CHEMOPREVENTIVE AGENTS--CARCINOGENESIS INHIBITION

本次更新申请的总体目标仍然是发现 衍生自天然产物的新型化学预防剂。 这 该项目将继续利用乳腺器官培养和体内 致癌模型（皮肤和乳腺），以评估生物学 潜在的化学预防剂的有效性， 初始屏幕。 正如本节目的主题所示， 被视为活性导联的部分将首先评估其 对7，12-二甲基苯并蒽（DMBA）的化学预防活性 在器官培养中诱导乳腺病变。 如果确切的显示戏剧性 活动在文化系统中，它将根据两个阶段进行评估 皮肤癌变模型 一些提取物或分离的级分将被 进一步表征，并再次评估它们的活性。 的 再次评估被认为是活性的新识别的试剂 防止乳腺病变形成。 然后将活性化合物 合成和致癌研究将开始。 乌洛托品宁和 选择绢毛蒙杜莱提取物（P00053） 基于体外测定结果的致癌实验 和器官培养实验（本项目）。 这些研究表明 对皮肤癌发生具有优异的抑制作用。 此外，我们建议 开展研究，评估新发现的 化学预防剂，其活性可以作为抗引发剂或作为 器官培养中的反启动子。 这将使我们能够在体内设计 研究，以确认这种阶段的具体影响，并了解 这些药物的作用机制。 各种其他致癌作用 在实验室建立了模型， 在其他靶器官的化学预防潜力，它们将被用于 按要求 总之，本项目将提供一个明确的 新发现的潜在化学预防的生物学终点 在这个项目中的代理人。

The overall objective of this renewal application remains to discover novel chemopreventive agents derived from the natural products. This project will continue to utilize mammary gland organ culture and in vivo carcinogenesis models (skin and mammary) to evaluate biological effectiveness of potential chemopreventive agents identified in the initial screen. As indicated in the theme of this program, extracts or fractions considered as active leads will be first evaluated for its chemopreventive activity against 7,12, dimethylbenz(a)anthracene (DMBA) induced mammary lesions in organ cultures. If the exact shows dramatic activity in the culture system, it will be evaluated against two stage skin carcinogenesis model. Some extracts or isolated fractions will be further characterized and again their activity will be assessed. The newly identified agent which is considered active is again evaluated against mammary lesion formation. The active compound is then synthesized and carcinogenesis studies will be initiated. Brassinin and the extract of Mundulea sericea (P00053) were selected for the carcinogenesis experiments based on the results from the in vitro assays and organ culture experiments (this project). These studies have shown excellent inhibition against skin carcinogenesis. In addition we propose to conduct studies to evaluate activity of newly identified chemopreventive agent for its activity either as an anti-initiator or as an anti-promoter in organ cultures. This will allow us to design in vivo studies to confirm such stage specific effects and to understand the mechanism of action of these agents. A variety of other carcinogenesis models have been established in our laboratory for assessing chemopreventive potential at other target organs, and they will be used as required. In summary, this project will serve to provide a definite biological end point for newly identified potential chemopreventive agents in this program project.