Limits...
Potential Biomarkers for Radiation-Induced Renal Toxicity following 177Lu-Octreotate Administration in Mice.

Schüler E, Larsson M, Parris TZ, Johansson ME, Helou K, Forssell-Aronsson E - PLoS ONE (2015)

Bottom Line: 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.Distinct dose-response relationships were found for several of the regulated transcripts.Correlations to functional and morphological effects further confirm applicability of these genes as markers of radiation damage in kidney tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.

ABSTRACT

Unlabelled: 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

99mTc-DMSA scintigraphy.Results from 99mTc-DMSA scintigraphy performed 4, 8, and 12 months after 177Lu-octreotate administration. The kidney uptake is presented as percent of injected activity normalized to controls. Error bars represent SEM and * indicates statistically significant difference compared with controls (p<0.05)
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4546116&req=5

pone.0136204.g007: 99mTc-DMSA scintigraphy.Results from 99mTc-DMSA scintigraphy performed 4, 8, and 12 months after 177Lu-octreotate administration. The kidney uptake is presented as percent of injected activity normalized to controls. Error bars represent SEM and * indicates statistically significant difference compared with controls (p<0.05)

Mentions: A statistically significant increase in uptake of 99mTc-DMSA compared with controls was observed at 4 months for mice injected with 30 and 150 MBq 177Lu-octreotate (p<0.05) (Fig 7). Furthermore, a time-dependent accumulation of the 99mTc was observed, with increased uptake at 8 and 12 months compared with 4 months.


Potential Biomarkers for Radiation-Induced Renal Toxicity following 177Lu-Octreotate Administration in Mice.

Schüler E, Larsson M, Parris TZ, Johansson ME, Helou K, Forssell-Aronsson E - PLoS ONE (2015)

99mTc-DMSA scintigraphy.Results from 99mTc-DMSA scintigraphy performed 4, 8, and 12 months after 177Lu-octreotate administration. The kidney uptake is presented as percent of injected activity normalized to controls. Error bars represent SEM and * indicates statistically significant difference compared with controls (p<0.05)
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4546116&req=5

pone.0136204.g007: 99mTc-DMSA scintigraphy.Results from 99mTc-DMSA scintigraphy performed 4, 8, and 12 months after 177Lu-octreotate administration. The kidney uptake is presented as percent of injected activity normalized to controls. Error bars represent SEM and * indicates statistically significant difference compared with controls (p<0.05)
Mentions: A statistically significant increase in uptake of 99mTc-DMSA compared with controls was observed at 4 months for mice injected with 30 and 150 MBq 177Lu-octreotate (p<0.05) (Fig 7). Furthermore, a time-dependent accumulation of the 99mTc was observed, with increased uptake at 8 and 12 months compared with 4 months.

Bottom Line: 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.Distinct dose-response relationships were found for several of the regulated transcripts.Correlations to functional and morphological effects further confirm applicability of these genes as markers of radiation damage in kidney tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at the University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.

ABSTRACT

Unlabelled: 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus