This drug discovery program is directed towards the discovery of new anticancer agents against colon cancer. The central element of the program is the multipletumordisc- diffusion assay which defines the specificity of test agents in terms of their cytotoxic activity in vitro against both clonogenic leukemia and murine and human colon tumors. Agents with cellular selectivity for the colon tumors will be evaluated against these same tumors in mice. Additionally, the cytotoxic materials (that are not highly selective for the colon tumors) will be reexamined against a murine colon adenocarcinoma and a normal population (CFUGM from the bone marrow and GI epithelial crypt cells) looking for agents with more cytotoxicity for the colon tumor than the normal cells. These materials will also be evaluated in mice. The majority of the test agents will be fermentations and synthetic organic compounds provided by the Upjohn Co. About 2000 of the former and 2000 of the latter will be examined each year. A number of studies will be carried out to define the mechanism of action of the most active agents. Those agents progressing toward clinical trials will be investigated in combination with either radiation or other anticancer agents. The biochemical pharmacology studies will examine effects on macromolecular synthesis, DNA binding, DNA damage and repair kinetics and resistance mechanisms. Depending upon the structure of the agents and the preliminary results on mechanism of action, other analyses will be done. Ageresponse cytotoxicity in terms of phase of cell cycle and proliferative dependency of the cytotoxic effect will be defined. Extensive in vivo pharmacological studies will be done on these agents as well. Experimental therapeutic examination will define the optimal route and schedule for administration of the agent and use appropriate in vivo models to examine the dose, interval and sequence dependency for their interaction. The compounds will also be tested for their inhibitory effects on growth and differentiation of a spectrum of human colon cancer cells. We will also examine their ability to modulate polyamine biosynthesis.
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