| 1. |
- Montelius, Mikael, 1979, et al.
(författare)
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Multiparametric MRI with spatiotemporal evaluation reveals potential therapy response biomarkers for 177Lu-octreotate therapy of mice with human neuroendocrine tumor
- 2017
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Ingår i: ISMRM 25th Annual Meeting. 22-27 April 2017, Honolulu, Hawaii, USA.
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Konferensbidrag (refereegranskat)abstract
- Tissue parameters derived from multiparametric MRI were evaluated as potential imaging biomarkers for therapy response assessment in mice with human neuroendocrine tumor treated with 177Lu-octreotate. Animals were imaged before and repeatedly after 177Lu-octreotate treatment, using T2w, IVIM-DWI, DCE-MRI, T1- and T2*-mapping techniques. MR-parameters were evaluated regionally and longitudinally, and quantitative proteomics was used to evaluate underlying biological response in central and peripheral tumor separately. Several MR-parameters showed strong correlation with tumor response, as verified by MRI-based tumor volume measurements, but also with proteins associated with radiobiological effects on tumor tissue. Spatial and temporal evaluation increased sensitivity of the methods.
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| 2. |
- 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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| 5. |
- Spetz, Johan, et al.
(författare)
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Spatial proteomic analysis of GOT1 human small intestine neuroendocrine tumor in nude mice following 177Lu-octreotate therapy
- 2016
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Ingår i: 62nd Annual International Meeting Radiation Research Society, Waikoloa, HI, USA, October 16-19, 2016.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: 177Lu-octreotate can be used for therapy of somatostatin receptor expressing neuroendocrine tumors (NET). 177Lu-octreotate therapy has achieved high cure rates in GOT1 (human small intestine NET) transplanted to nude mice. However, clinical studies result in moderate response, and complete tumor remission is rarely seen. Solid tumors often develop necrotic cores during growth due to e.g. insufficient vascularization, which may account for the different uptake kinetics and varying therapeutic success seen after 177Lu-octreotate treatment. It is therefore important to explore the cellular effects of 177Lu-octreotate to further optimize treatment parameters and identify biomarkers for treatment response assessment. Aim: To detect significant changes in protein profiles from peripheral and central samples of GOT1 tumor after 177Lu-octreotate therapy. Methods: GOT1 bearing BALB/c nude mice were i.v. injected with 15 MBq 177Lu-octreotate (corresponding to 4 Gy tumor absorbed dose) and killed after 13 days. Total cellular proteins were extracted from the peripheral and central parts of surgically excised tumor samples. Proteomic profiling was generated using liquid chromatography tandem-mass spectrometry (LC-MS/MS), followed by database-based protein identification and relative quantification. Functional annotation of proteins was performed using the DAVID bioinformatics resource tool. Results: The LC-MS/MS analysis identified 58 differentially expressed proteins (p<0.05, Fold Change>1.2) between the peripheral and central parts of tumor samples. Forty of these showed higher levels in the peripheral compared with the central samples, and among them were proteins associated with blood vessel/vasculature development (e.g. FAK1, H6ST1, LMA4, and SYWM), regulation of cell cycle and apoptosis (e.g. FAK1 and MK01), and cellular integrity (e.g. PDLI5, CALD1, FERM2, and NEB2). Conclusions: Taken together, these findings suggest spatial differences in tumor response to 177Lu-octreotate, mainly constituted by differences in vascularization and cellular integrity. These findings indicate potential venues for prognostic evaluation of NET therapy using 177Lu-octreotate. However, further studies are needed to determine whether these effects are time- and/or dose-dependent.
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| 6. |
- Larsson, Malin, et al.
(författare)
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Long-term transcriptomic and proteomic effects in Sprague Dawley rat thyroid and plasma after internal low dose 131I exposure.
- 2020
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 15:12
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Tidskriftsartikel (refereegranskat)abstract
- Radioiodide (131I) is commonly used to treat thyroid cancer and hyperthyroidis.131I released during nuclear accidents, have resulted in increased incidence of thyroid cancer in children. Therefore, a better understanding of underlying cellular mechanisms behind 131I exposure is of great clinical and radiation protection interest. The aim of this work was to study the long-term dose-related effects of 131I exposure in thyroid tissue and plasma in young rats and identify potential biomarkers.Male Sprague Dawley rats (5-week-old) were i.v. injected with 0.5, 5.0, 50 or 500 kBq 131I (Dthyroid ca 1-1000 mGy), and killed after nine months at which time the thyroid and blood samples were collected. Gene expression microarray analysis (thyroid samples) and LC-MS/MS analysis (thyroid and plasma samples) were performed to assess differential gene and protein expression profiles in treated and corresponding untreated control samples. Bioinformatics analyses were performed using the DAVID functional annotation tool and Ingenuity Pathway Analysis (IPA). The gene expression microarray data and LC-MS/MS data were validated using qRT-PCR and ELISA, respectively.Nine 131I exposure-related candidate biomarkers (transcripts: Afp and RT1-Bb, and proteins: ARF3, DLD, IKBKB, NONO, RAB6A, RPN2, and SLC25A5) were identified in thyroid tissue. Two dose-related protein candidate biomarkers were identified in thyroid (APRT and LDHA) and two in plasma (DSG4 and TGM3). Candidate biomarkers for thyroid function included the ACADL and SORBS2 (all activities), TPO and TG proteins (low activities). 131I exposure was shown to have a profound effect on metabolism, immune system, apoptosis and cell death. Furthermore, several signalling pathways essential for normal cellular function (actin cytoskeleton signalling, HGF signalling, NRF2-mediated oxidative stress, integrin signalling, calcium signalling) were also significantly regulated.Exposure-related and dose-related effects on gene and protein expression generated few expression patterns useful as biomarkers for thyroid function and cancer.
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| 7. |
- 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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| 9. |
- 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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