Page 242 - 2014 Printable Abstract Book
P. 242
(PS4-13) Radiation-induced renal toxicity from 177Lu-octreotate: long term effects and biomarker
2
2
1
1
development. Emil Schueler ; Maria Larsson ; Toshima Z. Parris ; Khalil Helou ; and Eva Forssell-
1
1
Aronsson, University of Gothenburg, Dept of Radiation Physics, Gothenburg, Sweden and University of
2
Gothenburg, Dept of Oncology, Gothenburg, Sweden
The development of novel biomarkers for radiation-induced renal toxicity is of great importance
for optimization of radionuclide therapy. Due to the large inter-individual variations in absorbed dose to
the kidneys and possibly difference in sensitivity to renal toxicity, the use of an easily available marker of
early renal toxicity would greatly reduce the potential of renal tissue damage. The aim of this study was
to explore the transcriptional and functional effects on normal mouse kidneys after 177Lu-octreotate
administration, and to identify potential biomarkers for radiation-induced renal toxicity. Female
C57BL/6N mice received i.v. injections of 0, 30, 60, 90, 120, and 150 MBq of 177Lu-octreotate. The
radiation induced effects were studied at 4, 8, and 12 months after administration. The gene
transcriptional variations in kidney cortex and medulla were studied by expression array (Illumina
platform) and the renal function was investigated by 99mTc-DTPA and 99mTc-DMSA scintigraphy.
Both time and dose specific variations in transcriptional regulation were observed. The highest number
of differentially regulated transcripts was observed at 12 months after 177Lu-octreotate administration.
Several genes displayed distinct monotonous increased expression with absorbed dose, e.g. Cdkn1a, C3,
Dbp, and Per2. The recurrently regulated transcripts were primarily observed as up-stream regulators of
Ifng, Tnf, and Il1B. The evaluation of the functional effects following 177Lu-octreotate administration
revealed reduced excretion of 99mTc-DTPA after injection of 150 MBq 177Lu-octreotate and an increased
retention of 99mTc-DMSA in all treated mice compared with controls. The present study is a
comprehensive investigation of the toxicity following 177Lu-octreotate on renal tissue. Clear negative
effects on renal function were observed by both 99mTc-DTPA and 99mTc-DMSA scintigraphy.
Furthermore, potential useful biomarkers, e.g. Cdkn1a, Dbp, and Per2 were identified. The correlation
between the functional and transcriptional response, together with previously published gene expression
data on the early transcriptional effects, indicate the applicability of these proposed biomarkers as early
predictors of late renal injury.
(PS4-14) ATR inhibitor, VE-821 causes heavy ion-induced G2 cell cycle checkpoint abrogation and
2
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1
enhances radiation sensitivity. Hiroshi Fujisawa ; Nakako Izumi. Nakajima ; Hirokazu Hirakawa ; Hirohiko
2
1
2
2
1
Yajima ; Akira Fujimori ; Ryuichi Okayasu ; and Mitsuru Uesaka, The University of Tokyo, Tokyo, Japan
2
and National Institute of Radiological Sciences, Chiba, Japan
The use of ion particles for cancer therapy is increasing throughout the world. Especially, the
heavy charged particle therapy using carbon ions is successfully used for treatments of solid tumors. In
order to further improve this kind of treatment, the basic biological study on cellular responses to heavy
ions is inevitable. We previously reported that the complex DNA double strand breaks (DSBs) enhance
DNA end resection during the repair process. This result indicates that irradiated cells by carbon ions show
higher activity of ataxia telangiectasia mutated and Rad3-related (ATR) protein kinase which is recruited
to replication protein A (RPA)-coated single strand DNA. However, the relationship between carbon ion
irradiation and ATR kinase is still not known. The purpose of this study is to investigate the carbon ion
radio-sensitizing effect with ATR kinase inhibitor, VE-821. Human cervical carcinoma HeLa cells, human
osteosarcoma U2OS cells, and normal human fibroblasts immortalized with hTERT, 1BR-hTERT cells
240 | P a g e
2
2
1
1
development. Emil Schueler ; Maria Larsson ; Toshima Z. Parris ; Khalil Helou ; and Eva Forssell-
1
1
Aronsson, University of Gothenburg, Dept of Radiation Physics, Gothenburg, Sweden and University of
2
Gothenburg, Dept of Oncology, Gothenburg, Sweden
The development of novel biomarkers for radiation-induced renal toxicity is of great importance
for optimization of radionuclide therapy. Due to the large inter-individual variations in absorbed dose to
the kidneys and possibly difference in sensitivity to renal toxicity, the use of an easily available marker of
early renal toxicity would greatly reduce the potential of renal tissue damage. The aim of this study was
to explore the transcriptional and functional effects on normal mouse kidneys after 177Lu-octreotate
administration, and to identify potential biomarkers for radiation-induced renal toxicity. Female
C57BL/6N mice received i.v. injections of 0, 30, 60, 90, 120, and 150 MBq of 177Lu-octreotate. The
radiation induced effects were studied at 4, 8, and 12 months after administration. The gene
transcriptional variations in kidney cortex and medulla were studied by expression array (Illumina
platform) and the renal function was investigated by 99mTc-DTPA and 99mTc-DMSA scintigraphy.
Both time and dose specific variations in transcriptional regulation were observed. The highest number
of differentially regulated transcripts was observed at 12 months after 177Lu-octreotate administration.
Several genes displayed distinct monotonous increased expression with absorbed dose, e.g. Cdkn1a, C3,
Dbp, and Per2. The recurrently regulated transcripts were primarily observed as up-stream regulators of
Ifng, Tnf, and Il1B. The evaluation of the functional effects following 177Lu-octreotate administration
revealed reduced excretion of 99mTc-DTPA after injection of 150 MBq 177Lu-octreotate and an increased
retention of 99mTc-DMSA in all treated mice compared with controls. The present study is a
comprehensive investigation of the toxicity following 177Lu-octreotate on renal tissue. Clear negative
effects on renal function were observed by both 99mTc-DTPA and 99mTc-DMSA scintigraphy.
Furthermore, potential useful biomarkers, e.g. Cdkn1a, Dbp, and Per2 were identified. The correlation
between the functional and transcriptional response, together with previously published gene expression
data on the early transcriptional effects, indicate the applicability of these proposed biomarkers as early
predictors of late renal injury.
(PS4-14) ATR inhibitor, VE-821 causes heavy ion-induced G2 cell cycle checkpoint abrogation and
2
2
1
enhances radiation sensitivity. Hiroshi Fujisawa ; Nakako Izumi. Nakajima ; Hirokazu Hirakawa ; Hirohiko
2
1
2
2
1
Yajima ; Akira Fujimori ; Ryuichi Okayasu ; and Mitsuru Uesaka, The University of Tokyo, Tokyo, Japan
2
and National Institute of Radiological Sciences, Chiba, Japan
The use of ion particles for cancer therapy is increasing throughout the world. Especially, the
heavy charged particle therapy using carbon ions is successfully used for treatments of solid tumors. In
order to further improve this kind of treatment, the basic biological study on cellular responses to heavy
ions is inevitable. We previously reported that the complex DNA double strand breaks (DSBs) enhance
DNA end resection during the repair process. This result indicates that irradiated cells by carbon ions show
higher activity of ataxia telangiectasia mutated and Rad3-related (ATR) protein kinase which is recruited
to replication protein A (RPA)-coated single strand DNA. However, the relationship between carbon ion
irradiation and ATR kinase is still not known. The purpose of this study is to investigate the carbon ion
radio-sensitizing effect with ATR kinase inhibitor, VE-821. Human cervical carcinoma HeLa cells, human
osteosarcoma U2OS cells, and normal human fibroblasts immortalized with hTERT, 1BR-hTERT cells
240 | P a g e
