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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Diagnostic Radiology Study Section (RNM)
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Harvard University
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Balagurumoorthy, Pichumani; Xu, Xiang; Wang, Ketai et al. (2012) Effect of distance between decaying (125)I and DNA on Auger-electron induced double-strand break yield. Int J Radiat Biol 88:998-1008
Mamlouk, Omar; Balagurumoorthy, Pichumani; Wang, Ketai et al. (2012) Bystander effect in tumor cells produced by Iodine-125 labeled human lymphocytes. Int J Radiat Biol 88:1019-27
Kassis, Amin I (2011) Molecular and cellular radiobiological effects of Auger emitting radionuclides. Radiat Prot Dosimetry 143:241-7
Balagurumoorthy, Pichumani; Adelstein, S James; Kassis, Amin I (2011) Novel method for quantifying radiation-induced single-strand-break yields in plasmid DNA highlights 10-fold discrepancy. Anal Biochem 417:242-6
Zhu, Xuping; Palmer, Matthew R; Makrigiorgos, G Mike et al. (2010) Solid-tumor radionuclide therapy dosimetry: new paradigms in view of tumor microenvironment and angiogenesis. Med Phys 37:2974-84
Singh, Amarjit; Yang, Yongliang; Adelstein, S James et al. (2008) Synthesis and application of molecular probe for detection of hydroxyl radicals produced by Na(125)I and gamma-rays in aqueous solution. Int J Radiat Biol 84:1001-10
Balagurumoorthy, Pichumani; Adelstein, S James; Kassis, Amin I (2008) Method to eliminate linear DNA from mixture containing nicked circular, supercoiled, and linear plasmid DNA. Anal Biochem 381:172-4
Balagurumoorthy, Pichumani; Chen, Kai; Adelstein, S James et al. (2008) Auger electron-induced double-strand breaks depend on DNA topology. Radiat Res 170:70-82
Kassis, Amin I (2008) Therapeutic radionuclides: biophysical and radiobiologic principles. Semin Nucl Med 38:358-66
Balagurumoorthy, Pichumani; Wang, Ketai; Adelstein, S James et al. (2008) DNA double-strand breaks induced by decay of (123)I-labeled Hoechst 33342: role of DNA topology. Int J Radiat Biol 84:976-83

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