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Renal Atrophy Secondary to Radiation Treatment of Abdominal Malignancies
I. J. Radiation Oncology d Biology d Physics
S84
Volume 72, Number 1, Supplement, 2008
evidenced clinically by improved cognitive preservation and histologically by decreased apoptosis. To better elucidate the mechanism of these radiation effects, here we depict lithium’s effects on two major DNA chromosomal double strand break (DSB) repair pathways: non homologous end joining (NHEJ), and homologous recombination (HR). In the study herein, we measure NHEJ and HR in normal hippocampal neurons and glioma cells. Additionally, we test whether lithium neuroprotection is affected by DNAPK inhibitors, which have been proposed for clinical radiosensitization of cancer. Materials/Methods: Cell populations included murine hippocampal neurons, HT-22 hippocampal cells, and GL261 glioma cells. Prior to radiation, cells were treated with ± lithium prophylaxis and ± DNA-PK inhibition (IC86621 and DMNB). Immunohistochemistry was performed to quantify DSB (g-H2AX), NHEJ (T2609), and HR (Rad51). NHEJ activity was also measured in vivo in mice using a plasmid-based end-joining assay facilitated by a GFP reporter. Apoptosis was assessed by quantifying cleaved caspase 3 and DNA condensation. Results: Lithium treatment of hippocampal neurons and HT-22 hippocampal cells prior to radiation resulted in reduced DNA DSB and increased NHEJ repair. NHEJ was concordantly increased in vivo in irradiated mice. Conversely, in GL261 glioma cells, lithium pre-treatment had no effect on radiation susceptibility to DNA DSB or NHEJ repair. Notably, lithium had negligible effects on HR repair in both hippocampal and glioma cell populations. DNA-PK inhibitors effected complete abrogation of lithium-induced NHEJ repair in hippocampal neurons and HT-22 hippocampal cells. DNA-PK inhibition had no effect on DNA repair in GL261 glioma cells. Conclusions: These results demonstrate lithium’s radioprotective effects on hippocampal neurons by a mechanistic increase in DNA DSB repair, through NHEJ repair but not HR. Importantly, these DNA repair effects are conferred on normal hippocampal neurons but not glioma cells. DNA-PK inhibitors, which are known to inhibit the NHEJ pathway, appear to reverse the radioprotective effects of lithium on hippocampal neurons. These investigations warrant future pre-clinical and clinical investigations of lithium neuronal radioprotection. Additionally, the use of DNA-PK inhibitors as cancer radiosensitizers must be further studied to determine whether these agents may adversely offset the potential clinical benefits of lithium neuroprotection. Author Disclosure: K.J. Niermann, None; E.S. Yang, None; H. Wang, None; G. Jiang, None; D.E. Hallahan, None; F. Xia, None.
RADIATION RESEARCH SOCIETY ABSTRACT
185
Renal Atrophy Secondary to Radiation Treatment of Abdominal Malignancies
Susan A. McCloskey1, Gary Y. Yang1, Leayn Flaherty1, Rameela Chandrasekhar1, Gregory Wilding1, Kilian Salerno May1, Rachel Hackett1, Gail M. Thompson1, Jorge A. Gomez1, Charles R. Thomas, Jr.,2 1
Roswell Park Cancer Institute, Buffalo, NY, 2Oregon Health and Science University, Portland, OR
RADIATION RESEARCH SOCIETY ABSTRACT
186
Differential Alterations in Infiltrated Lung Inflammatory Cells and the Effect of Different Agents on Radiation Pneumonitis
Lei Zhang, Liangjie Yin, Mei Zhang, Shanmin Yang, Yeping Tian, Yongbing Cao, Kunzhong Zhang, Steven Swarts, Bruce Fenton, Paul Okunieff, Lurong Zhang Department of Radiation Oncology, Rochester, NY
RADIATION RESEARCH SOCIETY ABSTRACT
187
Risk of Radiation-related Second Salivary Gland Carcinomas among Hodgkin Lymphoma Survivors: A Population-based Analysis
Houda Boukheris1, Rochelle E. Curtis1, Graca M. Dores2, Marilyn Stovall3, Susan A. Smith4, Elaine Ron5 1 Radiation Epidemiology Branch, Div. of Cancer Epidemiology and Genetics. NCI, NIH, Bethesda, Maryland, 2Medical Service, Dept. of Veterans Affairs Medical Center, Oklahoma City, OK, and Division of Cancer Epidemiology and Genetics National Cancer Institute, NIH, Bethesda, Maryland, 3Dept. of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 4Dept. of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 5 Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics NCI, NIH, Bethesda, Maryland
188
A Novel Technique for Predicting which Head and Neck Patients will Require Adaptive Therapy
C. E. Harris1, A. Uysnin1, B. Robison1, R. Seibert2, M. Neeley2, J. Danzer2, C. Ramsey1 1 Thomspon Cancer Survival Center, Knoxville, TN, 2University of Tennessee, Knoxville, TN Purpose/Objective(s): With the advent of CT-based Image-Guided Radiation Therapy (IGRT), it is now possible to actively measure the response of the tumor and normal tissues during the course of therapy. For Head & Neck (H&N) patients, there is often a strong clinical desire to adapt the treatment plan to compensate for these changes. Unfortunately, the clinical reality is that it is difficult to evaluate which H&N patients could benefit from adaptive radiation therapy (ART). The primary objective of this study was to develop a novel technique for automatically predicting early in the course of treatment which H&N patients will require adaptive therapy. Materials/Methods: Megavoltage CT (MVCT) images were acquired prior to the delivery of treatment for 43 H&N patients. Each patient was evaluated for tumor response, weight loss, and anatomical changes over the course of treatment using these images. Anatomical changes were evaluated for each fraction both visually and quantitatively. Between 15 and 25 cross-sectional
S84
Volume 72, Number 1, Supplement, 2008
evidenced clinically by improved cognitive preservation and histologically by decreased apoptosis. To better elucidate the mechanism of these radiation effects, here we depict lithium’s effects on two major DNA chromosomal double strand break (DSB) repair pathways: non homologous end joining (NHEJ), and homologous recombination (HR). In the study herein, we measure NHEJ and HR in normal hippocampal neurons and glioma cells. Additionally, we test whether lithium neuroprotection is affected by DNAPK inhibitors, which have been proposed for clinical radiosensitization of cancer. Materials/Methods: Cell populations included murine hippocampal neurons, HT-22 hippocampal cells, and GL261 glioma cells. Prior to radiation, cells were treated with ± lithium prophylaxis and ± DNA-PK inhibition (IC86621 and DMNB). Immunohistochemistry was performed to quantify DSB (g-H2AX), NHEJ (T2609), and HR (Rad51). NHEJ activity was also measured in vivo in mice using a plasmid-based end-joining assay facilitated by a GFP reporter. Apoptosis was assessed by quantifying cleaved caspase 3 and DNA condensation. Results: Lithium treatment of hippocampal neurons and HT-22 hippocampal cells prior to radiation resulted in reduced DNA DSB and increased NHEJ repair. NHEJ was concordantly increased in vivo in irradiated mice. Conversely, in GL261 glioma cells, lithium pre-treatment had no effect on radiation susceptibility to DNA DSB or NHEJ repair. Notably, lithium had negligible effects on HR repair in both hippocampal and glioma cell populations. DNA-PK inhibitors effected complete abrogation of lithium-induced NHEJ repair in hippocampal neurons and HT-22 hippocampal cells. DNA-PK inhibition had no effect on DNA repair in GL261 glioma cells. Conclusions: These results demonstrate lithium’s radioprotective effects on hippocampal neurons by a mechanistic increase in DNA DSB repair, through NHEJ repair but not HR. Importantly, these DNA repair effects are conferred on normal hippocampal neurons but not glioma cells. DNA-PK inhibitors, which are known to inhibit the NHEJ pathway, appear to reverse the radioprotective effects of lithium on hippocampal neurons. These investigations warrant future pre-clinical and clinical investigations of lithium neuronal radioprotection. Additionally, the use of DNA-PK inhibitors as cancer radiosensitizers must be further studied to determine whether these agents may adversely offset the potential clinical benefits of lithium neuroprotection. Author Disclosure: K.J. Niermann, None; E.S. Yang, None; H. Wang, None; G. Jiang, None; D.E. Hallahan, None; F. Xia, None.
RADIATION RESEARCH SOCIETY ABSTRACT
185
Renal Atrophy Secondary to Radiation Treatment of Abdominal Malignancies
Susan A. McCloskey1, Gary Y. Yang1, Leayn Flaherty1, Rameela Chandrasekhar1, Gregory Wilding1, Kilian Salerno May1, Rachel Hackett1, Gail M. Thompson1, Jorge A. Gomez1, Charles R. Thomas, Jr.,2 1
Roswell Park Cancer Institute, Buffalo, NY, 2Oregon Health and Science University, Portland, OR
RADIATION RESEARCH SOCIETY ABSTRACT
186
Differential Alterations in Infiltrated Lung Inflammatory Cells and the Effect of Different Agents on Radiation Pneumonitis
Lei Zhang, Liangjie Yin, Mei Zhang, Shanmin Yang, Yeping Tian, Yongbing Cao, Kunzhong Zhang, Steven Swarts, Bruce Fenton, Paul Okunieff, Lurong Zhang Department of Radiation Oncology, Rochester, NY
RADIATION RESEARCH SOCIETY ABSTRACT
187
Risk of Radiation-related Second Salivary Gland Carcinomas among Hodgkin Lymphoma Survivors: A Population-based Analysis
Houda Boukheris1, Rochelle E. Curtis1, Graca M. Dores2, Marilyn Stovall3, Susan A. Smith4, Elaine Ron5 1 Radiation Epidemiology Branch, Div. of Cancer Epidemiology and Genetics. NCI, NIH, Bethesda, Maryland, 2Medical Service, Dept. of Veterans Affairs Medical Center, Oklahoma City, OK, and Division of Cancer Epidemiology and Genetics National Cancer Institute, NIH, Bethesda, Maryland, 3Dept. of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 4Dept. of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 5 Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics NCI, NIH, Bethesda, Maryland
188
A Novel Technique for Predicting which Head and Neck Patients will Require Adaptive Therapy
C. E. Harris1, A. Uysnin1, B. Robison1, R. Seibert2, M. Neeley2, J. Danzer2, C. Ramsey1 1 Thomspon Cancer Survival Center, Knoxville, TN, 2University of Tennessee, Knoxville, TN Purpose/Objective(s): With the advent of CT-based Image-Guided Radiation Therapy (IGRT), it is now possible to actively measure the response of the tumor and normal tissues during the course of therapy. For Head & Neck (H&N) patients, there is often a strong clinical desire to adapt the treatment plan to compensate for these changes. Unfortunately, the clinical reality is that it is difficult to evaluate which H&N patients could benefit from adaptive radiation therapy (ART). The primary objective of this study was to develop a novel technique for automatically predicting early in the course of treatment which H&N patients will require adaptive therapy. Materials/Methods: Megavoltage CT (MVCT) images were acquired prior to the delivery of treatment for 43 H&N patients. Each patient was evaluated for tumor response, weight loss, and anatomical changes over the course of treatment using these images. Anatomical changes were evaluated for each fraction both visually and quantitatively. Between 15 and 25 cross-sectional