BIOMARKERS TO MOLECULAR INTERVENTIONS IN AFLATOXIN EXPOSED INDIVIDUALS

对黄曲霉毒素暴露个体进行分子干预的生物标志物

基本信息

批准号：
6467577
负责人：
THOMAS W KENSLER
金额：
$ 19.33万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-06-01 至 2002-05-31
项目状态：
已结题

项目摘要

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.

项目二。分子生物学标志物的开发及应用对黄曲霉毒素暴露个体的干预措施。公众的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了解提供了通过以下方式降低人类癌症发病率的机会分子、化学预防干预措施。然而，利用癌症评估新干预策略的终点确保缓慢以及代价高昂的进展。中间生物标志物的开发对于该领域的及时发展和成熟至关重要化学预防。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由食用引起可以通过摄入吡噻硫酮来调节受黄曲霉毒素污染的食物或叶绿素。吡噻硫酮和叶绿素都是有效的抑制剂动物模型中黄曲霉毒素诱导的肝癌发生的研究它们的作用机制似乎不同。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可预测评估化学预防的功效对黄曲霉毒素暴露个体的干预措施。结果在大鼠中最初的赠款期表明，对资金水平的衡量尿液中的黄曲霉毒素-N7-鸟嘌呤和血清中的黄曲霉毒素-白蛋白加合物反映黄曲霉毒素引起的靶器官遗传毒性。而且，喂食奥替普拉的动物这些物质的水平显着降低生物标志物与肝脏黄曲霉毒素水平的降低同时发生 DNA 加合物和肝癌发病率。分子流行病学研究还牢固地确立了这些生物标志物作为人类接触黄曲霉毒素以及随后发生黄曲霉毒素的风险肝细胞癌。拟议的研究旨在继续生物标志物的开发及其在化学预防中的应用黄曲霉毒素暴露和肝癌高危人群。一个另一种颇具前景的生物标志物是 8-羟基-2 prime- 脱氧鸟苷 (8-OHdG)。最近多个实验室表明用黄曲霉毒素 B1 治疗动物可提高 8-OhdG 水平存在于肝脏 DNA 中。拟议的研究将评估是否尿液中 8-OHdG 排泄的测量是一种有用的、可调节的评估化学预防功效的终点。这些研究将利用最近从大鼠和人类身上收集的尿液样本接受奥替普拉化学预防干预。这些研究还将通过与以下机构进行临床干预来延长启东人体内的抗癌物质叶绿素中华人民共和国，他们的饮食中含有黄曲霉毒素，并且随后患肝癌的风险很高。