Page 347 - 2014 Printable Abstract Book
P. 347
irradiated bilaterally using gamma irradiation (total body, Co-60, 0.6 Gy/min) in the dose range 5-12 Gy.
Following exposure, the animals were evaluated for up to 10 days through observation of clinical signs,
CBC counts and parameters associated with the development of the GI syndrome (including vomiting,
diarrhea, bacteria translocation, loss of crypts, shortening of villi, and decline in plasma citrulline).
Results and conclusion: A dose-dependent occurrence of all classical parameters associated with acute
GI-ARS occurs in the Gottingen minipig exposed to gamma radiation in the dose range between 5 and 12
Gy. These results suggest the Gottengen minipig may a suitable model to study GI-ARS. Knowledge of the
natural history as well as a determination of reliable endpoints for the different ARS sequelae, is required
for drug testing. This study is the first step toward determining such requirements and towards evaluating
the feasibility of using the Gottingen minipig for drug efficacy testing to treat the GI-ARS. Additional
studies are necessary to bracket radiation doses causing the GI syndrome in this model and to confirm
validity of endpoints for euthanasia. The views expressed here do not necessarily represent the Armed
Forces Radiobiology Research Institute, the Uniformed Services University of the Health Sciences, or the
Department of Defense.
(PS6-39) The role of necroptosis in the acute radiation syndrome. Katherine D. Castle; Everett J. Moding;
and David G. Kirsch, Duke University, Durham, NC
Exposure to ionizing radiation can cause lethal injury to normal tissue, resulting in acute radiation
toxicity. The symptoms associated with radiation toxicity include depletion of bone marrow cells
(hematopoietic syndrome) and irreparable damage of the epithelial cells in the gastrointestinal tract (GI
syndrome). Although the development of effective medical countermeasures requires an enhanced
understanding of the pathways regulating radiation injury, the mechanisms of cell death in the bone
marrow and GI epithelial cells after high doses of radiation are not completely understood. Necroptosis,
a type of programmed necrosis, has recently emerged as a novel mechanism of cell death that requires
the kinase activity of RIP3. In order to test whether necroptotic cell death contributes to the normal tissue
toxicity observed following irradiation, we exposed RIP3 null mice to either total body (TBI) or sub-total
body irradiation (SBI) to induce the hematopoietic and GI syndrome respectively. Our preliminary
experiments suggest that RIP3-mediated necroptosis does not contribute to the acute radiation
syndrome. Additional experiments to elucidate the role of necroptosis in normal tissue response to
radiation are ongoing.
(PS6-40) Acute hematopoietic syndrome in male rhesus macaque exposed to total-body irradiation.
1
2
2
1
Ruschelle Love, MS ; Norbert Makori, PhD ; Kyle C. O'Donnell, BS ; Ann M. Farese, MS ; Thomas J.
1
2
1
1
1
MacVittie, PhD ; Steve Glaza, BS ; Ronald Manning, PhD ; Thomas Beck, PhD ; Koichiro Fukuzaki, PhD ;
3
1
and Ryoichi Nagata, MD, PhD ; SNBL USA, Everett, WA ; University of Maryland, School of Medicine,
3
Baltimore, MD ; and Shin Nippon Biomedical Laboratories, Ltd., Kagoshima, Japan
2
To establish a dose response relationship (DRR) that defines LD50/60 and characterizes medical
management for a nonhuman primate total body irradiation (TBI) model of the acute hematopoietic
radiation syndrome (Animal Rule, 21CFR314, subpart 1). Forty-eight male rhesus monkeys (4 - 8 kg) were
randomized into six groups (n=8) in a blinded study and exposed to bilateral 6 MV linear accelerator
-1
photon radiation (Varian 600 C/D LINAC) at 0.80 Gy min , dose range 6.25 - 8.75 Gy. Animals were
345 | P a g e
Following exposure, the animals were evaluated for up to 10 days through observation of clinical signs,
CBC counts and parameters associated with the development of the GI syndrome (including vomiting,
diarrhea, bacteria translocation, loss of crypts, shortening of villi, and decline in plasma citrulline).
Results and conclusion: A dose-dependent occurrence of all classical parameters associated with acute
GI-ARS occurs in the Gottingen minipig exposed to gamma radiation in the dose range between 5 and 12
Gy. These results suggest the Gottengen minipig may a suitable model to study GI-ARS. Knowledge of the
natural history as well as a determination of reliable endpoints for the different ARS sequelae, is required
for drug testing. This study is the first step toward determining such requirements and towards evaluating
the feasibility of using the Gottingen minipig for drug efficacy testing to treat the GI-ARS. Additional
studies are necessary to bracket radiation doses causing the GI syndrome in this model and to confirm
validity of endpoints for euthanasia. The views expressed here do not necessarily represent the Armed
Forces Radiobiology Research Institute, the Uniformed Services University of the Health Sciences, or the
Department of Defense.
(PS6-39) The role of necroptosis in the acute radiation syndrome. Katherine D. Castle; Everett J. Moding;
and David G. Kirsch, Duke University, Durham, NC
Exposure to ionizing radiation can cause lethal injury to normal tissue, resulting in acute radiation
toxicity. The symptoms associated with radiation toxicity include depletion of bone marrow cells
(hematopoietic syndrome) and irreparable damage of the epithelial cells in the gastrointestinal tract (GI
syndrome). Although the development of effective medical countermeasures requires an enhanced
understanding of the pathways regulating radiation injury, the mechanisms of cell death in the bone
marrow and GI epithelial cells after high doses of radiation are not completely understood. Necroptosis,
a type of programmed necrosis, has recently emerged as a novel mechanism of cell death that requires
the kinase activity of RIP3. In order to test whether necroptotic cell death contributes to the normal tissue
toxicity observed following irradiation, we exposed RIP3 null mice to either total body (TBI) or sub-total
body irradiation (SBI) to induce the hematopoietic and GI syndrome respectively. Our preliminary
experiments suggest that RIP3-mediated necroptosis does not contribute to the acute radiation
syndrome. Additional experiments to elucidate the role of necroptosis in normal tissue response to
radiation are ongoing.
(PS6-40) Acute hematopoietic syndrome in male rhesus macaque exposed to total-body irradiation.
1
2
2
1
Ruschelle Love, MS ; Norbert Makori, PhD ; Kyle C. O'Donnell, BS ; Ann M. Farese, MS ; Thomas J.
1
2
1
1
1
MacVittie, PhD ; Steve Glaza, BS ; Ronald Manning, PhD ; Thomas Beck, PhD ; Koichiro Fukuzaki, PhD ;
3
1
and Ryoichi Nagata, MD, PhD ; SNBL USA, Everett, WA ; University of Maryland, School of Medicine,
3
Baltimore, MD ; and Shin Nippon Biomedical Laboratories, Ltd., Kagoshima, Japan
2
To establish a dose response relationship (DRR) that defines LD50/60 and characterizes medical
management for a nonhuman primate total body irradiation (TBI) model of the acute hematopoietic
radiation syndrome (Animal Rule, 21CFR314, subpart 1). Forty-eight male rhesus monkeys (4 - 8 kg) were
randomized into six groups (n=8) in a blinded study and exposed to bilateral 6 MV linear accelerator
-1
photon radiation (Varian 600 C/D LINAC) at 0.80 Gy min , dose range 6.25 - 8.75 Gy. Animals were
345 | P a g e
