The focus of this Program Project is the discovery of new anticancer agents against specific solid tumors: pancreas, colon and lung. The central screening assay is a multiple tumor disk- diffusion-assay that defines the specificity of test agents in terms of their cytotoxic activity in vitro against clonogenic solid tumor cells in comparison with a leukemia. The solid tumors are selected to be among the most drug insensitive tumors available (human and mice). In this way, redundancy discoveries are avoided, and the possibility of discovering more broadly active agents with unique mechanisms of action is increased. Agents that are more cytotoxic for solid tumors than for the leukemia will be tested against the same drug-insensitive solid tumor in mice. Active agents will then be evaluated in greater depth to define: a) breath of activity against other tumors, b) activity by other routes of administration, c) optimum schedule and the schedule category to which the agent belongs, d) linear or nonlinear pharmacokinetics (if relevant), e) cross-resistance behavior with standard agents, and f) host recovery time as well as short and long term toxicity problems. Promising agents will proceed to biochemical pharmacology and mechanism of action studies. These will include: a) effects on macromolecular synthesis, DNA-binding, DNA damage and repair kinetics, and resistance mechanisms. Cellular studies will be carried out to examine the age-response cytotoxicity in terms of phase of the cell cycle and proliferation dependently of the cytotoxic effect. The compounds will also be tested for their inhibitory effects on growth and differentiation (including modulation of polyamine biosynthesis) in a spectrum of human colon and lung cells. Depending on factors such as the uniqueness of action, breadth of activity, and therapeutic index in sensitive tumors, a decision will be made to undertake an analog search and synthesis program. Promising compounds will be studied in the clinic in the context of well controlled Phase I and II trials, focusing on the clinical correlation of our experimental results. Agents active in the clinic will be further studied in combination chemotherapy trials in murine tumors. The majority of the test agents for the total program will be supplied by the Upjohn Company, Eastman Pharmaceuticals and NCI. Approximately 2,000 fermentation materials and 6,000 synthetic organic chemicals will be evaluated yearly. Upjohn will carry out all fractionation, purification and identification of the active fermentations as well as a portion of the analog synthesis.
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