It is recognized that there are many variables that can dictate biological response of tissues that contain radioactivity. Among the many variables are tissue radiosensitivity, distribution of radioactivity at the macroscopic and cellular levels, radiations emitted (e.g. alpha, beta, Auger electrons), and bystander effects. We have a limited understanding of how these variables correlate with biological effects that result from nonuniform distribution of radioactivity. There is mounting evidence that bystander effects play an important role in determining biological response. These are current issues of major importance to human health as it relates to diagnostic and therapeutic nuclear medicine. They have become increasingly urgent to resolve in light of the likelihood of radiological terrorism involving radioactive materials. Over the last several years we have been working toward correlating biological response of tissues containing radioactivity with cellular absorbed dose and variables relating to the bystander effect. We have made substantial progress during our first grant period, including the revelation of important insights into the phenomenology and mechanisms of bystander effects caused by intracellular radioactivity. Our progress will have considerable impact on our capacity to predict the biological effects of incorporated radioactivity. Indeed, our contributions are recognized in the ICRU report on dose specification in nuclear medicine. Our work has also raised important new questions regarding the prediction of response to nonuniform distributions of radioactivity that are addressed in the present proposal. Overall, we hypothesize that the biological response of tissues containing incorporated radionuclides can be correlated with cellular absorbed dose and variables relating to the bystander effect. We will test this hypothesis using a step-wise approach with models of increasing complexity. We will use our original three dimensional (3D) multicellular cluster model to resolve fundamental and significant questions related to the shape of survival dose response curves. Recognizing the limitations of our original model, we have devoted considerable effort toward transitioning our studies on multicellular dosimetry and bystander effects to a new in vitro Cytomatrix model that mimics normal human tissue in vivo. This new 3D model will be used to assess cell cycle alterations, DNA damage, and cell killing caused by nonuniform distributions of radioactivity in both tumor and normal human cell types. Complementing this new model will be development of a theoretical multicellular dosimetry model that blends 3D pCT imaging and stylized analytical models of the cell. This will enable us to test whether our multicellular dosimetry approaches can predict responses in this more complex system. Finally, to initiate transition of our multicellular dosimetry approach to in vivo, we will carry out bystander studies in mouse testis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083838-07
Application #
7258337
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Stone, Helen B
Project Start
2000-01-01
Project End
2010-05-31
Budget Start
2007-06-06
Budget End
2008-05-31
Support Year
7
Fiscal Year
2007
Total Cost
$241,794
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
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Gonon, Geraldine; Groetz, Jean-Emmanuel; de Toledo, Sonia M et al. (2013) Nontargeted stressful effects in normal human fibroblast cultures exposed to low fluences of high charge, high energy (HZE) particles: kinetics of biologic responses and significance of secondary radiations. Radiat Res 179:444-57
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Howell, Roger W; Rajon, Didier; Bolch, Wesley E (2012) Monte Carlo simulation of irradiation and killing in three-dimensional cell populations with lognormal cellular uptake of radioactivity. Int J Radiat Biol 88:115-22
Akudugu, John M; Howell, Roger W (2012) A method to predict response of cell populations to cocktails of chemotherapeutics and radiopharmaceuticals: validation with daunomycin, doxorubicin, and the alpha particle emitter (210)Po. Nucl Med Biol 39:954-61
Akudugu, John M; Howell, Roger W (2012) Flow cytometry-assisted Monte Carlo simulation predicts clonogenic survival of cell populations with lognormal distributions of radiopharmaceuticals and anticancer drugs. Int J Radiat Biol 88:286-93
Akudugu, John M; Azzam, Edouard I; Howell, Roger W (2012) Induction of lethal bystander effects in human breast cancer cell cultures by DNA-incorporated Iodine-125 depends on phenotype. Int J Radiat Biol 88:1028-38
Howell, Roger W (2011) Patient exposures and consequent risks from nuclear medicine procedures. Health Phys 100:313-7

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