This application is for continuation of a comprehensive program involving design, synthesis, biological evaluation in vitro and in vivo against human tumor xenografts, murine tumors and selected viruses, biochemical screening and in-depth investigations of mechanism of action and tumor distribution, and pharmacological studies of new anticancer agents of the following classes: analogs of natural and carbocyclic purines, pyrimidines and their nucleosides, antifolates, analogs of the ultimate alkylating agents derivable from cyclophosphamide, ifosfamide and trofosfamide, and chemically-reactive haloethylating agents. New agents will be evaluated for cytotoxicity in vitro against a panel of human solid tumors and leukemias and murine tumors, for biochemical effects against a series of enzymes involved in purine, pyrimidine, and nucleic acid metabolism, and for antiviral activity in vitro. Agents of interest will be evaluated in vivo against selected human tumor xenografts and murine tumors and against selected viruses 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 and viruses and also for pharmacologic disposition and metabolism and their solid tumor distribution characteristics. 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 structureactivity relationships and mechanisms of action. Specifically, five synthesis-biochemistry projects will provide new agents for biochemical and biological evaluations and investigations; a project on DNA primase will concentrate on this enzyme as a suitable target for cancer chemotherapy; another project will examine distribution of agents in a murine mammary tumor in vivo and correlation with tumor cell kill, and the core components will provide preparative-scale synthesis and analytical services, chemotherapy evaluations in vitro and in vivo, screening against a panel of enzymes involved in nucleic acid metabolism, pharmacologic evaluation, and antiviral evaluation in vitro and in vivo, resulting in a unified and interrelated program of drug development.
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