The goals of this program project are to create new chemopreventive entities through a focused effort on protein kinase C, a critical enzyme in tumor promotion, growth regulation, differentiation and development. The underlying conceptualization is that protein kinase C is regulated by positive and negative lipid second messengers derived from membrane glycerolipids and sphingolipids, respectively. Studies of structure-function relationships of these natural activators, sn-1,2-diacylglycerols (DAG), and inhibitors, sphingosine, may lead to the development of inhibitors of protein kinase C. Such drugs would be expected to interfere with the promotional and progressive steps of carcincogenesis. The programs are: 1) Chemistry, where DAG and sphingosine analogues will be prepared; 2) Enzyme Activity Assessments/Mechanisms where the effects of these analogues on protein kinase C activity, (3H)PDBu binding, and on the activities of enzymes of DAG and sphingosine metabolism will be determined; 3) Cellular Activity Assessments where the active analogues will be tested on cellular protein kinase C activity in human platelets, A431 cells, human HL60 cells and other transformed cells for anti- transformation activity, and in the keratinocytes/papilloma cultures for anti-tumor promotional activity; and, 4) Animal Activity Assessments where the pharmacokinetics, metabolism, toxicology, and anti-tumor promotional activities of selected agents will be determined in mice. These studies should create new tools (drugs) which will facilitate acquisition of basic knowledge pertinent to testing the major conceptualizations developed. These drugs may rapidly translate into new chemopreventive agents.
Showing the most recent 10 out of 13 publications
