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 process of mutagenesis 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 both repair- proficient (K1, AA8) and repair-deficient (xrs-5, EM9) CHO cell lines, as well as with a human lymphoblastoid cell line designated L33, by assaying for radiation and/or drug-induced mutations at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus as a function of radioprotector chemicals on these processes will also be determined. Tumor systems 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. DNA damage and repair will be measured through the 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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