CELLULAR AND BIOCHEMICAL EFFECTS OF TUMOR PROMOTERS

这一建议的目的是扩大我们的研究机制， 在生物化学和遗传水平上，肿瘤促进剂的作用。 基于 肿瘤启动子-受体结合几种类型的立体化学模型 的化合物将被合成并测试体外活性 已知肿瘤促进剂的特征和可能的抗促进剂 活动 佛波醇酯的荧光和光亲和衍生物将 也可用于机械研究。 酶蛋白 激酶C，（PKC），佛波酯肿瘤促进剂的假定作用位点 和相关化合物，将被纯化至同质， 以及通过重组DNA技术克隆的PKC基因。 这将允许 直接分析这种酶在肿瘤促进中的作用。 我们将 也探索了某些类型的肿瘤促进剂产生 直接作用于线粒体和/或直接活性膜相关 磷脂酶 所定义的两亲性多肽将被用于 这些研究中有几项是为了确定它们是否模拟或拮抗 已知的肿瘤促进剂的作用。 最后，我们将研究 肿瘤促进剂可以与细胞癌基因协同作用，和/或 在多阶段癌变过程中激活LTR样DNA序列。 希望这些研究能为检测 环境中潜在的肿瘤促进剂，并导致新的策略， 癌症预防。

The purpose of this proposal is to extend our studies on the mechanism of action, at the biochemical and genetic levels, of tumor promoters. Based on a stereochemical model of tumor promoter-receptor binding several types of compounds will be synthesized and tested for in vitro activities characteristic of known tumor promoters and for possible anti-promoter activity. Fluorescent and photoaffinity derivatives of phorbol esters will also be prepared and used for mechanistic studies. The enzyme protein kinase C, (PKC), a putative site of action of phorbol ester tumor promoters and related compounds, will be purified to homogeneity, antibodies prepared and the PKC gene(s) cloned by recombinant DNA techniques. This will permit a direct analysis of the role of this enzyme in tumor promotion. We will also explore the possibility that certain types of tumor promoters produce direct effects on mitochondria and/or directly active membrane-associated phospholipases. Defined amphiphilic polypeptides will be utilized in several of these studies to determine if they mimic or antagonize the action of known tumor promoters. Finally, we will study the possibility that tumor promoters can act synergistically with cellular oncogenes and/or activate LTR-like DNA sequences during multistage carcinogenesis. Hopefully, these studies will provide a more rational basis for detecting potential tumor promoters in the environment and lead to new strategies of cancer prevention.