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- Dalmo, Johanna, et al.
(författare)
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Biodistribution of 177Lu-octreotate and 111In-minigastrin in female nude mice transplanted with human medullary thyroid carcinoma GOT2.
- 2012
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Ingår i: Oncology reports. - : Spandidos Publications. - 1791-2431 .- 1021-335X. ; 27:1, s. 174-181
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Tidskriftsartikel (refereegranskat)abstract
- To be able to evaluate new radiopharmaceuticals and optimize diagnostic and therapeutic procedures, relevant animal models are required. The aim of this study was to evaluate the medullary thyroid carcinoma GOT2 animal model by analyzing the biodistribution of 177Lu-octreotate and 111In-minigastrin (MG0). BALB/c nude mice, subcutaneously transplanted with GOT2, were intravenously injected with either 177Lu-octreotate or 111In-MG0, with or without excess of unlabeled human minigastrin simultaneously with 111In-MG0. Animals were sacrificed 1-7 days after injection in the 177Lu-octreotate study and 1h after injection of 111In-MG0. The activity concentrations in organs and tissues were determined and mean absorbed doses from 177Lu were calculated. There was a specific tumor uptake of either 177Lu-octreotate or 111In-MG0. 177Lu-octreotate samples showed high activity concentrations in tissues expressing somatostatin receptors (SSTR). For both radiopharmaceuticals the highest activity concentrations were found in the kidneys. Compared to results from similar studies in mice with another MTC cell line (TT) the biodistribution was favorable (higher tumor uptake) for the GOT2 model, while compared to other animal models expressing SSTR, the tumor uptake of 177Lu-octreotate was modest. In conclusion, the GOT2 animal model is a valuable model for evaluation and optimization of diagnostic and therapeutic procedures using radiolabeled somatostatin, CCK2 and gastrin analogues prior to clinical studies.
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| 4. |
- Langen, Britta, et al.
(författare)
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Transcriptional gene regulation in abdominal organs and the lung after i.v. injection of 211At in mouse
- 2012
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Ingår i: Radiation research society. San Juan, Puerto Rico. 2012.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Astatine-211 (211At) is a promising radionuclide for radiation therapy with a nearly optimal biological effectiveness of emitted α-particles. Despite its potential, few studies have analysed 211At-induced normal tissue responses in vivo. In order to determine the quality and extent of 211At-induced cellular responses in vivo, the transcriptional gene regulation was analysed in the kidney cortex and medulla, liver, lung, and spleen. Female BALB/c nude mice were i.v. injected with 0.064, 0.64, 1.8, 14, and 42 kBq 211At and killed after 24h. Respective organs were excised and stored at -80°C until further analysis. Extracted total RNA was analysed with the Illumina MouseRef-8 Whole Genome Beadchip platform and data processing was performed with Nexus Expression 2.0. A common strong decrease in the total number of regulated transcripts was seen between 0.64 and 1.8 kBq 211At corresponding to absorbed doses between 2 and 50 mGy for all investigated tissues. Only minor responses in previously identified radiation-associated transcripts could be observed at any exposure. Among tissues at similar absorbed dose levels, the similarity in transcript up- and down-regulation decreased with increased absorbed dose. This phenomenon was more pronounced when the increase in absorbed dose corresponded also to an increase between 0.64 and 1.8 kBq 211At. Biological processes associated with regulated transcripts were categorised to assess the regulatory profiles in each tissue at a given exposure. These profiles showed distinct patterns which mirrored the threshold behaviour on the categorical and sub-categorical level of biological processes. The strong regulatory change demonstrated at the low absorbed doses in the tissues studied might be due to both radiation-induced effects of each tissue and physiological response from radiation-induced effects on the 211At-accumulating thyroid gland. These findings demonstrate the complexity of responses in vivo and highlight the need for a better understanding of the physiology when studying effects of ionizing radiation exposure.
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| 5. |
- Larsson, Maria, 1972, et al.
(författare)
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Kidney toxicity in mice treated with 177Lu-octreotate
- 2012
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Ingår i: 25th Annual Congress on European Association of Nuclear Medicine, Milano, Italy, October 27-31, 2012 . (European Journal of Nuclear Medicine and Molecular Imaging). - 1619-7070.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 6. |
- Rudqvist, Nils, et al.
(författare)
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Astatine-211 exposure of Balb/c mice in vivo resulted in distinct effets on thyroid at 1, 6 hours and 7 days after injection
- 2012
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Ingår i: 58th Annual Meeting of the Radiation Research Society, San Juan, Puerto Rico, September 30 - October 3, 2012.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Astatine-211 (211At) is a promising therapeutic radionuclide due to a nearly optimal linear energy transfer for generating double stand breaks in DNA. However, free 211At targets the thyroid gland due to chemical similarities with iodine. There are gaps in our knowledge about the general radiation-induced changes in basal cellular functions in thyroid tissue. The specific aim of this study was to investigate how global gene expression levels in thyroids change with time after 211At injection in mice. Female BALB/c nude mice were i.v. injected with 1.7 kBq 211At in the tail vein. The animals were killed at 1 hour, 6 hours, and 7 days post injection and the thyroids were removed and snap-frozen. The thyroids in each group were pooled and total RNA was extracted and processed using Illumina MouseRef-8 Whole-Genome Expression Beadchips. The gene expression in irradiated thyroids was compared with mock treated controls and regulated transcripts were associated with biological functions using Nexus Expression 2.0. Analysis revealed a distinct impact on global gene expression at all time points in thyroids exposed to 211At. The number of regulated transcripts decreased with time after injection (358, 260, and 193 at 1 h, 6 h, and 7 d, respectively). Generally, transcripts were more often down- than up-regulated. A total of 48 transcripts were detected at all time points (8 up- and 40 down-regulated). The regulated transcripts at the three separate times were associated with 66, 60, and 65 Gene Ontology terms (p < 0.05). At 1 and 6 h, DNA and gene expression integrity were affected and at 7 d after injection, an impact on cellular integrity was seen. A significant impact on transcripts involved in the immune system was also seen at all time points, but this was more pronounced at 1 h and 7 d. An inflammatory response was detected at 1 h but was even more distinct at 7 d. Conclusively, exposure to 211At caused a significant impact on normal cellular functions in thyroid tissue. Processes related to gene expression were affected early while at a later time point, radiation had an impact on processes related to cellular integrity. Interestingly, there was a decrease in the immune and inflammatory response at 6 h compared to either 1 hour or 7 d. Also, 48 transcripts were detected at all time points, which may be of interest for retrospective biodosimetry.
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| 8. |
- Rudqvist, Nils, et al.
(författare)
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Transcriptional response of BALB/c mouse thyroids following in vivo astatine-211 exposure reveals distinct gene expression profiles.
- 2012
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Ingår i: EJNMMI research. - 2191-219X. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Astatine-211 (211At) is an alpha particle emitting halogen with almost optimal linear energytransfer for creating DNA double-strand breaks and is thus proposed for adionuclide therapy when bound to tumor-seeking agents. Unbound 211At accumulates in the thyroid gland, and the concept of basal radiation-induced biological effects in the thyroid tissue is, to a high degree, unknown and is most valuable. METHODS: Female BALB/c nude mice were intravenously injected with 0.064 to 42 kBq of 211 At, resulting in absorbed doses of 0.05 to 32 Gy in the thyroid gland. Thyroids were removed 24h after injection; total RNA was extracted from pooled thyroids and processed in triplicate using Illumina MouseRef-8 Whole-Genome Expression Beadchips. RESULTS: Thyroids exposed to 211 At revealed distinctive gene expression profiles compared to nonirradiated controls. A larger number of genes were affected at low absorbed doses (0.05 and 0.5 Gy) compared to intermediate (1.4 Gy) and higher absorbed doses (11 and 32 Gy). The proportion of dose-specific genes increased with decreased absorbed dose. Additionally, 1.4 Gy often exerted opposite regulation on gene expression compared to the other absorbed doses. Using Gene Ontology data, an immunological effect was detected at 0.05 and 11 Gy. Effects on cellular response to external stress and cell cycle regulation and proliferation were detected at 1.4 and 11 Gy. CONCLUSIONS: Conclusively, the cellular response to ionizing radiation is complex and differs with absorbed dose. The response acquired at high absorbed doses cannot be extrapolated down to low absorbed doses or vice versa. We also demonstrated that the thyroid - already at absorbed doses similar to those obtained in radionuclide therapy - responds with expression of a high number of genes. Due to the increased heterogeneous irradiation at low absorbed doses, we suggest that this response partly originates from non-irradiated cells in the tissue, i.e., bystander cells.
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| 9. |
- Schüler, Emil, et al.
(författare)
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Biological effects of 177Lu-octreotate therapy in mouse: in vivo normal kidney tissue response evaluated with gene expression microarray
- 2012
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Ingår i: 58th Annual Meeting of the Radiation Research Society. San Juan, Puerto Rico. 2012.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The kidneys are the dose limiting organ when patients undergo 177Lu-octreotate therapy. The purpose of the present study was to investigate alterations in gene expression levels in the kidney following exposure to various absorbed doses of 177Lu. Female Balb/c mice were i.v. injected with 1.3-140 MBq 177Lu-octreotate, corresponding to an absorbed dose to the kidneys of 0.13-13 Gy. Control animals did not receive any 177Lu-octreotate. The animals were killed 24 hours after injection and the kidneys were removed, followed by dissection of the kidney medulla and cortex. Total RNA was extracted and processed using the Illumina Mouse-Ref-8 Whole-Genome Expression Beadchips to identify differentially expressed transcripts between irradiated and non-irradiated kidney tissues. The total number of differentially regulated transcripts was 480 and 281 in the kidney medulla and cortex, respectively. Of these, 39 and 32 transcripts were regulated at all absorbed doses in the two renal tissues. Of the affected biological processes, three and five processes were affected at all absorbed dose levels in the medulla and cortex, respectively; glycerol metabolism, immune response, and defense response in the medulla, and immune response, amino acid transport, circadian rhythm, rhythmic processes, and regulation of lipoprotein lipase activity in the cortex. In general, metabolic processes were strongly expressed at all absorbed dose levels studied, however, inversely related to increasing absorbed dose. Furthermore, cellular and developmental processes were strongly associated with kidney medulla, while a strong association with transport and immune response was seen in kidney cortex. The results demonstrate distinct differences in the response seen after 177Lu exposure to different absorbed doses. Effects on metabolism and stress responses were frequently seen, while no processes associated with maintaining DNA integrity were found, which indicates a very diverse response following 177Lu exposure.
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