| 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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| 7. |
- 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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| 8. |
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| 10. |
- Pearce, Ruth, et al.
(författare)
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Development of FETs and resistive devices based on epitaxially grown single layer graphene on SiC for highly sensitive gas detection
- 2012
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Ingår i: Materials Science Forum Vols 717 - 720. - : Trans Tech Publications Inc.. - 9783037854198 ; , s. 687-690
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Konferensbidrag (refereegranskat)abstract
- Epitaxially grown single layer graphene on silicon carbide (SiC) resistive sensors were characterised for NO2 response at room and elevated temperatures, with an n-p type transition observed with increasing NO2 concentration for all sensors. The concentration of NO2 required to cause this transition varied for different graphene samples and is attributed to varying degrees of substrate induced Fermi-level (E-F) pinning above the Dirac point. The work function of a single layer device increased steadily with increasing NO2 concentration indicating no change in reaction mechanism for high and low concentrations despite a change in sensor response direction. Epitaxially grown graphene device preparation is challenging due to poor adhesion of the graphene layer to the substrate. A field effect transistor (FET) device is presented which does not require wire bonding to contacts on graphene.
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| 14. |
- Sandblom, Viktor, 1987, et al.
(författare)
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Radiolabelled pharmaceuticals MIBG and octreotate for treatment of metastatic pheochromocytoma and paraganglioma
- 2014
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Ingår i: SweRays Workshop, Malmö, Sweden, Aug 20-22, 2014.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: The 5-year survival for patients with metastatic pheochromocytoma (PC) and paraganglioma (PGL) is less than 50%. There is a clear need for development of better diagnostic and therapeutic options for these patients. Radionuclide therapy offers the possibility to treat spread PC/PGL. The norepinephrine (NE) analogue metaiodobenzylguanidine (MIBG) and the somatostatin (SST) analogues octreotate or octreotide are possible molecules that could be used for this purpose. These analogues have different biodistribution and different organs at risk, when used for therapy. Thus, combined therapy, using both radiolabelled NE and SST analogues, might be beneficial for these patients. Aim: The aim of this study was to evaluate the possibility of using 177Lu-octreotate and/or 131I-MIBG for treatment of patients with metastatic PC/PGL. Materials and Methods: Three patients with metastatic PC/PGL were injected with 131I-MIBG and 111In-octreotide, and four patients with metastatic PC/PGL were injected with 111In-octreotide, before surgical removal of the primary tumour. During surgery, tissue samples of tumour, blood, fat and muscle were collected and weighed, and the radioactivity was measured in a gamma counter. The activity concentration in these tissue samples was then calculated for each radionuclide. Additionally, tumour-to-blood activity concentration ratios (T/B) were calculated. Results: The activity concentrations and T/B values showed large variations between patients. For 111In-octreotide, T/B values were 25-590 and for 131I-MIBG, the corresponding values were 0-1600. Conclusion: The sometimes high T/B values show a clear possibility of using 177Lu-octreotate and 131I-MIBG for treatment of some patients with metastatic PC/PGL. However, due to the large variation between patients, individual investigation of tumour uptake prior to treatment is required.
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| 15. |
- Schüler, Emil, et al.
(författare)
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Time- and dose rate-related effects of internal (177)Lu exposure on gene expression in mouse kidney tissue.
- 2014
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Ingår i: Nuclear medicine and biology. - : Elsevier BV. - 1872-9614 .- 0969-8051. ; 41:10, s. 825-32
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Tidskriftsartikel (refereegranskat)abstract
- The kidneys are the dose-limiting organs in some radionuclide therapy regimens. However, the biological impact of internal exposure from radionuclides is still not fully understood. The aim of this study was to examine the effects of dose rate and time after i.v. injection of (177)LuCl3 on changes in transcriptional patterns in mouse kidney tissue.
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| 16. |
- Spetz, Johan, et al.
(författare)
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Biodistribution and dosimetry of free (211)at, (125)i(-) and (131)i(-) in rats.
- 2013
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 28:9, s. 657-64
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Tidskriftsartikel (refereegranskat)abstract
- Abstract (131)I is widely used for therapy in the clinic and (125)I and (131)I, and increasingly (211)At, are often used in experimental studies. It is important to know the biodistribution and dosimetry for these radionuclides to determine potential risk organs when using radiopharmaceuticals containing these radionuclides. The purpose of this study was to investigate the biodistribution of (125)I(-), (131)I(-), and free (211)At in rats and to determine absorbed doses to various organs and tissues. Male Sprague Dawley rats were injected simultaneously with 0.1-0.3MBq (125)I(-) and 0.1-0.3MBq (131)I(-), or 0.05-0.2MBq (211)At and sacrificed 1 hour to 7 days after injection. The activities and activity concentrations in organs and tissues were determined and mean absorbed doses were calculated. The biodistribution of (125)I(-) was similar to that of (131)I(-) but the biodistribution of free (211)At was different compared to (125)I(-) and (131)I(-). The activity concentration of radioiodine was higher compared with (211)At in the thyroid and lower in all extrathyroidal tissues. The mean absorbed dose per unit injected activity was highest to the thyroid. (131)I gave the highest absorbed dose to the thyroid, and (211)At gave the highest absorbed dose to all other tissues studied.
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| 22. |
- 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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| 23. |
- Spetz, Johan, et al.
(författare)
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Effects of internal irradiation from 177Lu-octreotate on transcriptional expression in GOT1 midgut carcinoid in nude mice
- 2014
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Ingår i: SweRays Workshop, Malmö, Sweden, Aug 20-22.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Neuroendocrine (NE) tumors expressing somatostatin receptors (SSTR) are often treated with 177Lu-octreotate. The treatment is highly successful in animal models, but low cure rates in clinical studies suggests optimization of treatment protocol is needed. Little is known about which cellular responses play a crucial role in neuroendocrine tumors after irradiation. It is therefore important to identify the effects of 177Lu-octreotate on biological functions for future optimization of treatment parameters and the identification of biomarkers predicting treatment response. The aim of this study was to investigate the transcriptional response of GOT1 midgut carcinoid in nude mice following 177Lu-octreotate treatment. Methods: GOT1 bearing BALB/c nude mice were i.v. injected with 15 MBq 177Lu-octreotate and tumor size was measured twice a week using calipers. Animals were killed after 1, 3, 7 or 41 days and tumor samples excised and snap frozen in liquid nitrogen. Total RNA was extracted from tumor samples and subjected to Illumina microarray expression analysis. Differential transcriptional profiles were identified by comparing treated and untreated tumor samples using Nexus Expression 3.0 software. Associated biological functions and biological pathways (according to Gene Ontology terms) were compared using Nexus Expression 3.0 and Ingenuity IPA. Results: The mean tumor volume was clearly reduced after 177Lu-octreotate treatment. Microarray analysis showed clear difference in regulation pattern between the time points. The analysis of associated biological functions revealed clear effect on cell death and survival, and cell cycle after 1, 3, and 7 days, while cellular movement and cellular development were clearly influenced after 41 days. Cellular growth and proliferation was also affected after 1 day but not at the other time points studied. Conclusions: : Analysis of the transcriptional regulation in GOT1 tumors in nude mice following 177Lu-octreotate treatment revealed responses in different cellular functions that were distinct for each time point. These findings indicate potential venues for increasing clinical effectiveness of midgut carcinoid therapy with 177Lu-octreotate.
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| 24. |
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| 25. |
- Spetz, Johan, et al.
(författare)
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Fractionated 177Lu-octreotate therapy of human GOT1 tumors in nude mice increases treatment efficacy, possibly via SSTR up-regulation
- 2014
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Ingår i: 3rd Swedish Cancer Research Meeting, Stockholm, Sweden, September 2-3, 2014.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: The radiolabelled somatostatin analogue 177Lu-octreotate is a promising treatment option for malignant neuroendocrine tumors that overexpress somatostatin receptors. The human midgut carcinoid GOT1 cell line has shown promising treatment response to 177Lu-octreotate in xenografted mice. In clinical studies, however, only low cure rates have been achieved to date. In vitro and preclinical in vivo studies have shown that irradiation can up-regulate the expression of somatostatin receptors and thereby give an increased uptake of 177Lu-octreotate. The cellular processes that underlie positive treatment response to 177Lu-octreotate are otherwise largely unknown. Genome-wide analysis of tumor cell responses in this successful mouse model offers a venue to identify critical treatment parameters and to optimize clinical effectiveness of 177Lu-octreotate therapy. Aim: To investigate the genome-wide transcriptional response of xenografted GOT1 midgut carcinoid after fractionated treatment giving a priming administration before the main administration of 177Lu-octreotate. Methods: GOT1 bearing BALB/c nude mice were i.v. injected with 5, 10, 15 or 30 MBq 177Lu-octreotate. The groups receiving 5 and 10 MBq 177Lu-octreotate were given an additional 10 or 5 MBq 177Lu-octreotate 24 h after the first injection, respectively. Control animals were injected with NaCl. Animals were killed after 1, 3, 7 or 41 days for the 5+10, 10+5 and 15 MBq treatments and controls and after 41 days for the 30 MBq treatment. Tumor samples were excised and snap frozen in liquid nitrogen, followed by total RNA extraction. Microarray analysis was performed on samples from treated animals and untreated controls (Illumina HumanHT-12 Beadchips) and differentially regulated transcripts were identified (change, ≥1.5-fold; P-adjusted < 0.05). Associated biological functions and affected biological pathways (according to Gene Ontology terms, P-adjusted < 0.05) were analyzed using Nexus Expression and Ingenuity IPA. Results: The mean tumor volume was clearly reduced after 177Lu-octreotate treatment in all groups. The mean absorbed dose to the tumor tissue was almost 110 % higher for the 5+10 MBq than for the 15 MBq group. The best overall therapeutic effects were obtained in the 5+10 MBq group. Microarray analysis showed clear differences in transcriptional response between treated groups and time points. Affected associated biological processes were e.g. cell death and survival, and cell cycle regulation after 1, 3, and 7 days; cellular movement and cellular development were influenced after 41 days. Cellular growth and proliferation was affected after 1 day but not at later time points. Conclusions: Microarray analysis of 177Lu-octreotate-induced effects in xenografted GOT1 tumors showed distinct differences in transcriptional responses and associated cellular functions, both with regard to treatment fractionation and time-of-response. The use of priming activity offers a new venue for increasing clinical effectiveness of 177Lu-octreotate therapy of midgut carcinoid tumors, probably due to increased somatostatin receptor expression.
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| 26. |
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| 27. |
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| 28. |
- 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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