The Consortium Group members from the University of Illinois at Chicago (UIC), Research Triangle Institute (RTI) and Bristol-Myers Squibb, Pharmaceutical Research Institute (BMS-PRI) have combined their vast experience in the isolation and structure elucidation of biologically active natural products to develop a consolidated, Integrated program for the isolation of novel, selective anticancer agents of plant origin which will have the potential for development as cancer chemotherapeutic agents. Plant materials for analysis (500 per year) will be collected by established botanists located primarily in tropical countries, either on the basis of their endemic nature, their taxonomic representation in primarily unstudied or little-studied genera, or based on a process, using the NAPRALERT database at UIC, of ranking plants previously shown experimentally to have some form of anticancer activity and for which the active principle is not known. Plants acquired as a result of this novel collection strategy will be extracted at UIC to afford extracts which will be evaluated in a battery of assays based on a diverse approach of cytotoxicity, mechanism-based and tumor growth related assays currently established and operational at UIC, RTI and BMS-PRI. Data from these assays will be stored and analyzed in detail so that a priority list of plants for recollection and fractionation can be formulated by an evaluation panel. Dereplication of known active compounds will be accomplished by a combination of the use of computerized literature surveys and HPLC/MS. Bioassay-directed fractionation procedures will be employed (at UIC, RTI and BMS-PRI) for the procurement of pure active principles, which will be structurally characterized. Analogs of active natural products will be synthesized at RTI. Novel, active compounds thus discovered will be further evaluated in our battery of bioassays. Based on these data and the structure of the isolate, a decision will be made regarding further development of the agent for potential use as a chemotherapeutic agent. These more advanced stages of biological and toxicological testing, as well as synthesis or isolation of larger quantities of lead compounds will be sponsored by BMS-PRI. The Consortium welcomes the involvement of NCI staff throughout the discovery process, and plans to hold regular meetings of the key scientific personnel at all three sites in order to enhance ongoing communication, exchanges of information and decision-making processes. Excellent facilities for isolation, structure determination, chemical modification, synthesis and in vitro and in vivo biological evaluation are available at the consortial sites for the conduct of this work.
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