MECHANISMS OF CHEMOPROTECTION BY OLTIPRAZ

预防癌症是一个紧迫而有希望的方向 生物研究。饮食因素被认为与 占每年癌症发病率的三分之一。尽管潜在的生物化学 机制是有争议的，与饮食诱变剂摄入量有很强的关联 结肠癌的风险已经被提出。膳食成分 与降低癌症发病率相关的包括布鲁塞尔的西兰花 芽菜、花椰菜和卷心菜。这些蔬菜的特点是价格高。 二硫代硫酮和其他物质的水平。奥蒂普拉兹，一名合成纤维 二硫代硫酮，是新药开发的先导化合物 可防止诱变的化学预防药剂。一直以来 提出奥替拉兹通过提高第二阶段的活动来发挥作用 解毒酶(包括DT-黄递酶)，主要通过诱导 转录活性。虽然我们和其他人已经证明了 通过一些顺式作用元件(包括 AP-1和NF-kappaB)，可能是解毒酶表达上调的原因 活性，奥替拉兹影响反式激活因子的基础仍然存在 未知。此外，我们最近提出的证据表明， 替代的作用机制，通过证明奥替拉兹诱导 DNA加合物的修复，一个主要通过核苷酸切除发生的过程 修理。我们推测这两种机制都可能起到保护正常 细胞，因此我们建议对这些操作进行详细分析 在分子水平上。我们的具体目标是：1)确定 奥替拉兹诱导DT-黄递酶的转录激活，以及2) 确定奥替拉兹刺激DNA修复的基础。我们还将 筛选一系列二硫代硫酮类似物诱导NER活性的能力。 这些研究的结果将使设计更具选择性和毒性更低 化学防护剂。

The prevention of cancer is an urgent and promising direction of biological research. Dietary factors are believed to account for as much as one-third of the annual incidence of cancer. Though the underlying biochemical mechanisms are controversial, strong associations with dietary mutagen intake and the risk of colon cancer have been presented. Dietary constituents associated with a lowered incidence of cancer include broccoli, Brussels sprouts, cauliflower and cabbage. These vegetables are characterized by high levels of dithiolethiones and other substances. Oltipraz, a synthetic dithiolethione, is the lead compound in the development of novel chemopreventive agents that may protect against mutagenesis. It has been proposed that oltipraz functions by elevating the activities of Phase II detoxicating enzymes (including DT-diaphorase), primarily through the induction of transcriptional activity. While we and others have shown that transcriptional induction through a number of cis-acting elements (including AP-1 and NF-kappaB), may account for the upregulation in detoxicating enzyme activity, the basis for oltipraz's effects on transactivating factors remains unknown. Furthermore, we have recently presented evidence that suggests an alternative mechanisms of action, by demonstrating that oltipraz induces the repair of DNA adducts, a process that occurs primarily by nucleotide excision repair. We postulate that both of these mechanisms may act to protect normal cells, and therefore we propose to perform a detailed analysis of these actions at a molecular level. Our specific aims are: 1) To determine the basis for the transcriptional activation of DT-diaphorase induced by oltipraz, and 2) To determine the basis for the stimulation of DNA repair by oltipraz. We will also screen a series of dithiolethione analogues for their ability to induce NER activity. The results of these studies will enable the design of more selective and less toxic chemopreventive agents.