Discovery of Anticancer Agents of Diverse Natural Orgin

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DESCRIPTION (provided by applicant): This application represents a substantially revised program based on the comments of reviewers in the prior submission. Again, this program project applicant group is represented by The Ohio State University (OSU), the University of Illinois at Chicago (UIC), Research Triangle Institute (RTI), and Bristol-Myers Squibb (B-MS) who have combined their vast collaborative experience in the isolation, structure elucidation, and biological evaluation of natural products, to consummate a consolidated, highly integrated program for the discovery of novel anticancer agents of diverse origin for development as effective cancer chemotherapeutic agents. Plant materials will be collected by established botanists located in tropical countries with the assistance of the NAPRALERT database, and cyanobacteria and filamentous fungi will also be accessed. Organisms acquired will be extracted and evaluated in a diverse battery of relevant mechanism-based, cell based, and tumor-growth related assays currently operational at OSU, UIC, RTI, and B-MS (Projects 1-3; Cores A and C). Dereplication of known active compounds will be accomplished at OSU, UIC, and RTI using computerized literature surveys and LC-MS coupled to bioassays. Bioassay-directed fractionation will be employed (OSU, UIC, RTI; Projects 1-3, respectively) for the elucidation of active principles. Lead development of active natural products via synthetic and medicinal chemistry will be conducted at OSU (Core B). Novel, active compounds thus discovered will be further evaluated in our panel of in vitro and in vivo bioassays (Projects 1 and 3, Cores A and C), supported by biostatistics (Core D). Group decisions will be made regarding the further development of agents for potential use as anticancer agents. The more advanced states of biological and toxicological testing, as well as the procurement of larger quantities of lead compounds will be sponsored by B-MS (Core C). Management of experimental data will be centralized through the NAPIS database (Core D). The Consortium will work with the involvement of the NCI Program Director in the discovery process, and plans to hold regular meetings of key scientific personnel (inclusive of our External Advisory Panel) to enhance communication and decision-making processes (Core D). Excellent facilities for all technical and administrative aspects of this proposed project are available. Relevance of Research to Public Health: Cancer is responsible for one in every four deaths in the United States, and new treatments are urgently needed. It is the overall goal of the integrated studies of this program project to discover novel chemicals from selected tropical rainforest plants, as well as cyanobacteria and fungi, for development as cancer chemotherapeutic agents, particularly for tumors that can not be cured by present treatment methods.