The objective of the proposed research is to elucidate the implications of densely ionizing radiations emitted by diagnostic and therapeutic radionuclides (Auger electrons and alpha particles) for both radiation protection and cancer therapy. We intend to explore mechanisms producing DNA damage in well-characterized simple systems (plasmids) and in higher order chromatin structures (mammalian cell nuclei) and assess the consequence of spatial positioning of the decaying nuclide (ascertained by computational modeling methods) as well as changes in the surrounding environment. We also plan to determine the quantitative relationships between microscopic dose and detrimental biologic effects by (i) associating radionuclide-decay-induced apoptosis with the physical decay characteristics of these radionuclides, their site of decay, cell type, and cell radiosensitivity; (ii) investigating the bystander effect in fn-vivo tumor models; (iii) assessing the mutagenic response to the decay of these radionuclides following cytoplasmic localization and examining whether this is a consequence of direct or indirect mechanisms; and (iv) determining doses that lead to alterations in gene expression and neoplastic transformation in normal mammalian cells. Finally, we will exploit an animal tumor model as a preclinical system for determining the utility of the thymidine analog 5-[12Sl]iodo-2'-deoxyuridine in cancer therapy.
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