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Protection of Kidney Function with Human Antioxidation Protein α 1 -Microglobulin in a Mouse 177 Lu-DOTATATE Radiation Therapy Model

Kristiansson, Amanda LU ; Ahlstedt, Jonas LU ; Holmqvist, Bo LU ; Brinte, Anders ; Tran, Thuy A. LU ; Forssell-Aronsson, Eva ; Strand, Sven Erik LU ; Gram, Magnus LU and Akerström, Bo LU (2019) In Antioxidants and Redox Signaling 30(14). p.1746-1759
Abstract


Aims: Peptide receptor radionuclide therapy (PRRT) is in clinical use today to treat metastatic neuroendocrine tumors. Infused, radiolabeled, somatostatin analog peptides target tumors that are killed by irradiation damage. The peptides, however, are also retained in kidneys due to glomerular filtration, and the administered doses must be limited to avoid kidney damage. The human radical scavenger and antioxidant, α
1
-microglobulin (A1M), has previously been shown to protect bystander tissue against irradiation damage and has pharmacokinetic... (More)


Aims: Peptide receptor radionuclide therapy (PRRT) is in clinical use today to treat metastatic neuroendocrine tumors. Infused, radiolabeled, somatostatin analog peptides target tumors that are killed by irradiation damage. The peptides, however, are also retained in kidneys due to glomerular filtration, and the administered doses must be limited to avoid kidney damage. The human radical scavenger and antioxidant, α
1
-microglobulin (A1M), has previously been shown to protect bystander tissue against irradiation damage and has pharmacokinetic and biodistribution properties similar to somatostatin analogs. In this study, we have investigated if A1M can be used as a renal protective agent in PRRT. Results: We describe nephroprotective effects of human recombinant A1M on the short- and long-term renal damage observed following lutetium 177 (
177
Lu)-DOTATATE (150 MBq) exposure in BALB/c mice. After 1, 4, and 8 days (short term),
177
Lu-DOTATATE injections resulted in increased formation of DNA double-strand breaks in the renal cortex, upregulated expression of apoptosis and stress response-related genes, and proteinuria (albumin in urine), all of which were significantly suppressed by coadministration of A1M (7 mg/kg). After 6, 12, and 24 weeks (long term),
177
Lu-DOTATATE injections resulted in increased animal death, kidney lesions, glomerular loss, upregulation of stress genes, proteinuria, and plasma markers of reduced kidney function, all of which were suppressed by coadministration of A1M. Innovation and Conclusion: This study demonstrates that A1M effectively inhibits radiation-induced renal damage. The findings suggest that A1M may be used as a radioprotector during clinical PRRT, potentially facilitating improved tumor control and enabling more patients to receive treatment.

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Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Lu-DOTATATE, cancer, PRRT, radionuclide therapy, renal protection, α -microglobulin
in
Antioxidants and Redox Signaling
volume
30
issue
14
pages
14 pages
publisher
Mary Ann Liebert, Inc.
external identifiers
  • pmid:29943622
  • scopus:85063966377
ISSN
1523-0864
DOI
10.1089/ars.2018.7517
language
English
LU publication?
yes
id
4bf54171-f517-4879-bdf8-e2ff94158c12
date added to LUP
2019-04-24 13:39:44
date last changed
2019-12-03 02:06:33
@article{4bf54171-f517-4879-bdf8-e2ff94158c12,
  abstract     = {<p><br>
                                                         Aims: Peptide receptor radionuclide therapy (PRRT) is in clinical use today to treat metastatic neuroendocrine tumors. Infused, radiolabeled, somatostatin analog peptides target tumors that are killed by irradiation damage. The peptides, however, are also retained in kidneys due to glomerular filtration, and the administered doses must be limited to avoid kidney damage. The human radical scavenger and antioxidant, α                             <br>
                            <sub>1</sub><br>
                                                         -microglobulin (A1M), has previously been shown to protect bystander tissue against irradiation damage and has pharmacokinetic and biodistribution properties similar to somatostatin analogs. In this study, we have investigated if A1M can be used as a renal protective agent in PRRT. Results: We describe nephroprotective effects of human recombinant A1M on the short- and long-term renal damage observed following lutetium 177 (                             <br>
                            <sup>177</sup><br>
                                                         Lu)-DOTATATE (150 MBq) exposure in BALB/c mice. After 1, 4, and 8 days (short term),                              <br>
                            <sup>177</sup><br>
                                                         Lu-DOTATATE injections resulted in increased formation of DNA double-strand breaks in the renal cortex, upregulated expression of apoptosis and stress response-related genes, and proteinuria (albumin in urine), all of which were significantly suppressed by coadministration of A1M (7 mg/kg). After 6, 12, and 24 weeks (long term),                              <br>
                            <sup>177</sup><br>
                                                         Lu-DOTATATE injections resulted in increased animal death, kidney lesions, glomerular loss, upregulation of stress genes, proteinuria, and plasma markers of reduced kidney function, all of which were suppressed by coadministration of A1M. Innovation and Conclusion: This study demonstrates that A1M effectively inhibits radiation-induced renal damage. The findings suggest that A1M may be used as a radioprotector during clinical PRRT, potentially facilitating improved tumor control and enabling more patients to receive treatment.                         <br>
                        </p>},
  author       = {Kristiansson, Amanda and Ahlstedt, Jonas and Holmqvist, Bo and Brinte, Anders and Tran, Thuy A. and Forssell-Aronsson, Eva and Strand, Sven Erik and Gram, Magnus and Akerström, Bo},
  issn         = {1523-0864},
  language     = {eng},
  number       = {14},
  pages        = {1746--1759},
  publisher    = {Mary Ann Liebert, Inc.},
  series       = {Antioxidants and Redox Signaling},
  title        = {Protection of Kidney Function with Human Antioxidation Protein α                         
                        <sub>1</sub>
                                                 -Microglobulin in a Mouse                          
                        <sup>177</sup>
                                                 Lu-DOTATATE Radiation Therapy Model},
  url          = {http://dx.doi.org/10.1089/ars.2018.7517},
  doi          = {10.1089/ars.2018.7517},
  volume       = {30},
  year         = {2019},
}