Recombinant α<sub>1</sub>-Microglobulin Is a Potential Kidney Protector in <sup>177</sup>Lu-Octreotate Treatment of Neuroendocrine Tumors

Andersson, Charlotte; Shubbar, Emman; Schüler, Emil; Åkerström, Bo; Gram, Magnus; Forssell-Aronsson, Eva

doi:10.2967/jnumed.118.225243

Cited by 12 publications

(17 citation statements)

References 19 publications

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“…This showed that rA1M does not interfere with the uptake nor therapeutic effect of [ 177 Lu]Lu-PSMA-617 in our preclinical model of prostate cancer as no significant differences could be seen between mice given vehicle or rA1M together with [ 177 Lu]Lu-PSMA-617. This is in line with previously published results by Andersson et al [ 33 ] who combined [ 177 Lu]-octreotate with rA1M in a model of neuroendocrine tumors.…”

Section: Discussionsupporting

confidence: 93%

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177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging

et al. 2021

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Anti-prostate specific membrane antigen (PSMA) radioligand therapy is promising but not curative in castration resistant prostate cancer. One way to broaden the therapeutic index could be to administer higher doses in combination with radioprotectors, since administered radioactivity is kept low today in order to avoid side-effects from a high absorbed dose to healthy tissue. Here, we investigated the human radical scavenger α1-microglobulin (A1M) together with 177-Lutetium (177Lu) labeled PSMA-617 in preclinical models with respect to therapeutic efficacy and kidney toxicity. Nude mice with subcutaneous LNCaP xenografts were injected with 50 or 100 MBq of [177Lu]Lu-PSMA-617, with or without injections of recombinant A1M (rA1M) (at T = 0 and T = 24 h). Kidney absorbed dose was calculated to 7.36 Gy at 4 days post a 100 MBq injection. Activity distribution was imaged with Single-Photon Emission Computed Tomography (SPECT) at 24 h. Tumor volumes were measured continuously, and kidneys and blood were collected at termination (3–4 days and 3–4 weeks after injections). In a parallel set of experiments, mice were given [177Lu]Lu-PSMA-617 and rA1M as above and dynamic technetium-99m mercaptoacetyltriglycine ([99mTc]Tc-MAG3) SPECT imaging was performed prior to injection, and 3- and 6-months post injection. Blood and urine were continuously sampled. At termination (6 months) the kidneys were resected. Biomarkers of kidney function, expression of stress genes and kidney histopathology were analyzed. [177Lu]Lu-PSMA-617 uptake, in tumors and kidneys, as well as treatment efficacy did not differ between rA1M and vehicle groups. In mice given rA1M, [99mTc]Tc-MAG3 imaging revealed a significantly higher slope of initial uptake at three months compared to mice co-injected with [177Lu]Lu-PSMA-617 and vehicle. Little or no change compared to control was seen in urine albumin, serum/plasma urea levels, RT-qPCR analysis of stress response genes and in the kidney histopathological evaluation. In conclusion, [99mTc]Tc-MAG3 imaging presented itself as a sensitive tool to detect changes in kidney function revealing that administration of rA1M has a potentially positive effect on kidney perfusion and tubular function when combined with [177Lu]Lu-PSMA-617 therapy. Furthermore, we could show that rA1M did not affect anti-PSMA radioligand therapy efficacy.

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Section: Discussionsupporting

confidence: 93%

“…Moreover, in a recent study exogenously injected A1M, shown to be mainly localized to the kidney cortex [ 30 ], protected the kidneys against radiotoxicity during 177 Lu-DOTATATE treatment in a mouse model. A follow-up study later established that the tumor treatment itself was not affected by A1M [ 30 , 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging

et al. 2021

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“…In the short-term, the mice that received A1M had less DNA damage and upregulation of apoptotic genes in the kidneys [ 59 ]. In a follow-up study, it was confirmed that A1M did not interfere with tumor treatment or with the biodistribution of the radiopeptides [ 60 ]. Using A1M as a radioprotector may therefore constitute a possibility to improve cancer therapy with PRRT by allowing higher or more frequent radioactivity doses.…”

Section: A1mmentioning

confidence: 99%

“…Acute and hyperhemolytic episodes are associated with renal damage, which may be temporary or permanent. It has been shown previously that A1M can protect against renal damage following radiation treatment and rhabdomyolysis [ 59 , 60 ]; however, its protective role during active RBC hemolysis is not clear, and Ofori-Acquah et al have shown a correlation between kidney damage and increased A1M-bound heme in sickle cell disease [ 62 , 63 ]. Thus, the role of A1M protection in hemolytic transfusion reactions needs to be examined further ( Figure 5 ).…”

Section: Hemolytic Conditionsmentioning

confidence: 99%

The Role of α1-Microglobulin (A1M) in Erythropoiesis and Erythrocyte Homeostasis—Therapeutic Opportunities in Hemolytic Conditions

Kristiansson

Gram

Flygare

et al. 2020

IJMS

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α1-microglobulin (A1M) is a small protein present in vertebrates including humans. It has several physiologically relevant properties, including binding of heme and radicals as well as enzymatic reduction, that are used in the protection of cells and tissue. Research has revealed that A1M can ameliorate heme and ROS-induced injuries in cell cultures, organs, explants and animal models. Recently, it was shown that A1M could reduce hemolysis in vitro, observed with several different types of insults and sources of RBCs. In addition, in a recently published study, it was observed that mice lacking A1M (A1M-KO) developed a macrocytic anemia phenotype. Altogether, this suggests that A1M may have a role in RBC development, stability and turnover. This opens up the possibility of utilizing A1M for therapeutic purposes in pathological conditions involving erythropoietic and hemolytic abnormalities. Here, we provide an overview of A1M and its potential therapeutic effect in the context of the following erythropoietic and hemolytic conditions: Diamond-Blackfan anemia (DBA), 5q-minus myelodysplastic syndrome (5q-MDS), blood transfusions (including storage), intraventricular hemorrhage (IVH), preeclampsia (PE) and atherosclerosis.

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“…A 1 -microglobulin is an antioxidation and radical scavenger protein [ 92 ] that is, after intravenous administration, mostly localized in the kidneys [ 93 ]. Preclinical experiments demonstrated that the administration of the α 1 -microglobulin in 177 Lu-DOTATATE-treated mice reduced the radiation damage of the kidneys [ 94 ], without affecting the treatment efficacy [ 95 ].…”

Section: Treatment Optimizationmentioning

confidence: 99%

Strategies Towards Improving Clinical Outcomes of Peptide Receptor Radionuclide Therapy

et al. 2021

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Purpose of Review Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3] octreotate is an effective and safe second- or third-line treatment option for patients with low-grade advanced gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). In this review, we will focus on possible extensions of the current use of PRRT and on new approaches which could further improve its treatment efficacy and safety. Recent Findings Promising results were published regarding PRRT in other NENs, including lung NENs or high-grade NENs, and applying PRRT as neoadjuvant or salvage therapy. Furthermore, a diversity of strategic approaches, including dosimetry, somatostatin receptor antagonists, somatostatin receptor upregulation, radiosensitization, different radionuclides, albumin binding, alternative renal protection, and liver-directed therapy in combination with PRRT, have the potential to improve the outcome of PRRT. Also, novel biomarkers are presented that could predict response to PRRT. Summary Multiple preclinical and early clinical studies have shown encouraging potential to advance the clinical outcome of PRRT in NEN patients. However, at this moment, most of these strategies have not yet reached the clinical setting of randomized phase III trials.

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Recombinant α₁-Microglobulin Is a Potential Kidney Protector in ¹⁷⁷Lu-Octreotate Treatment of Neuroendocrine Tumors

Cited by 12 publications

References 19 publications

177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging

177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging

The Role of α1-Microglobulin (A1M) in Erythropoiesis and Erythrocyte Homeostasis—Therapeutic Opportunities in Hemolytic Conditions

Strategies Towards Improving Clinical Outcomes of Peptide Receptor Radionuclide Therapy

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Recombinant α1-Microglobulin Is a Potential Kidney Protector in 177Lu-Octreotate Treatment of Neuroendocrine Tumors

Cited by 12 publications

References 19 publications

177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging

177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging

The Role of α1-Microglobulin (A1M) in Erythropoiesis and Erythrocyte Homeostasis—Therapeutic Opportunities in Hemolytic Conditions

Strategies Towards Improving Clinical Outcomes of Peptide Receptor Radionuclide Therapy

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Recombinant α₁-Microglobulin Is a Potential Kidney Protector in ¹⁷⁷Lu-Octreotate Treatment of Neuroendocrine Tumors