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II。生物标志物在分子上的开发和应用对黄曲霉毒素暴露的个体进行干预措施。公众的主要目标健康实践是预防疾病。我们最近的进步了解癌变的基本机制提供了减少人类癌症发病率的机会分子，化学预防干预措施。但是，使用癌症评估新干预策略的终点可确保缓慢和昂贵的进步。中间生物标志物的发展是对于及时发展和成熟的领域至关重要化学预防。这些研究的持续目标是确定是否由消费引起的黄曲霉病的生物标志物黄曲霉毒素污染的食物可以通过摄入Oltipraz来调节或叶绿素。 oltipraz和脉络膜蛋白都是有效的抑制剂黄曲霉毒素诱导的动物模型中肝癌发生他们的作用机制似乎是不同的。这是我们的假设生物学有效剂量黄曲霉毒素的生物标志物水平将预测评估化学预防的功效对黄曲霉毒素暴露的个体进行干预措施。导致大鼠在最初的赠款期表明测量尿液中的黄曲霉毒素-N7-瓜氨酸和血清中的黄曲霉毒素加合物反映靶器官中黄曲霉毒素诱导的遗传毒性。而且，饲喂oltipraz的动物在这些水平上显示出明显的降低生物标志物与肝黄曲霉毒素水平的降低并联 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指标人类黄曲霉毒素的暴露以及随后发生的风险肝细胞癌。拟议的研究试图继续生物标志物在化学预防中的开发和应用黄曲霉毒素暴露和肝癌的高风险人群。一个众多承诺的其他生物标志物是8-羟基-2 Prime- 脱氧鸟苷（8-OHDG）。最近显示了几个实验室用黄曲霉毒素B1的动物治疗可提高8-OHDG的水平在肝DNA中。拟议的研究将评估是否尿液中8-OHDG排泄的测量是有用的，可调节的评估化学预防功效的终点。这些研究会利用最近有大鼠和人类收集的尿液样本接受了oltipraz的化学预防干预措施。这些研究还将通过进行临床干预来扩展来自Qidong的个体中的抗癌叶绿素，peopl〜s 中国的偏僻，在饮食中暴露于黄曲霉毒素的中国随后，肝癌发展的风险很高。