Recombinant α<sub>1</sub>-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a <sup>177</sup>Lu-DOTATATE Mouse Radiation Model
<sup>177</sup>Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although <sup>177</sup>Lu-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal t...
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| Format: | Article |
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MDPI AG
2023-06-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/6/928 |
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| author | Abdul Ghani Alattar Amanda Kristiansson Helena Karlsson Suvi Vallius Jonas Ahlstedt Eva Forssell-Aronsson Bo Åkerström Sven-Erik Strand Johan Flygare Magnus Gram |
| author_facet | Abdul Ghani Alattar Amanda Kristiansson Helena Karlsson Suvi Vallius Jonas Ahlstedt Eva Forssell-Aronsson Bo Åkerström Sven-Erik Strand Johan Flygare Magnus Gram |
| author_sort | Abdul Ghani Alattar |
| collection | DOAJ |
| description | <sup>177</sup>Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although <sup>177</sup>Lu-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal toxicity are still side effects that should be considered. Amino acids are often used to minimize renal radiotoxicity, however, they are associated with nausea and vomiting in patients. α<sub>1</sub>-microglobulin (A1M) is an antioxidant with heme- and radical-scavenging abilities. A recombinant form (rA1M) has previously been shown to be renoprotective in preclinical models, including in PRRT-induced kidney damage. Here, we further investigated rA1M’s renal protective effect in a mouse <sup>177</sup>Lu-DOTATATE model in terms of administration route and dosing regimen and as a combined therapy with amino acids (Vamin). Moreover, we investigated the protective effect of rA1M on peripheral blood and bone marrow cells, as well as circulatory biomarkers. Intravenous (i.v.) administration of rA1M reduced albuminuria levels and circulatory levels of the oxidative stress-related protein fibroblast growth factor-21 (FGF-21). Dual injections of rA1M (i.e., at 0 and 24 h post-<sup>177</sup>Lu-DOTATATE administration) preserved bone marrow cellularity and peripheral blood reticulocytes. Administration of Vamin, alone or in combination with rA1M, did not show any protection of bone marrow cellularity or peripheral reticulocytes. In conclusion, this study suggests that rA1M, administered i.v. for two consecutive days in conjunction with <sup>177</sup>Lu-DOTATATE, may reduce hematopoietic and kidney toxicity during PRRT with <sup>177</sup>Lu-DOTATATE. |
| first_indexed | 2024-03-11T02:41:49Z |
| format | Article |
| id | doaj.art-75f059fe93d84de5ae531b78fc83fa73 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-11T02:41:49Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-75f059fe93d84de5ae531b78fc83fa732023-11-18T09:30:47ZengMDPI AGBiomolecules2218-273X2023-06-0113692810.3390/biom13060928Recombinant α<sub>1</sub>-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a <sup>177</sup>Lu-DOTATATE Mouse Radiation ModelAbdul Ghani Alattar0Amanda Kristiansson1Helena Karlsson2Suvi Vallius3Jonas Ahlstedt4Eva Forssell-Aronsson5Bo Åkerström6Sven-Erik Strand7Johan Flygare8Magnus Gram9Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, 221 84 Lund, SwedenPediatrics, Department of Clinical Sciences Lund, Skåne University Hospital, Lund University, 221 84 Lund, SwedenPediatrics, Department of Clinical Sciences Lund, Skåne University Hospital, Lund University, 221 84 Lund, SwedenPediatrics, Department of Clinical Sciences Lund, Skåne University Hospital, Lund University, 221 84 Lund, SwedenDepartment of Clinical Sciences Lund, CIPA, Lund University, 221 84 Lund, SwedenDepartment of Medical Radiation Sciences, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, SwedenDepartment of Clinical Sciences Lund, Section for Infection Medicine, Lund University, 221 84 Lund, SwedenDepartment of Clinical Sciences Lund, Oncology, Lund University, 222 42 Lund, SwedenDivision of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 221 84 Lund, SwedenPediatrics, Department of Clinical Sciences Lund, Skåne University Hospital, Lund University, 221 84 Lund, Sweden<sup>177</sup>Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although <sup>177</sup>Lu-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal toxicity are still side effects that should be considered. Amino acids are often used to minimize renal radiotoxicity, however, they are associated with nausea and vomiting in patients. α<sub>1</sub>-microglobulin (A1M) is an antioxidant with heme- and radical-scavenging abilities. A recombinant form (rA1M) has previously been shown to be renoprotective in preclinical models, including in PRRT-induced kidney damage. Here, we further investigated rA1M’s renal protective effect in a mouse <sup>177</sup>Lu-DOTATATE model in terms of administration route and dosing regimen and as a combined therapy with amino acids (Vamin). Moreover, we investigated the protective effect of rA1M on peripheral blood and bone marrow cells, as well as circulatory biomarkers. Intravenous (i.v.) administration of rA1M reduced albuminuria levels and circulatory levels of the oxidative stress-related protein fibroblast growth factor-21 (FGF-21). Dual injections of rA1M (i.e., at 0 and 24 h post-<sup>177</sup>Lu-DOTATATE administration) preserved bone marrow cellularity and peripheral blood reticulocytes. Administration of Vamin, alone or in combination with rA1M, did not show any protection of bone marrow cellularity or peripheral reticulocytes. In conclusion, this study suggests that rA1M, administered i.v. for two consecutive days in conjunction with <sup>177</sup>Lu-DOTATATE, may reduce hematopoietic and kidney toxicity during PRRT with <sup>177</sup>Lu-DOTATATE.https://www.mdpi.com/2218-273X/13/6/928peptide receptor radionuclide therapyα<sub>1</sub>-microglobulinradiationoxidative stressbone marrow toxicityrenal damage |
| spellingShingle | Abdul Ghani Alattar Amanda Kristiansson Helena Karlsson Suvi Vallius Jonas Ahlstedt Eva Forssell-Aronsson Bo Åkerström Sven-Erik Strand Johan Flygare Magnus Gram Recombinant α<sub>1</sub>-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a <sup>177</sup>Lu-DOTATATE Mouse Radiation Model Biomolecules peptide receptor radionuclide therapy α<sub>1</sub>-microglobulin radiation oxidative stress bone marrow toxicity renal damage |
| title | Recombinant α<sub>1</sub>-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a <sup>177</sup>Lu-DOTATATE Mouse Radiation Model |
| title_full | Recombinant α<sub>1</sub>-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a <sup>177</sup>Lu-DOTATATE Mouse Radiation Model |
| title_fullStr | Recombinant α<sub>1</sub>-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a <sup>177</sup>Lu-DOTATATE Mouse Radiation Model |
| title_full_unstemmed | Recombinant α<sub>1</sub>-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a <sup>177</sup>Lu-DOTATATE Mouse Radiation Model |
| title_short | Recombinant α<sub>1</sub>-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a <sup>177</sup>Lu-DOTATATE Mouse Radiation Model |
| title_sort | recombinant α sub 1 sub microglobulin ra1m protects against hematopoietic and renal toxicity alone and in combination with amino acids in a sup 177 sup lu dotatate mouse radiation model |
| topic | peptide receptor radionuclide therapy α<sub>1</sub>-microglobulin radiation oxidative stress bone marrow toxicity renal damage |
| url | https://www.mdpi.com/2218-273X/13/6/928 |
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