CHEMOPREVENTIVE AGENTS--PROVISION OF SOURCE MATERIALS

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The overall long term objectives and specific aims of this proposal concern the selection, procurement and extraction of plant materials having potential carcinogenesis inhibitory activity. The materials will be used for studies leading to the discovery and development of cancer chemopreventive agents. At the same time, this project will provide literature information services to the other projects in this Program Project. Selection of plant materials for study will be focused on (1) edible plants, primarily non-USA; (2) plants reported to have activity in an assay pertinent to cancer chemoprevention, but which have not been investigated chemically; (3) plants with no history of toxicity and minimal level of phytochemical studies; and (4) not previous investigated or minimally investigated plant species have the potential to yield novel chemical compounds. These candidate plants will be identified by an analysis of natural products literature with the aid of the NAPRALERT database. The candidate plant materials will be field collected, cultivated and/or commercially purchased. They will be dried, milled, and extracted for bioassay (Projects 3 and 4), and a decision will then be made to proceed with bioassay-directed fractionation for novel cancer chemopreventive agents from the most promising active leads. These materials (1-10 kg lots) will be extracted and supplied to Project 2 for the isolation of the active principles. All plant materials will be identified and authenticated. This project will also perform initial extraction of plant materials and scale-up isolation of confirmed active phytochemicals. The active compounds (0.05 - 1.0 g scale) will be isolated according to protocols developed by Project 2, the LC/MS/MS Core or from published literature, for evaluation of mechanism of action or chemopreventive efficiency studies (Projects 3 and 4). In addition, this project will conduct literature searched on all plants chosen for bioassay directed fractionation, and known chemical and pharmacological work on each of plant will be assembled and provided to the Principal Investigator and the Project Leaders. Issues on property rights and intellectual property rights for plant materials acquired and used for the proposed project will be carefully considered and applied, and appropriate measures will be taken to provide reciprocity (share of benefits) to collaborators and to source countries of the raw plant materials. GRANT-P01CA48112-08A1-0002 In this Program Project competitive renewal application, it is proposed to continue the discovery of novel natural products from plant sources as potential inhibitors of chemical carcinogenesis, using bioactivity- fractionation techniques. Selected non-polar and polar plant extracts prepared in another Program have shown to be active in either or both in vitro assays in a program and secondary assay in yet another program will be chromatographed according to well-established phytochemical procedures, with the fractions so obtained being monitored by the short- term in vitro bioassay in which the greatest activity was originally demonstrated. Spectroscopic and chemical methods will be used to determine the structures of pure bioactive compounds. In concert with literature data surveillance and studies in the LC/MS/MS Core, efforts will be made to minimize the re-isolation of compounds with known chemopreventive activity. Thus, it is expected that this project will continue to provide new chemical entities with cancer inhibitory activity for detailed biological evaluation. Such naturally occurring compounds might have mechanistic or even clinical value per se, or alternatively might serve as new lead compounds for subsequent synthetic modifications in the last project of this Program Project.