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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA046738-03
Application #
3549095
Study Section
(SRC)
Project Start
1987-09-01
Project End
1992-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
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Fine, R L; Chambers, T C; Sachs, C W (1996) P-glycoprotein, multidrug resistance and protein kinase C. Stem Cells 14:47-55
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Khan, W A; Dobrowsky, R; el Touny, S et al. (1990) Protein kinase C and platelet inhibition by D-erythro-sphingosine: comparison with N,N-dimethylsphingosine and commercial preparation. Biochem Biophys Res Commun 172:683-91
Okazaki, T; Bell, R M; Hannun, Y A (1989) Sphingomyelin turnover induced by vitamin D3 in HL-60 cells. Role in cell differentiation. J Biol Chem 264:19076-80

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