The objectives of this investigation are (1) to characterize the response of cells from normal and tumor tissue to ionizing radiation and/or selected chemotherapeutic agents as a function of therapeutic protocol and (2) to use chemical modifiers such as radioprotectors to elucidate the underlying mechanisms of action leading to the observed effects. This study will focus on maximizing therapeutic gain while minimizing the inductive effects of radiation on the processes of mutagenesis and carcinogenesis in normal tissues exposed during treatment. Both in vitro and in vivo cell systems will be used to assess the effectiveness of selected radioprotectors, which include 2-[(aminopropyl)amino] ethanethiol (WR1065) and [S-2-(3-aminopropylamino) ethyl phosphorothioic acid] (WR2721). Mutagenesis studies will be performed with V79 Chinese hamster cells by assaying for radiation and/or drug-induced mutations at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus as a function of radioprotector concentration and timing of administration. In vivo systems will include a neonatal Sprague Dawley rat system used to assess, in relatively short periods of time, the induction of preneoplastic lesions (altered hepatocyte foci) as a function of exposure to radiation, chemotherapy agents, and/or radioprotectors. Tumor systms to be used to assess therapeutic gain include a methylcholanthrene-induced fibrosarcoma (FSa), a spontaneously arisen fibrosarcoma (NFSA), and a spontaneously arisen mammary carcinoma (MCa-K). These tumors will be grown in both defined flora and conventionally maintained C3Hf/Sed mice. Time dose studies will be performed to assess therapeutic effectiveness with respect to both tumor control and induction of mutagenic and carcinogenic processes in non-neoplastic cell systems. DNA damage and repair will be measured through the techniques of alkaline and neutral elution. Where required, biophysical techniques such as centrifugal elutriation will be used to isolate unique cell populations for study. Through the integration of these systems it will be possible to evaluate the usefulness of chemical modifiers such as radioprotectors to not only improve therapeutic gain but also significantly reduce the associated risk of therapy-induced mutagenesis and carcinogenesis in exposed normal tissues.
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