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.
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