The objective of the proposed research is to elucidate the relationships between the intracellular localization of Auger- electron-emitting radionuclides and the biological consequences of the resulting microdistribution of energy. This knowledge will be used to pursue the therapeutic implications of the Auger effect and to determine the potential toxicity of Auger and conversion- electron emitters commonly used in nuclear medicine. To this end, we propose: I. To determine the quantitative relationships between the microscopic distribution of dose (nuclear, cytoplasmic, or plasma- membrane-bound) and the detrimental biological effects (radiotoxicity, malignant transformation, mutagenesis, and molecular consequences on DNA) of several agents bearing 125I, 123I, 77Br, 99mTc, or 111In. II. To explore the spatial relationships between the site of the Auger decay and the DNA target that affect the degree of radiotoxicity. These experiments will make use of DNA- intercalating agents whose spatial arrangement will position the Auger emitter at various distances from the DNA core. III. To test the radiotherapeutic efficacy of 123/125I/77Br labeled pyrimidine nucleosides and DNA intercalators in a mouse ovarian tumor model and to optimize the conditions for using radiohalogenated pyrimidine deoxynucleosides as therapeutic agents in experimental cancer therapy. A further objective will continue to examine the use of alpha- particle-emitting radionuclides in cancer therapy. Working with the alpha emitters astatine-211 and bismuth-212, we will a) compare their relative toxicities when localized on cell surfaces, in the cytoplasm, and in the nucleus, and b) extend our exploration of the use of 211AT-colloid-bearing macrophages for the treatment of an intraperitoneal tumor. Finally the use of combined therapeutic modalities such as x-rays plus alpha or Auger emitters will be explored.
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