CELLULAR AND BIOCHEMICAL EFFECTS OF TUMOR PROMOTERS

这项建议的目的是扩大我们对 在生物化学和遗传水平上，肿瘤促进剂的作用。基座 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进行体外活性测试 已知肿瘤促进剂的特性及其可能的抗启动子 活动。佛波醇酯的荧光和光亲和衍生物将 也要为机械学研究做好准备和使用。酶蛋白 蛋白激酶C，佛波酯类肿瘤促进剂的可能作用部位 和相关化合物，将被提纯到均一，制备抗体 利用基因重组技术克隆了S蛋白激酶C基因。这将允许 直接分析这种酶在促进肿瘤中的作用。我们会 也探索某些类型的肿瘤促进剂产生的可能性 对线粒体和/或直接活性膜相关的直接作用 磷脂酶。定义的两亲性多肽将用于 其中几项研究旨在确定它们是模仿还是对抗 已知肿瘤促进剂的作用。最后，我们将研究这种可能性 肿瘤促进剂可以与细胞癌基因和/或 在多阶段癌变过程中激活LTR样DNA序列。 希望这些研究将为检测提供更合理的基础 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.