Cancer is a recalcitrant disease of enormous socioeconomic importance. Although notable therapeutic progress has been made, definitive treatment is rarely achieved. Thus, alternative approaches to solving this dilemma are worth exploring. Based on our current understanding of human carcinogenesis, it is anticipated that full implementation of prevention strategies could reduce the incidence of cancer by 70% or more. Primary prevention strategies (e.g., cessation of cigarette smoking, reduction of exposure to chemical carcinogens), early diagnosis, dietary modification and cancer training programs are all of vital importance. In addition, however, the potential health benefit of cancer chemoprevention )(i.e., prevention of cancer in human populations by ingestion of chemical agents) is now generally recognized. To aid in this endeavor, the primary objective of this continuation application is the discovery and characterization of cancer chemopreventive agents from natural sources. An overview of the scientific literature reveals the structures and activities of a number of cancer chemopreventive agents, many of which are present in dietary materials. Nonetheless, nearly all of these agents were uncovered by (semi) empirical methods rather than systematic investigation, and it is certain that additional chemopreventive agents have yet to be discovered. During the previous period, we were able to mobilize all of the necessary components for the implementation of a successful drug discovery program in the area of cancer chemoprevention. This entailed the coordinated effort of five multidisciplinary, integrated research programs: (1) selection and provision of source materials, (2) isolation and identification of active principles, (3) short-term in vitro bioassays to direct fractionation and studies isolates, (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. This experiment approach has led to the procurement of various active principles that are currently considered viable candidates for more advanced testing and development. In addition, all logistical challenges have been abrogated, the program project has been streamlined, and a number of promising leads have been identified and are currently under investigation. Thus, this continuation builds on our accumulated experience in this unique field of research and summarizes our ability to realize progress in this area. Our overall objective is consistent with prevention strategies touted by the National Cancer Institute, the American Cancer Society and others. Specifically, this project will provide chemical entities and activity profiles of sufficient depth to permit erudite consideration of the agents as candidates for intervention trials. To adequately promote this goal, we will cooperate with investigators whose expertise exceeds that encompassed by the program project.
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