MECHANISMS OF CHEMOPROTECTION BY OLTIPRAZ

癌症的预防是一个紧迫而有希望的方向， 生物学研究据信，饮食因素 占每年癌症发病率的三分之一。虽然潜在的生化 机制是有争议的，与膳食诱变剂摄入量密切相关 和患结肠癌的风险。膳食成分 与癌症发病率降低有关的蔬菜包括西兰花、布鲁塞尔 芽菜花椰菜和卷心菜。这些蔬菜的特点是高 二硫代硫醚和其他物质的水平。奥替普拉，一种合成药物 二硫杂环硫酮，是开发新的 可以防止诱变的化学预防剂。已经 提出奥替普拉通过提高II期的活性来发挥作用， 解毒酶（包括DT-心肌黄酶），主要通过诱导 转录活性。虽然我们和其他人已经表明， 转录诱导通过一些顺式作用元件（包括 AP-1和NF-κ B），可能是解毒酶上调的原因 活性，oltipraz对反式激活因子作用的基础仍然存在 未知此外，我们最近提出的证据表明， 替代的作用机制，通过证明奥替普拉诱导 DNA加合物的修复，主要通过核苷酸切除发生的过程 修复.我们假设这两种机制都可以保护正常的 细胞，因此，我们建议对这些行动进行详细分析 在分子水平上。我们的具体目标是：（1）确定 由奥替普拉诱导的DT-黄递酶的转录激活，和2）To 确定由oltipraz刺激DNA修复的基础。我们还将 筛选一系列具有诱导NER活性能力的二硫杂环硫酮类似物。 这些研究的结果将使设计更具选择性和毒性更小的 化学预防剂

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.