Molecular Mechanisms of Chemoprevention: Dithiolethiones

化学预防的分子机制：二硫代硫酮

基本信息

批准号：
7338689
负责人：
THOMAS W KENSLER
金额：
$ 50.21万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-09-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7338689
关键词：
4 hydroxynonenal Abbreviations Accounting Affect Aflatoxins Alanine Transaminase Aldehyde Reductase Alkaline Phosphatase Animal Model Anticarcinogenic Agents Antioxidants Aspartate Transaminase Benzo(a)pyrene Biochemical Biological Biological Assay Biological Markers Biological Models CCAAT-Enhancer-Binding Proteins Cancer Burden Carcinogen Metabolism Carcinogens Chemoprevention Chemopreventive Agent Cirrhosis Class Clinical Trials Cytoprotection DNA Adducts DNA Damage Development Dimethylnitrosamine Drug Kinetics End Point Environmental Carcinogens Enzymes Experimental Models Exposure to Fibrosis Gamma-glutamyl transferase Genes Glutathione Glutathione S-Transferase Goals Hepatic Hepatitis B Virus Human Immunohistochemistry Interferons Intervention Investigation LTB gene Lesion Leukotriene B4 Libraries Lipopolysaccharides Liver Liver Cirrhosis Malignant Neoplasms Malignant neoplasm of liver Manganese Superoxide Dismutase Modeling Molecular Mus Mutagenesis NF-E2-related factor 2 Nature Nitric Oxide Oxidoreductase Pathway interactions Pharmacodynamics Population Primary carcinoma of the liver cells Protective Agents Protein Overexpression Quinones Reporter Response Elements Reverse Transcriptase Polymerase Chain Reaction Risk Role STAT1 protein Series Signal Transduction Solid Structure Thiones Tissues Tobacco smoke Toxic Environmental Substances Toxic effect Transforming Growth Factors Transgenic Animals Transgenic Organisms Translations Tumorigenicity Validation Western Blotting Work aflatoxin B1 aldehyde reductase analog anethole benzoquinone cancer prevention carcinogenesis cell type clinically relevant cytotoxic dithiolethione dorsal motor nucleus exposed human population gene discovery genotoxicity heme oxygenase-1 human NOS2A protein in vitro Assay in vivo lymphotoxin beta multicatalytic endopeptidase complex novel oltipraz pre-clinical stressor

项目摘要

DESCRIPTION (provided by applicant): Cancer prevention involving reduction or elimination of human exposure to environmental carcinogens may not always be possible. Inhibition of the development of cancer by the administration of anticarcinogenic agents may offer a practical alternative for reducing human cancer burden. However, the successful utilization of chemopreventive interventions will require solid mechanistic understanding of the action(s) of these agents. Dithiolethiones are amongst the most broadly effective classes of chemopreventive agents in experimental models; clinical trials also indicate their efficacy in populations exposed to dietary aflatoxins or tobacco smoke. The objectives of this investigation remain to define the mechanisms of chemoprevention afforded by dithiolethiones and related compounds. Highly quantitative animal model systems for interrelating the molecular, biochemical, and biological actions of these chemopreventive agents have been developed and will be used in i) the development and characterization of new, potent dithiolethiones, ii) the identification of novel genes modulated by dithiolethiones, iii) probing the specific contributions of these induced genes to chemoprevention, and iv) the validation of intermediate biomarkers to assess the efficacy of anticarcinogenic interventions. Recent gene discovery activities indicate that dithiolethiones affect the expression of many genes that are likely to repress the cytotoxic and autopromoting actions of carcinogens in addition to their genotoxic ones. Thus, investigations of the cytoprotective mechanisms of dithiolethiones form the primary focus of this renewal. Functional consequences of induction of protective pathways by dithiolethiones, including STAT signaling, proteasome activation, and carcinogen metabolism by aldehyde reductases, will be probed through a series of in vitro assays and studies in transgenic animals using a panel of validated intermediate biomarkers. Structure-activity studies of a large dithiolethione library will probe their tissue and cell-type specific pharmacodynamic action in a reporter mouse to better inform matching of agents with target tissues. This library will also be screened for analogs in addition to oltipraz that inhibit and reverse the development of fibrosis and cirrhosis, a key step in liver cancer. Collectively, these studies will further the goal of effectively using dithiolethiones as protective agents in human populations exposed to environmental toxicants.

描述（由申请人提供）：通过减少或消除人类接触环境致癌物来预防癌症并不总是可行的。通过施用抗癌剂抑制癌症的发展可能为减轻人类癌症负担提供一种实用的替代方案。然而，成功利用化学预防干预措施需要对这些药物的作用有坚实的机制理解。二硫代硫酮是实验模型中最广泛有效的化学预防剂之一；临床试验还表明它们对接触膳食黄曲霉毒素或烟草烟雾的人群有效。这项研究的目的仍然是确定二硫代硫酮和相关化合物提供的化学预防机制。用于关联这些化学预防剂的分子、生化和生物学作用的高度定量的动物模型系统已经开发出来，并将用于i)新的、有效的二硫烯酮的开发和表征，ii)由二硫烯酮调节的新基因的鉴定， iii) 探讨这些诱导基因对化学预防的具体贡献，以及 iv) 验证中间生物标志物以评估抗癌干预措施的功效。最近的基因发现活动表明，二硫烯硫酮影响许多基因的表达，这些基因除了抑制基因毒性外，还可能抑制致癌物的细胞毒性和自身促进作用。因此，对二硫代硫酮的细胞保护机制的研究构成了这一更新的主要焦点。二硫代硫酮诱导保护途径的功能后果，包括 STAT 信号传导、蛋白酶体激活和醛还原酶的致癌物代谢，将通过一系列体外测定和转基因动物研究，使用一组经过验证的中间生物标志物进行探讨。对大型二硫硫酮文库的结构活性研究将在报告小鼠中探测其组织和细胞类型特异性药效作用，以更好地告知药物与靶组织的匹配。该文库还将筛选除吡普拉之外的类似物，这些类似物可以抑制和逆转纤维化和肝硬化的发展，这是肝癌的关键步骤。总的来说，这些研究将进一步实现有效使用二硫代硫酮作为暴露于环境毒物的人群的保护剂的目标。