BIOMARKERS TO MOLECULAR INTERVENTIONS IN AFLATOXIN EXPOSED INDIVIDUALS

项目II.分子生物标志物的开发和应用 对黄曲霉毒素接触者的干预。公众的一个主要目标 健康实践就是预防疾病。我们的最新进展 对致癌的基本机制的理解有 提供了通过以下方式降低人类癌症发病率的机会 分子、化学预防干预。然而，癌症的使用 评估新干预策略的终点确保速度缓慢 以及代价高昂的进步。中间生物标志物的发展是 对及时发展和成熟这一领域至关重要 化学预防。这些研究的持续目标是确定 黄曲霉毒素中毒的生物标志物是否因摄入 被黄曲霉毒素污染的食物可通过摄取奥替拉来调节 或者是叶绿素。奥替拉兹和叶绿素都是有效的抑制剂。 黄曲霉毒素在动物模型中诱发肝癌的研究 他们的行动机制似乎截然不同。这是我们的假设 黄曲霉毒素生物有效剂量的生物标志物水平 将对评估化学预防的有效性具有预测性 对黄曲霉毒素接触者的干预。在大鼠身上的结果 最初的赠款期限表明，对以下水平的衡量 尿中黄曲霉毒素-N7-鸟氨酸和血清中黄曲霉毒素-白蛋白加合物 反映黄曲霉毒素对靶器官的遗传毒性。此外， 喂食奥替普拉兹的动物表现出这些水平的显著降低。 与肝脏黄曲霉毒素水平下降同步的生物标志物- DNA加合物与肝癌发病率。分子流行病学 研究也坚定地确立了这些生物标志物作为 人类接触黄曲霉毒素及其随后发生的风险 肝细胞癌。建议的研究旨在继续 生物标志物的开发和在化学预防中的应用 黄曲霉毒素暴露和肝癌的高危人群。一个 另外一个很有希望的生物标志物是8-羟基-2-基团- 脱氧鸟苷(8-OHdG)。几个实验室最近显示 用黄曲霉毒素B1治疗动物可提高8-OHdG水平 在肝脏DNA中。拟议的研究将评估 尿中8-OHdG排泄量的测定是一种有用的、可调节的 评估化学预防效果的终点。这些研究将 利用最近从老鼠和人类身上收集的尿样 使用奥替拉兹进行化学预防干预。这些研究 也将通过进行临床干预来延长 启东地区人群中抗癌物质叶绿素的研究~S 中国的代表，他们饮食中接触黄曲霉毒素， 随之而来的是患肝癌的高风险。

Project II. Development and application of biomarkers to molecular interventions in aflatoxin-exposed individuals. A major goal of public health practice is disease prevention. Recent advances in our understanding of the fundamental mechanisms of carcinogenesis have provided opportunities to reduce human cancer incidence through molecular, chemopreventive interventions. However, use of cancer endpoints in the evaluation of new intervention strategies ensures slow and costly progress. The development of intermediate biomarkers is essential to the timely development and maturation of the field of chemoprevention. The continuing goal of these studies is to determine whether biomarkers of aflatoxicosis caused by consumption of aflatoxin-contaminated foods can be modulated by ingestion of oltipraz or chlorophyllin. Both oltipraz and chorophyllin are effective inhibitors of aflatoxin-induced hepatocarcinogenesis in animal models, although their mechanisms of action appear to be distinct. It is our hypothesis that levels of biomarkers for the biologically effective dose of aflatoxin will be predictive for assessing the efficacy of chemopreventive interventions in aflatoxin-exposed individuals. Results in rats during the initial grant period suggest that measurements of the levels of aflatoxin-N7-guanine in urine and aflatoxin-albumin adducts in serum reflect aflatoxin-induced genotoxicity in target organs. Moreover, animals fed oltipraz exhibited marked reductions in the levels of these biomarkers in parallel with reductions in the levels of hepatic aflatoxin- DNA adducts and liver cancer incidence. Molecular epidemiology studies have also firmly established these biomarkers as indices of aflatoxin exposure in humans and for subsequent risk of developing hepatocellular carcinoma. The proposed studies seek to continue the development and application of biomarkers to chemoprevention in populations at high risk for aflatoxin exposure and liver cancer. An additional biomarker of considerable promise is 8-hydroxy-2 prime- deoxyguanosine (8-OHdG). Several laboratories have shown recently that treatment of animals with aflatoxin B1 elevates levels of 8-OhdG in hepatic DNA. The proposed studies will evaluate whether measurement of 8-OHdG excretion in urine is a useful, modulatable endpoint for assessing chemopreventive efficacy. These studies will utilize urine samples collected from rats and humans that have recently undergone chemopreventive interventions with oltipraz. These studies will also be extended by conducting a clinical intervention with the anticarcinogen chlorophyllin in individuals from Qidong, Peopl~s Repubic of China, who are exposed to aflatoxins in their diets and are subsequently at high risk for development of liver cancer.