Potential Biomarkers for Radiation-Induced Renal Toxicity following 177Lu-Octreotate Administration in Mice.
The kidneys are one of the main dose-limiting organs in peptide receptor radionuclide therapy and due to large inter-individual variations in renal toxicity, biomarkers are urgently needed in order to optimize therapy and reduce renal tissue damage. The aim of this study was to investigate the transcriptional, functional, and morphological effects on renal tissue after 177Lu-octreotate administration in normal mice, and to identify biomarkers for radiation induced renal toxicity.


METHODS
C57BL/6N mice were i.v. injected with 0, 30, 60, 90, 120, or 150 MBq 177Lu-octreotate (0, 16, 29, 40, 48, and 54 Gy to the kidneys). At 4, 8, and 12 months after administration, radiation-induced effects were evaluated in relation to (a) global transcriptional variations in kidney tissues, (b) morphological changes in the kidneys, (c) changes in white and red blood cell count as well as blood levels of urea, and (d) changes in renal function using 99mTc-DTPA/99mTc-DMSA scintigraphy.


RESULTS
In general, the highest number of differentially regulated transcripts was observed at 12 months after administration. The Cdkn1a, C3, Dbp, Lcn2, and Per2 genes displayed a distinct dose-dependent regulation, with increased expression level with increasing absorbed dose. Ifng, Tnf, and Il1B were identified as primary up-stream regulators of the recurrently regulated transcripts. Furthermore, previously proposed biomarkers for kidney injury and radiation damage were also observed. The functional investigation revealed reduced excretion of 99mTc-DTPA after 150 MBq, an increased uptake of 99mTc-DMSA at all dose levels compared with the controls, and markedly increased urea level in blood after 150 MBq at 12 months.


CONCLUSIONS
Distinct dose-response relationships were found for several of the regulated transcripts. The Cdkn1a, Dbp, Lcn2, and Per2 genes are proposed as biomarkers for 177Lu-octreotate exposure of kidney. Correlations to functional and morphological effects further confirm applicability of these genes as markers of radiation damage in kidney tissue.
Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
Emil
E
Schüler
Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
Maria
M
Larsson
Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
Toshima Z
TZ
Parris
Department of Laboratory Medicine, Lund University, SUS Malmö, Malmö, Sweden.
Martin E
ME
Johansson
Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
Khalil
K
Helou
Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Medical Physics and Medical Bioengineering, Sahlgrenska University Hospital, Gothenburg, Sweden.
Eva
E
Forssell-Aronsson
D000209:Acute-Phase Proteins / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D015870:Gene Expression / Q000528:radiation effects; D007668:Kidney / Q000293:injuries / Q000378:metabolism* / Q000528:radiation effects*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics; D008187:Lutetium / Q000008:administration & dosage / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D015282:Octreotide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D015513:Oncogene Proteins / Q000235:genetics; D056950:Period Circadian Proteins / Q000235:genetics; D011833:Radiation Injuries, Experimental / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D011868:Radioisotopes / Q000008:administration & dosage / Q000009:adverse effects*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000009:adverse effects*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics
C554548:177Lu-octreotate; D000209:Acute-Phase Proteins; D015415:Biomarkers; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C498260:Dbp protein, mouse; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D014157:Transcription Factors; C071332:Lcn2 protein, mouse; D008187:Lutetium; D015282:Octreotide