This application is for continuation of a comprehensive program involving design, synthesis, biological evaluation in vitro and in vivo against murine tumors and human tumor xenografts, biochemical screening and in- depth investigations of mechanism of action of new anticancer agents of the following classes; analogs of purines and pyrimidines and their nucleosides and nucleotides and analogs of penclomedine, a new agent entering phase I clinical trials for breast cancer. New agents will be evaluated for cytotoxicity in vitro against a panel of human solid tumors and leukemias and murine tumors, and nucleoside analogs will be investigated for biochemical effects against a series of enzymes involved in purine, pyrimidine, and nucleic acid metabolism. Agents of interest will be evaluated in vivo against selected murine tumors and human tumor xenografts and also subjected to in-depth biochemical studies on their mechanism of action. Agents determined to be of clinical potential will be evaluated against additional tumor models. The results of the biological and biochemical investigations will be used to guide synthesis projects with respect to selection of agents that merit further study and the design of new agents on the basis of observations on structure-activity relationships and mechanisms of action. Specifically, three synthesis- biochemistry projects will provide new agents for biochemical and biological evaluations and investigations, and the core components will provide preparative-scale synthesis and analytical services, chemotherapy evaluations in vitro and in vivo and elementary toxicology evaluation, and screening against a panel of enzymes involved in nucleic acid metabolism, resulting in a unified and interrelated program of drug development.
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