NATURAL INHIBITORS OF CARCINOGENESIS

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It is well known that human cancer can result from exposure to a variety of natural and synthetic chemical carcinogens, many of which are ubiquitous environmental contaminants. Conversely, a number of substances have been established as inhibitors of chemically-induced tumorigenesis (e.g., antioxidants, indoles, aromatics isothiocyanates, coumarins, flavones, diterpenes, and vitamins). Most of these substances are naturally occurring and found in the diet of humans. However, since a systematic effort of exploring natural products as sources of chemopreventive agents has never been implemented, it is reasoned that many agents of interest remain to be uncovered. Thus, we currently proposed a program project comprised of six multidisciplinary, integrated research programs. The major aim of this program project is the identification, isolation and characterization (structural and mechanistic) of unique cancer chemopreventive agents from natural sources. For the accomplishment of these goals, the individual research programs involve (1) the provision of source material, (2) isolation and identification of active principles, (3) short term in vitro and in vivo biological studies to provide bioassay- directed purification capability and mechanistic information, (4) in vivo evaluations to establish efficacy, and (5) chemical synthesis, semisynthesis and structural modification to aid in the establishment of structure, mechanism and efficacy. In additional, core facilities will contribute to the Program Project in a number of ways, such as data management and biostatistical analysis. Also, databases will be utilized to aid in the establishment of structure, decrease the chance of isolating known chemopreventive entities, and predict which materials may demonstrate the desired activity. Over a period of five years, approximately 250 materials (primarily plants) will be evaluated for chemopreventive activity. Initial selections will be based on reputed activity (literature surveillance) and preliminary studies. As a result of this work, long-term contributions that are anticipated include: the development, characterization and provision of procedures for identifying dietary materials capable of preventing human cancer; the provision of heretofore unknown chemical entities that are capable of preventing human cancer; synthetic procedures that are capable of providing sufficient quantities of chemopreventive entities (or derivatives thereof) to permit more thorough evaluations in the future; mechanistic information of general value concerning the prevention of tumorigenesis. Overall, this project should provide a better understanding of the relationship between diet and cancer (cause and prevention), and establish a scientifically valid approach of comprehensively studying this relationship.