The objective of this application is to develop an activity-directed fractionation procedure designed to isolate from higher plants novel inhibitors of carcinogenesis. Based on previous experience in the isolation of novel antineoplastic agents from higher plants and using mammalial cell culture assays designed to detect the inhibitors of interest a variety of human foods shown to be correlated to reduced cancer incidence will be studied as follows: 1) Development of cell culture assays for detection of potential inhibitors of carcinogenesis. These assays will measure hydrocarbon metabolism, hydrocarbon-DNA interactions, and hydrocarbon-induced mutations in mammalian systems. 2) Acquisition of selected higher plants for initial screening leading to identification of a convenient assay to guide fractionation. 3) Bioassay-directed fractionation of plants including members of the Cruciferae, Umbelliferae, Leguminosae, and others which show reproducible activity in the bioassays in order to isolate pure, crystalline active components. 4) Determination of the complete structure and stereochemistry of crystalline actives using modern spectroscopic methods including nuclear magnetic resonance spectroscopy (NMR), mass spectrometry (MS), and X-ray crystallography. 5) Determine the mechanism of action of selected active components with high chemopreventive potential. 6) Development of analytical methods including HPLC, GCMS, and MSMS to detect these compounds at low levels in biological systems and other plants for purpose of dereplication, identification of other inhibitors, and other plant sources of inhibitors. The identification of these novel inhibitors will lead to a variety of agents with the potential of preventing human cancer, and in addition will provide a better understanding of the total inhibitor activity present in the plants, and their mechanism of action.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038151-03
Application #
3176197
Study Section
(SSS)
Project Start
1984-07-01
Project End
1987-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Purdue University
Department
Type
Schools of Pharmacy
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Chae, Y H; Ho, D K; Cassady, J M et al. (1992) Effects of synthetic and naturally occurring flavonoids on metabolic activation of benzo[a]pyrene in hamster embryo cell cultures. Chem Biol Interact 82:181-93
Liu, Y L; Ho, D K; Cassady, J M et al. (1992) Isolation of potential cancer chemopreventive agents from Eriodictyon californicum. J Nat Prod 55:357-63
Chae, Y H; Coffing, S L; Cook, V M et al. (1991) Effects of biochanin A on metabolism, DNA binding and mutagenicity of benzo[a]pyrene in mammalian cell cultures. Carcinogenesis 12:2001-6
Chae, Y H; Marcus, C B; Ho, D K et al. (1991) Effects of synthetic and naturally occurring flavonoids on benzo[a]pyrene metabolism by hepatic microsomes prepared from rats treated with cytochrome P-450 inducers. Cancer Lett 60:15-24
Cassady, J M; Baird, W M; Chang, C J (1990) Natural products as a source of potential cancer chemotherapeutic and chemopreventive agents. J Nat Prod 53:23-41
Cassady, J M; Zennie, T M; Chae, Y H et al. (1988) Use of a mammalian cell culture benzo(a)pyrene metabolism assay for the detection of potential anticarcinogens from natural products: inhibition of metabolism by biochanin A, an isoflavone from Trifolium pratense L. Cancer Res 48:6257-61
Baird, W M; Zennie, T M; Ferin, M et al. (1988) Glucolimnanthin, a plant glucosinolate, increases the metabolism and DNA binding of benzo[a]pyrene in hamster embryo cell cultures. Carcinogenesis 9:657-60
al-Yahya, M A; el-Sayed, A M; Mossa, J S et al. (1988) Potential cancer chemopreventive and cytotoxic agents from Pulicaria crispa. J Nat Prod 51:621-4
Zennie, T M; Cassady, J M; Raffauf, R F (1986) Funebral, a new pyrrole lactone alkaloid from Quararibea funebris. J Nat Prod 49:695-8