The Consortium Group members from the University of Illinois at Chicago (UIC), Research Triangle Institute (RTI) and Bristol-Myers Squibb (BMS-PRI) have combined their vast experience in the isolation, structure elucidation and biological evaluation of natural products to develop a consolidated, integrated program for the isolation of novel, selective anti-cancer agents of plant origin (both secondary metabolites and the products of endophytic microorganisms associated with plants) with 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 primary 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 type of anti-cancer activity for which the active principle(s) is(are) 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 screens based on a diverse approach of mechanism-base, cell-based, and tumor growth related assays currently established and operationalized at UIC, RTI and BMS-PRI, as well as others to be developed. 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. Lead development of active natural products will be conducted at BMS-PRI. Novel, active compounds thus discovered will be further in our battery of in vitro and in vivo bioassays.,. Based on the biological 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. The 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 regulating meetings of the key scientific personnel at the various consortial 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 body of this work.
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