The objective of the proposed research is to understand 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 plan to elucidate the radiation biophysics of these short-range, high-LET particles and to use the information in studies of various radiobiologic effects and in experimental therapeutics. To this end, we propose to examine the microscopic distribution of damage in well-characterized and relatively simple systems (e.g. oligonucleotides, plasmids) in response to spatial positioning of the decaying nuclide and to changes in the surrounding environment. In addition, we will utilize individual cells as test systems for determining the quantitative relationships between microscopic dose and detrimental biologic effects by (i) exploring the molecular consequences of noncovalent DNA binding of Auger-electron emitting radiohalides as expressed by DNA strand breaks; and (ii) determining the radiotoxicity and mutagenic effects of the diagnostic radionuclides 99mTC and 111In when they are concentrated by cells and relating the results to the microscopic distribution of their conversion electrons. Studies will be repeated in the presence of radical scavengers to explore the role of hydroxyl radicals in these processes. In addition, we plan to continue our studies of cytotoxicity mutagenesis, and cellular transformation following the decay of the alpha particle emitters 211At and 212Bi when localized extra-cellularly, on plasma membranes, and intranuclearly. We will also exploit animal tumor models as pre-clinical systems for determining the utility of these agents in therapy and for establishing preliminary time-dose relationships. These models will include closed systems (brain, spinal cord, peritoneum) for the introduction of radiopharmaceuticals and one system accessible by differential perfusion (liver). Finally, in an attempt to extend the utility of radionuclide particle therapy, we plan to initiate combined modality experiments with photons plus alpha particle or Auger electron emitters.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA015523-25
Application #
2856183
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Stone, Helen B
Project Start
1977-05-01
Project End
2002-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
25
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Harvard University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
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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