MECHANISMS OF ANTICARCINOGENESIS BY DITHIOLETHIONES

二硫硫磷的抗癌机制

• 批准号: 2089821
• 负责人: THOMAS W KENSLER
• 金额: $ 45.83万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2089821
• 关键词: NAD(P)H dehydrogenase; aflatoxins; antineoplastics; cancer prevention; carcinogen testing; carcinogenesis inhibitor; chemical carcinogen; chemical carcinogenesis; chemical structure function; chemical synthesis; chemoprevention; enzyme activity; enzyme induction /repression; glutathione transferase; hepatocellular carcinoma; hepatotoxin; laboratory rat; liver metabolism; mutagen testing; neoplasm /cancer genetics; nucleic acid sequence; nutrition related tag; thiones; thiophenes; toxin metabolism

Strategies for 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 chemoprotective interventions will require solid mechanistic understanding of the action(s) of these agents. The proposed study will continue to investigate the modes of protection afforded by oltipraz and other 1,2-dithiole-3-thiones on aflatoxin B1 hepatocarcinogenesis in the rat. Oltipraz is an effective and potent inhibitor of experimental carcinogenesis in may tissues and holds strong promise for use in human interventions. Specifically, we will investigate the chemistry of dithiolethiones with respect to (a) new methods for synthesis of these related molecules; (b) synthesis of compounds designed to test emerging structure-activity relationships, leading to more active compounds; (c) synthesis of oltipraz metabolites for evaluation in bioassays; (d) synthesis of radiolabeled dithiolethiones for mechanistic studies; and (e) synthesis of dithiolethiones suitable for production of antibodies. We will also investigate the structure-activity relationships of the synthesized compounds on (a) phase I & II enzyme activities; (b) mechanisms of induction of phase II enzymes: (c) altered carcinogen-DNA adduct formation; and (d) inhibition of AFB1-induced tumorigenesis in rats. Finally, we will utilize a molecular genetic approach to identify and characterize the spectrum of genes induced by dithiolethiones in rat liver. A cDNA library prepared from the livers of rats treated with 1,2- dithiole-3-thione will be screened by differential/subtractive hybridization techniques. Isolated clones will then be identified and characterized by hybridization and DNA sequence analyses. Collectively, these multifaceted, integrated studies will more fully define the chemical, molecular, biochemical and biological mechanisms of action of this of this versatile class of chemoprotective agents. The long term goal of this work is to facilitate the most efficient and effective use dithiolethiones as protective agents in human populations exposed to environmental toxicants.

癌症预防策略包括减少或消除 人类接触环境致癌物质并不总是可能的。 通过施用抑制癌症的发展 抗癌剂可能提供一种实用的替代方案来减少 人类癌症负担。 然而，成功利用 化学保护干预措施需要坚实的机制 了解这些代理的行为。 拟议的研究将 继续研究吡噻硫酮提供的保护模式和 其他 1,2-二硫醇-3-硫酮对黄曲霉毒素 B1 肝癌发生的影响 鼠。 Oltipraz 是一种有效且有效的实验抑制剂 多种组织中的致癌作用，在人类中的应用前景广阔 干预措施。 具体来说，我们将研究以下物质的化学性质： 关于（a）二硫代硫酮的新合成方法 相关分子； (b) 旨在测试新兴化合物的合成 结构-活性关系，产生更活性的化合物； (三) 用于生物测定评估的奥替普拉代谢物的合成； (四) 合成放射性标记的二硫代硫酮用于机理研究；和 (e)适合于生产抗体的二硫代硫酮的合成。 我们还将研究结构与活性的关系 合成的化合物对 (a) I 期和 II 期酶活性的影响； (二) II 相酶的诱导机制：(c) 改变的致癌物-DNA 加合物形成； (d) 抑制 AFB1 诱导的肿瘤发生 老鼠。 最后，我们将利用分子遗传学方法来识别 并表征大鼠中二硫代硫酮诱导的基因谱 肝。 从用 1,2- 处理的大鼠肝脏制备的 cDNA 文库 二硫醇-3-硫酮将通过差异/消减法进行筛选 杂交技术。 然后将鉴定分离的克隆并 通过杂交和 DNA 序列分析来表征。 总的来说， 这些多方面的综合研究将更全面地定义 化学、分子、生物化学和生物作用机制 这是这种多功能的化学保护剂。 长期来看 这项工作的目标是促进最有效和最有效的利用 二硫代硫酮作为暴露人群的保护剂 环境毒物。