| 1. |
- 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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| 2. |
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| 3. |
- Forssell-Aronsson, Eva, 1961, et al.
(författare)
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Radionuclide therapy via SSTR - future aspects from experimental animal studies.
- 2013
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 97:1, s. 86-98
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Forskningsöversikt (refereegranskat)abstract
- There is need for better therapeutic options for neuroendocrine tumours. The aim of this review was to summarize results of experimental animal studies and raise ideas for future radionuclide therapy based on high expression of somatostatin (SS) receptors by many neuroendocrine tumours. In summary, one of the major options is individualized treatment for each patient, including choice of SS analogues, radionuclides and treatment schedules. Other options are methods to increase the treatment effect on tumour tissue (increasing tumour uptake and retention by upregulation of receptor expression and avoiding saturation of receptor binding), methods to increase the tumour tissue response (by choice of radionuclides, SS analogues or combined therapies), and methods to reduce side effects (diminished uptake and retention in critical organs and reduced normal tissue response). Furthermore, combination therapy with other radiopharmaceuticals, cytotoxic drugs or radiosensitizers can be considered to enhance the effects of radiolabelled SS analogues.
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| 4. |
- Spetz, Johan, et al.
(författare)
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Effects of internal irradiation from 177Lu-octreotate on gene expression in GOT1 midgut carcinoid in nude mice
- 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
- Radionuclide therapy using the somatostatin analog 177Lu-octreotate is promising for treatment of malignant neuroendocrine tumors, e.g. carcinoids and endocrine pancreatic tumors, with high expression of somatostatin receptors. Little is known about molecular mechanisms after irradiation of neuroendocrine tumors. The aim of this study was to investigate the regulation of gene expression in the human midgut carcinoma cell line GOT1. Female GOT1 bearing BALB/c nude mice were intravenously injected with 7 MBq 177Lu-octreotate. After 24 hours, all animals were sacrificed and tumors were excised. Radioactivity measurements were performed on the tumor tissues and absorbed doses were determined to about 2 Gy. Total RNA was extracted from the tumors and processed using Illumina MouseRef-8 Whole-Genome Expression Beadchips. Nexus Expression 2.0 was used for data analysis of both regulated genes and biological processes. The data was compared with that of a control group receiving only NaCl solution intravenously. Analysis revealed a strong up-regulation of four genes after irradiation, compared to controls. These genes were identified and classified using Gene Ontology terms. Two of the genes (CXCL9, encoding a cytokine and the SERPINA3, encoding a serpin peptidase inhibitor) were found to be associated with e.g. immune and inflammatory response, while the other two (ACTA1, encoding actin and MYL1, encoding myosin light chain 1/3) were associated with e.g. muscle contraction. ACTA1 was also found to be associated to cell growth. These preliminary results show that 177Lu-octreotate caused a significant impact on gene expression of a few genes in GOT1 tumors, especially on genes associated with immune response. These interesting results show that the effects of 177Lu-octreotate on tumor tissue needs to be studied further and studies on absorbed dose- and time relationships are ongoing.
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| 5. |
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| 6. |
- Spetz, Johan, et al.
(författare)
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Specific binding and uptake of 131I-MIBG and 111In-octreotide in malignant paraganglioma - tools for choice of radionuclide therapy
- 2012
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 44:5, s. 400-404
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Tidskriftsartikel (refereegranskat)abstract
- Tumor-specific uptake of the radiolabeled nor-epinephrine analogue meta-iodobenzylguanidine via norepinephrine transporter or radiolabeled somatostatin analogues octreotide/octreotate via somatostatin receptors offers possibilities to diagnose and treat metastatic pheochromocytoma/paraganglioma. High uptake of 123I-meta-iodobenzylguanidine is dependent on high expression of vesicular monoamine transporters responsible for mediating uptake of biogenic amines into dense core granules. A patient with metastatic paraganglioma (liver and bone metastases) underwent surgical removal of the primary after injection of 131I-meta-iodobenzylguanidine and 111In-octreotide. Radioactivity was determined in biopsies from tumor and normal tissue biopsies. The tumor/blood concentration value was high: 180 for 131I-meta-iodobenzylguanidine 3 h after injection and 590 for 111In-octreotide 27 h after injection. Studies of primary tumor cell cultures demonstrated increased cell membrane binding and internalization over time for 131I-meta-iodobenzylguanidine. The vesicular monoamine transporter antagonist reserpine and the norepinephrine transporter inhibitor clomipramine reduced internalization by 90% and 70%, respectively, after 46 h of incubation. The results demonstrated increased cell membrane binding and internalization over time also for 111In-octreotide. Internalization was highest for a low concentration of 111In-octreotide. Excess of octreotide reduced internalization of 111In-octreotide with 75% after 46 h of incubation. In conclusion, uptake and tumor/blood concentration values of radiolabeled meta-iodobenzylguanidine and somatostatin analogues can be determined for metastatic pheochromocytoma/paraganglioma to evaluate the possibility to use one or both agents for therapy. For this patient, the high tumor/blood values clearly demonstrated that therapy using both radiopharmaceuticals would be most beneficial. In vitro studies verified specific cell-membrane binding and internalization in tumor cells of both radiopharmaceuticals.
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