Discovery of Anticancer Agents of Diverse Natural Origin

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DESCRIPTION (provided by applicant): In this revised Program Project renewal application, the applicant group is representative of three primary institutions. The Ohio State University (OSU), the University of Illinois at Chicago (UIC), and the University of North Carolina at Greensboro (UNCG). The participants have combined their vast experience in the isolation, structure elucidation, and biological evaluation of natural products, to continue the development of a consolidated, integrated program for the discovery of novel anticancer agents of diverse origin for development as cancer chemotherapeutic agents. Plant materials to be studied in Project 1 (OSU) will be collected by established botanists located in tropical countries with the assistance of the NAPRALERT database (Project 2; UIC), and cyanobacteria (Project 2) and filamentous fungi (Project 3 UNCG) 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 (Project 1), UIC (Core A), Columbia University (through Project 3), and a new pharmaceutical company partner, Eisai Inc., Andover, MA (through Core C at OSU). Dereplication of known active compounds will be accomplished at OSU, UIC, and UNCG using computerized literature surveys and LC-MS coupled to bioassays. Bioassay-directed fractionation will be employed in Projects 1-3, for the elucidation of active principles. Lead development of active natural products via medicinal chemistry and pharmacokineticsrelated studies will be conducted at OSU (Core B), facilitated by the OSU Biostatistics group (Core C). 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 Eisai). 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 Eisai (through Core C). 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 and OSU Internal Advisory panels) to enhance communication and decision-making processes, to be organized by Core C. Excellent facilities for the isolation, structure determination, chemical modification, synthesis, and in vitro and in vivo biological evaluation, and overall project data management are available. RELEVANCE (See instructions): Cancer is responsible for about one in every four deaths in the United States, and new treatments are urgently needed. It is the overall goal of the integrated studies in this renewal application to discover novel chemicals from selected tropical rainforest plants, as well as cyanobacteria and fungi, for development as cancer chemotherapeutic agents, particularly for tumors not cured by present treatment methods.