧鸟苷水平中的抗氧化作用；(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效应。本研究结果将有助于评价GTP对人肝癌的化学保护作用，了解GTP在明确的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.