Radionuclide Therapy via SSTR: Future Aspects from Experimental Animal Studies

Forssell-Aronsson, Eva; Spetz, Johan; Ahlman, Håkan

doi:10.1159/000336086

Cited by 23 publications

(21 citation statements)

References 269 publications

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“…The kidneys are one of the major sites of side effects of 177 Lu-octreotate therapy of neuroendocrine tumors due to the high uptake of the radiopharmaceutical in this organ [3], [5], [30]–[32]. Basic insight into how normal kidney tissue responds to 177 Lu-octreotate exposure is therefore vital for the continued optimization of therapy with this radiopharmaceutical.…”

Section: Discussionmentioning

confidence: 99%

“…Kidney cortical tissue should be given extra attention because 177 Lu-octreotate uptake takes place to a somewhat higher extent in this part of the kidney by, e.g., receptor-mediated endocytosis via the megalin/cubulin complex and somatostatin receptors, amino acid/oligopeptide transporters, pinocytosis, and passive diffusion [3], [5], [32]. Furthermore, it has previously been shown that the radioactivity localizes in the proximal tubules of the cortex, with less activity in the distal tubules and glomeruli, as evaluated by micro-autoradiography [3], and 177 Lu-octreotate induced damage has been found in the cortical tissue [4].…”

Section: Discussionmentioning

confidence: 99%

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Distinct microRNA Expression Profiles in Mouse Renal Cortical Tissue after 177Lu-octreotate Administration

et al. 2014

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AimThe aim of this study was to investigate the variation of the miRNA expression levels in normal renal cortical tissue after 177Lu-octreotate administration, a radiopharmaceutical used for treatment of neuroendocrine cancers.MethodsFemale BALB/c nude mice were i.v. injected with 1.3, 3.6, 14, 45, or 140 MBq 177Lu-octreotate, while control animals received saline. The animals were killed at 24 h after injection and total RNA, including miRNA, was extracted from the renal cortical tissue and hybridized to the Mouse miRNA Oligo chip 4plex to identify differentially regulated miRNAs between exposed and control samples.ResultsIn total, 57 specific miRNAs were differentially regulated in the exposed renal cortical tissues with 1, 29, 21, 27, and 31 miRNAs identified per dose-level (0.13, 0.34, 1.3, 4.3, and 13 Gy, respectively). No miRNAs were commonly regulated at all dose levels. miR-194, miR-107, miR-3090, and miR-3077 were commonly regulated at 0.34, 1.3, 4.3, and 13 Gy. Strong effects on cellular mechanisms ranging from immune response to p53 signaling and cancer-related pathways were observed at the highest absorbed dose. Thirty-nine of the 57 differentially regulated miRNAs identified in the present study have previously been associated with response to ionizing radiation, indicating common radiation responsive pathways.ConclusionIn conclusion, the 177Lu-octreotate associated miRNA signatures were generally dose-specific, thereby illustrating transcriptional regulation of radiation responsive miRNAs. Taken together, these results imply the importance of miRNAs in early immunological responses in the kidneys following 177Lu-octreotate administration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Distinct microRNA Expression Profiles in Mouse Renal Cortical Tissue after 177Lu-octreotate Administration

et al. 2014

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“…GOT1 cells were derived from a liver metastasis and expressed neuroendocrine markers, including somatostatin receptor type 2 (SSTR2). This cell line has been used as a model for optimisation of SSTR2-mediated peptide receptor radionuclide therapy (PRRT) (Kölby et al 2005, Bernhardt et al 2007, Forssell-Aronsson et al 2013, Dalmo et al 2017. More recently, in 2009, three cell lines were established from a patient with metastatic SINET disease (Pfragner et al 2009).…”

Section: Introductionmentioning

confidence: 99%

The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines

Hofving¹,

Arvidsson²,

Almobarak³

et al. 2018

Endocrine-Related Cancer

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Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number profiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2. Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors.

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“…Specifically, treatment with the somatostatin analogue 177 Lu-octreotate has shown promising results [4–11]. However, few patients achieve complete remission and there is a need for improvement of 177 Lu-octreotate treatment, with some options being (1) increasing the therapeutic effect on tumour tissue or (2) reducing the uptake in healthy organs at risk [12]. By lowering the uptake in organs at risk, the administered activity, and hence the absorbed dose to the tumour, could be increased.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of two intraoperative gamma detectors for assessment of 177Lu activity concentration in vivo

et al. 2017

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BackgroundPatients with somatostatin receptor-expressing neuroendocrine tumours can be treated with intravenously administered 177Lu-octreotate. Few patients are cured with the present protocol due to the current dose limitation of normal organs at risk, such as the kidneys. By locally administering 177Lu-octreotate to the liver for the purpose of treating liver metastases, a substantially reduced absorbed dose to organs at risk could be achieved. The development of such a technique requires the capability of measuring the 177Lu activity concentration in tissues in vivo. The aim of this study was to evaluate different performance parameters of two commercially available intraoperative gamma detectors in order to investigate whether intraoperative gamma detector measurements could be used to determine 177Lu activity concentration in vivo.ResultsMeasurements were made using different sources containing 177Lu. Response linearity, sensitivity, spatial resolution and its depth dependence, organ thickness dependence of the measured count rate and tumour detectability were assessed for two intraoperative gamma detectors. The two detectors (a scintillation and a semiconductor detector) showed differences in technical performance. For example, the sensitivity was higher for the scintillation detector, while the spatial resolution was better for the semiconductor detector. Regarding organ thickness dependence and tumour detectability, similar results were obtained for both detectors, and even relatively small simulated tumours of low tumour-to-background activity concentration ratios could be detected.ConclusionsAcceptable results were obtained for both detectors, although the semiconductor detector proved more advantageous for our purpose. The measurements demonstrated factors that must be corrected for, such as organ thickness or dead-time effects. Altogether, intraoperative gamma detector measurements could be used to determine 177Lu activity concentration in vivo.

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Radionuclide Therapy via SSTR: Future Aspects from Experimental Animal Studies

Cited by 23 publications

References 269 publications

Distinct microRNA Expression Profiles in Mouse Renal Cortical Tissue after 177Lu-octreotate Administration

Distinct microRNA Expression Profiles in Mouse Renal Cortical Tissue after 177Lu-octreotate Administration

The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines

Evaluation of two intraoperative gamma detectors for assessment of 177Lu activity concentration in vivo

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