Page 176 - 2014 Printable Abstract Book
P. 176
the timing when the diets are changed in relation to time of irradiation. Aim: To test effects of different
diets and their timing on the late effects of radiation injury to the lung and kidney. Methods: Male and
female WAG/RijCmcr rats (8-10 weeks old) were placed on a low antioxidant diet (modified AIN-76A) two
weeks prior to irradiation to test the effects of irradiation on an animal with low antioxidant status. Next
we placed rats on the same diet 1 week after irradiation to test the effects of low antioxidant status on
the progression of radiation induced lung and renal damage. These groups were tested against our base
diet, Teklad 8904. Total body irradiation (TBI) with bone marrow transplant or TBI with a leg shield model
were used for these experiments. Lastly, we switched the protein in the modified AIN-76A diet from casein
to soy to study the effect of different protein sources. The rats were followed for 120 days. Body weight,
survival and renal function were monitored. Results: The results show that the modified AIN-76A diet low
in antioxidants exacerbates morbidity during pneumonitis and radiation nephropathy when started 2
weeks prior to irradiation compared to the Teklad 8904 diet. But AIN-76A started 1 week after irradiation
mitigates radiation pneumonitis and nephropathy. Switching the protein source in the modified AIN-76A
diet in a mitigation regimen did not diminish its beneficial effect. Conclusion: Dietary changes play a major
role in late developing experimental radiation injuries. The timing of these changes can alter the outcome
of radiation-pneumonitis and nephropathy in rats. Funding: Supported in part by NIH/NIAID Contract
AI067734, NCI R01-CA103180 and the Department of Radiation Oncology at the Medical College of
Wisconsin.
(PS2-70) Development of lisinopril for mitigation of late effects from radiation exposure. Jayashree
1;2
1;2
1
1
1
Narayanan, MS ; Feng Gao, MD ; Marylou Mader ; Elizabeth R. Jacobs, MD, MBA ; Eric P. Cohen, MD ;
1
1
John E. Moulder, PhD ; Brian L. Fish, BS ; and Meetha Medhora, PhD, 1;2 Medical College of Wisconsin,
1
2
Wauwatosa, WI and Zablocki VAMC, Milwaukee, WI
Introduction: We have developed a partial body irradiation model (PBI) in rats to test mitigators
for late effects (up to 150 days), including toxicities to the lungs and kidneys. In this model we used 12.5
Gy to avoid lethal gastrointestinal (GI) toxicity and shielded one leg of the rat to enable autologous bone
marrow reconstitution. We have also identified the angiotensin converting enzyme (ACE) inhibitor
lisinopril as able to improve survival after irradiation, i.e. lisinopril mitigates morbidity requiring
euthanization as directed by the IACUC. Goal: To further develop lisinopril as a countermeasure for late
effects of radiation by testing compatibility with G-CSF and enrofloxacin, reagents for supportive care.
Methods: Rats (female WAG/RijCmcr at 12 weeks of age) were randomized into 6 groups: (i) no irradiation
2
(n=8) (ii) 12.5 Gy PBI (n=10) (iii) 12.5 Gy PBI+lisinopril (7 days-end, 24 mg/m /day , n=10) (iv) Group
iii+enrofloxacin (enro, 2-28 days, 10 mg/kg/day, n=9) (v) Group iii+G-CSF (1-14 days 100 mg/kg/day, n=9)
(vi) Group iii+enro+G-CSF (n=10). Survival was examined by the Peto-Peto Wilcoxon test while breathing
rates and blood urea nitrogen (BUN) were measured up to 150 days. Results: Survival in all groups of
drug-treated rats was greater than that of rats receiving 12.5 Gy PBI alone (group ii). While 10/10 rats
were morbid in Group ii by 150 days, only 2 rats were morbid from combined groups (iii-vi). Breathing
rates were increased at 56 days after 12.5 Gy PBI alone (group ii) and this effect was not observed or
delayed in group iii-vi. The BUN in group ii but not any other group was different from group iii (12.5 Gy
PBI+lisinopril). Conclusions: Two reagents used for supportive care, G-CSF and enrofloxacin, did not
interfere with the ability of lisinopril to improve long-term survival after 12.5 Gy PBI. Grant: NIAID
1U01AI107305-01 and 1R01AI101898-01.
174 | P a g e
diets and their timing on the late effects of radiation injury to the lung and kidney. Methods: Male and
female WAG/RijCmcr rats (8-10 weeks old) were placed on a low antioxidant diet (modified AIN-76A) two
weeks prior to irradiation to test the effects of irradiation on an animal with low antioxidant status. Next
we placed rats on the same diet 1 week after irradiation to test the effects of low antioxidant status on
the progression of radiation induced lung and renal damage. These groups were tested against our base
diet, Teklad 8904. Total body irradiation (TBI) with bone marrow transplant or TBI with a leg shield model
were used for these experiments. Lastly, we switched the protein in the modified AIN-76A diet from casein
to soy to study the effect of different protein sources. The rats were followed for 120 days. Body weight,
survival and renal function were monitored. Results: The results show that the modified AIN-76A diet low
in antioxidants exacerbates morbidity during pneumonitis and radiation nephropathy when started 2
weeks prior to irradiation compared to the Teklad 8904 diet. But AIN-76A started 1 week after irradiation
mitigates radiation pneumonitis and nephropathy. Switching the protein source in the modified AIN-76A
diet in a mitigation regimen did not diminish its beneficial effect. Conclusion: Dietary changes play a major
role in late developing experimental radiation injuries. The timing of these changes can alter the outcome
of radiation-pneumonitis and nephropathy in rats. Funding: Supported in part by NIH/NIAID Contract
AI067734, NCI R01-CA103180 and the Department of Radiation Oncology at the Medical College of
Wisconsin.
(PS2-70) Development of lisinopril for mitigation of late effects from radiation exposure. Jayashree
1;2
1;2
1
1
1
Narayanan, MS ; Feng Gao, MD ; Marylou Mader ; Elizabeth R. Jacobs, MD, MBA ; Eric P. Cohen, MD ;
1
1
John E. Moulder, PhD ; Brian L. Fish, BS ; and Meetha Medhora, PhD, 1;2 Medical College of Wisconsin,
1
2
Wauwatosa, WI and Zablocki VAMC, Milwaukee, WI
Introduction: We have developed a partial body irradiation model (PBI) in rats to test mitigators
for late effects (up to 150 days), including toxicities to the lungs and kidneys. In this model we used 12.5
Gy to avoid lethal gastrointestinal (GI) toxicity and shielded one leg of the rat to enable autologous bone
marrow reconstitution. We have also identified the angiotensin converting enzyme (ACE) inhibitor
lisinopril as able to improve survival after irradiation, i.e. lisinopril mitigates morbidity requiring
euthanization as directed by the IACUC. Goal: To further develop lisinopril as a countermeasure for late
effects of radiation by testing compatibility with G-CSF and enrofloxacin, reagents for supportive care.
Methods: Rats (female WAG/RijCmcr at 12 weeks of age) were randomized into 6 groups: (i) no irradiation
2
(n=8) (ii) 12.5 Gy PBI (n=10) (iii) 12.5 Gy PBI+lisinopril (7 days-end, 24 mg/m /day , n=10) (iv) Group
iii+enrofloxacin (enro, 2-28 days, 10 mg/kg/day, n=9) (v) Group iii+G-CSF (1-14 days 100 mg/kg/day, n=9)
(vi) Group iii+enro+G-CSF (n=10). Survival was examined by the Peto-Peto Wilcoxon test while breathing
rates and blood urea nitrogen (BUN) were measured up to 150 days. Results: Survival in all groups of
drug-treated rats was greater than that of rats receiving 12.5 Gy PBI alone (group ii). While 10/10 rats
were morbid in Group ii by 150 days, only 2 rats were morbid from combined groups (iii-vi). Breathing
rates were increased at 56 days after 12.5 Gy PBI alone (group ii) and this effect was not observed or
delayed in group iii-vi. The BUN in group ii but not any other group was different from group iii (12.5 Gy
PBI+lisinopril). Conclusions: Two reagents used for supportive care, G-CSF and enrofloxacin, did not
interfere with the ability of lisinopril to improve long-term survival after 12.5 Gy PBI. Grant: NIAID
1U01AI107305-01 and 1R01AI101898-01.
174 | P a g e
