This Program Project application combines the different expertise of four collaborating laboratories to perform research on the radiation sensitizing and bioreductive activity in cancer of novel compounds including bifunctional and other nitroheterocyclic agents, fused pyrazine mono-N- oxides and quinonoid analogs of mitomycin C. The four projects which comprise this application and their general objectives are: Project 1. Identification and Evaluation of Bioreductive Drugs. The broad aim of this project is to optimize the selection and development of novel bioreductive drugs that may be used as clinical radiation sensitizers and hypoxia-selective drugs for use in chemotherapy. Project 2. Microenvironments and Effectiveness of Bioreductive Drugs in Spheroids. Multicellular tumor spheroids of human and rodent cell lines will be used to assess structure-activity relationships for cytotoxicity and chemosensitization, and the role of cell microenvironments. Project 3. Efficacy and Mechanisms of Bioreductive Drugs as Chemosensitizing Agents. The central goal of this project is to determine the effectiveness and mechanisms of action of these bioreductive drugs as in vitro and in vivo hypoxic cell cytotoxins or chemopotentiating agents. Project 4. Mechanisms of Oncogenic Transformation by Bioreductive Drugs. The basic aim is to elucidate the mechanisms and factors that determine oncogenicity and provide input to identify the ideal physico-chemical properties of a bioreductive drug. Information provided by the experiments in these four projects will be integrated to guide the development of a new generation of bioreductive drugs for application in the treatment and diagnosis of cancer.
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