Page 174 - 2014 Printable Abstract Book
P. 174
(PS2-66) Vitamin-E analog gamma tocotrienol (GT3) suppresses radiation-induced cytogenetic damage
1
1
2
in mice. Rupak Pathak, Ph.D ; Sanchita P. Ghosh, Ph.D ; and Martin Hauer-Jensen, Division of Radiation
1
Health, Little Rock, AR and Armed Forces Radiobiology Research Institute, Bethesda, MD
2
Radiation-induced numerical and/or structural abnormalities in chromosomes, i.e., cytogenetic
alterations, are known to associate with cancer, hematopoietic, gastrointestinal, neurological and
cardiovascular diseases. We reported that the vitamin-E analog gamma tocotrienol (GT3) protects mice
from lethal doses of ionizing radiation and also suppresses oxidative stress in irradiated endothelial cells.
The rationale of GT3-mediated radio-protection could be due to its antioxidant properties, ability to
induce G-CSF, and/or its ability to inhibit the enzyme hydroxy-methyl-glutaryl-coenzyme a reductase
(HMGCR), all of which are known to mitigate radiation toxicity. Moreover, we also found that GT3
regulates more genes compared to other vitamin E analogs and provides considerable protection to
hematopoietic stem and progenitor cells in irradiated mice. Considering all these beneficial effects, we
reasoned that GT3 pre-treatment could prevent radiation-induced cytogenetic damage. To prove our
hypothesis, C57BL/6 mice were exposed to γ-rays with or without GT3 pretreatment and cytogenetic
damage in metaphase spreads of bone marrow cells were scored at 24 hr and 30 days after radiation
exposure using conventional Giemsa staining, Fluorescence in situ Hybridization (FISH)-based
chromosome painting and spectral karyotyping (SKY) techniques. GT3 pre-treatment attenuated
radiation-induced chromosome aberrations. FISH painting reveals GT3 reduced aberrations involving
chromosome-1 and -2 in irradiated mice. Moreover, GT3 suppressed radiation-induced DNA double
strand breaks in endothelial cells as measured by the γH2AX assay. These data clearly indicate that GT3
plays critical role in modulating cytogenetic damage in irradiated cells and may be used in the
management of cytogenetic disorders caused by radiation exposure.
(PS2-67) Neupogen® supportive care in mouse and nonhuman primate irradiation models for
biodosimetry. Natalia Ossetrova, PhD; Patrick Ney; Katya Krasnopolsky; Donald Condliffe; David
Sandgren; Shilpa Kulkarni, PhD; Saule Nurmukhambetova; William Blakely, PhD; and Kevin Hieber
AFRRI/USUHS, Bethesda, MD
The potential radiation exposure of large numbers of individuals will require an accurate assessment of
radiation dose received in rapid and effective triage in order to provide better management of valuable
emergency resources. Successful administration of intensive supportive care and possible prompt
administration of myeloid cytokines is expected to shorten the duration of neutropenia in irradiated
individuals and promote faster recovery. We have succeeded in evaluating a panel of radiation-responsive
proteins in animal (Mus musculus, Macaca mulatta) total-body-irradiation (TBI) models that have been
applied, along with other biomarkers, in a multiparamer biodosimetry algorithm with a threshold for γ-
exposure detection of ~1 Gy from 1 to 7 d after exposure. Herein, we evaluate the efficacy of Neupogen®
supportive care by analyzing the hematological and serum protein profiles in mouse (B6D2F1 female) and
60
nonhuman primate (NHP, Macaca mulatta, male and female) models, total-body irradiated with Co γ-
rays at 0.6 Gy/min to doses of 6 - 14 Gy and 6.5 Gy, respectively. In mouse studies, animals received
Neupogen® (0.17 mg/kg) injections for three days starting at day 1 after TBI. Neupogen® had no consistent
effects on blood cell counts during the first 7 days following TBI. In addition, estimated survival rates for
Neupogen®-treated animals in our study were consistent with those reported for non-treated mice of the
same strain. Neupogen® appears to be limited as a supportive care agent in our murine model. In NHP
172 | P a g e
1
1
2
in mice. Rupak Pathak, Ph.D ; Sanchita P. Ghosh, Ph.D ; and Martin Hauer-Jensen, Division of Radiation
1
Health, Little Rock, AR and Armed Forces Radiobiology Research Institute, Bethesda, MD
2
Radiation-induced numerical and/or structural abnormalities in chromosomes, i.e., cytogenetic
alterations, are known to associate with cancer, hematopoietic, gastrointestinal, neurological and
cardiovascular diseases. We reported that the vitamin-E analog gamma tocotrienol (GT3) protects mice
from lethal doses of ionizing radiation and also suppresses oxidative stress in irradiated endothelial cells.
The rationale of GT3-mediated radio-protection could be due to its antioxidant properties, ability to
induce G-CSF, and/or its ability to inhibit the enzyme hydroxy-methyl-glutaryl-coenzyme a reductase
(HMGCR), all of which are known to mitigate radiation toxicity. Moreover, we also found that GT3
regulates more genes compared to other vitamin E analogs and provides considerable protection to
hematopoietic stem and progenitor cells in irradiated mice. Considering all these beneficial effects, we
reasoned that GT3 pre-treatment could prevent radiation-induced cytogenetic damage. To prove our
hypothesis, C57BL/6 mice were exposed to γ-rays with or without GT3 pretreatment and cytogenetic
damage in metaphase spreads of bone marrow cells were scored at 24 hr and 30 days after radiation
exposure using conventional Giemsa staining, Fluorescence in situ Hybridization (FISH)-based
chromosome painting and spectral karyotyping (SKY) techniques. GT3 pre-treatment attenuated
radiation-induced chromosome aberrations. FISH painting reveals GT3 reduced aberrations involving
chromosome-1 and -2 in irradiated mice. Moreover, GT3 suppressed radiation-induced DNA double
strand breaks in endothelial cells as measured by the γH2AX assay. These data clearly indicate that GT3
plays critical role in modulating cytogenetic damage in irradiated cells and may be used in the
management of cytogenetic disorders caused by radiation exposure.
(PS2-67) Neupogen® supportive care in mouse and nonhuman primate irradiation models for
biodosimetry. Natalia Ossetrova, PhD; Patrick Ney; Katya Krasnopolsky; Donald Condliffe; David
Sandgren; Shilpa Kulkarni, PhD; Saule Nurmukhambetova; William Blakely, PhD; and Kevin Hieber
AFRRI/USUHS, Bethesda, MD
The potential radiation exposure of large numbers of individuals will require an accurate assessment of
radiation dose received in rapid and effective triage in order to provide better management of valuable
emergency resources. Successful administration of intensive supportive care and possible prompt
administration of myeloid cytokines is expected to shorten the duration of neutropenia in irradiated
individuals and promote faster recovery. We have succeeded in evaluating a panel of radiation-responsive
proteins in animal (Mus musculus, Macaca mulatta) total-body-irradiation (TBI) models that have been
applied, along with other biomarkers, in a multiparamer biodosimetry algorithm with a threshold for γ-
exposure detection of ~1 Gy from 1 to 7 d after exposure. Herein, we evaluate the efficacy of Neupogen®
supportive care by analyzing the hematological and serum protein profiles in mouse (B6D2F1 female) and
60
nonhuman primate (NHP, Macaca mulatta, male and female) models, total-body irradiated with Co γ-
rays at 0.6 Gy/min to doses of 6 - 14 Gy and 6.5 Gy, respectively. In mouse studies, animals received
Neupogen® (0.17 mg/kg) injections for three days starting at day 1 after TBI. Neupogen® had no consistent
effects on blood cell counts during the first 7 days following TBI. In addition, estimated survival rates for
Neupogen®-treated animals in our study were consistent with those reported for non-treated mice of the
same strain. Neupogen® appears to be limited as a supportive care agent in our murine model. In NHP
172 | P a g e
