The twin focus of this Program Project is drug discovery and clinical development of new anticancer agents being discovered in our laboratories through the Corbett/Valeriote assays. The synthetic compounds and their analogs are obtained from both the inventories and synthetic chemistry laboratories of Lilly Pharmaceutical Company at a rate of 5,000 per year (Core D). These compounds are tested in Core C against the common human drug resistant epithelial tumors: colon, breast and lung. While we expect that a variety of classes of chemotherapeutic agents will be taken to clinical trial, they must first be active against either murine or human tumors both in vitro and in vivo. Extensive in vivo secondary analysis is carried out in appropriate murine and human tumor models. This includes breadth of activity against various tumors, schedule and route analysis and hot recovery and toxicity information. These are done under Corbett's Project. This Project also supports the analysis of analogs of in vivo active agents and concomitant structure-activity relationship studies. The analogs are studied both in vivo and in vitro with emphasis on the tumor types indicated above. Promising compounds will be tested in the clinic in the context of well-controlled Phase I and II trials, focussing on the clinical correlation of our experimental results (Valeriote's Project). The Phase I trials will include patients with any type of tumor resistant to therapy. The Phase II trials will be carried out specifically on those tumors which demonstrated sensitivity in the experimental studies and will be limited to colon, pancreas, breast, ovary, prostate and lung. Another component of this Program is the analysis of both pharmacokinetic data and mechanism of action studies on the compound (Valeriote's Project). The pharmacokinetic information will be used in the Phase I trials to escalate the dose according to new non- Fibronacci schemes which make use of comparative AUC information. Metabolite and excretion studies will also be carried out on the compounds. Specific mechanism of action studies will be done which are amenable to being carried out on patient material. At present, we have a number of chemotherapeutic agents at this stage of development.
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