Chemoprevention of Green Tea Polyphenol on Liver Cancer

描述（由申请人提供）：本修订申请的长期目标是设计有效的预防策略，以降低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。这种恶性肿瘤的不良预后导致其成为世界上第三大癌症死亡原因。B型肝炎病毒（HBV）慢性感染和黄曲霉毒素暴露是肝癌高发区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。化学预防已被提出作为针对这些高危人群的良好工具。在各种已鉴定的化学预防剂中，绿色茶多酚（GTP）在生物测定和动物模型中已被证明对不同靶器官部位的致癌物诱导的诱变和肿瘤发生具有安全和高效的抑制作用，包括黄曲霉毒素诱导的肝肿瘤。本研究的具体目的是（1）将黄曲霉毒素暴露、HBV感染和氧化性DNA损伤的分子生物标志物分析纳入正在进行的GTP随机、双盲和安慰剂对照干预试验中，该试验在中华人民共和国广西壮族自治区扶绥县的1，800名HBsAg和黄曲霉毒素-白蛋白加合物双重血清阳性的居民中进行;通过监测研究人群中危险因素特异性分子生物标志物水平的变化和HCC的实际发病率来确定化学预防试验的疗效。(2)通过测量在研究的不同时间从300名参与者收集的血清中的黄曲霉毒素-白蛋白加合物和尿液中的各种黄曲霉毒素生物标志物来检查和评估GTP在降低黄曲霉毒素生物标志物方面的功效。将确定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。(3)探讨GTP对HBV相关标志物HBV-DNA复制和HBV诱导的免疫学改变的抑制作用。(4)确定GTP在抑制从研究参与者收集的尿样中的8-羟基-2 '-脱氧鸟苷水平中的抗氧化作用，和（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作用。本研究结果将有助于评估GTP对人肝癌的化学保护作用，并了解GTP在由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.