| 1. |
- Erlandsson, Ann, et al.
(författare)
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Binding of TS1, an anti-keratin 8 antibody, in small cell lung cancer after 177Lu-DOTA-Tyr3-octreotate treatment: a histological study in xenografted mice
- 2011
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Ingår i: EJNMMI Research. - 2191-219X. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background Small-cell lung carcinoma (SCLC) is an aggressive malignancy characterised by an early relapse, a tendency towards drug resistance, and a high incidence of metastasis. SCLC cells are of neuroendocrine origin and express high levels of somatostatin receptors; therefore, future treatment might involve targeting tumours with radiolabelled somatostatin analogues. This therapy induces abundant necrotic patches that contain exposed keratins; thus, keratin 8, which is one of the most abundant cytoskeletal proteins may represent an interesting secondary target for SCLC. This study aimed to investigate the effects of177Lu-DOTA-Tyr3-octerotate and the binding of the monoclonal anti-keratin 8 antibody, TS1, in vitro in treated SCLC- and midgut-xenografted mouse models. Methods NCI-H69- and GOT1-xenotransplanted mice were treated with three doses of 30 MBq177Lu-DOTA-Tyr3-octreotate administered 24 h apart. Mice xenotransplanted with NCI-H69 were sacrificed 1, 5, 12, 20 and 150 days post-injection or when the tumour had regrown to its original size. GOT1-xenotransplanted mice were sacrificed 3 days post-injection. Immunohistochemistry was performed to evaluate TS1 staining in tumours and in seven human biopsies of primary SCLC from pulmonary bronchi. Central cell density and nucleus size were determined in NCI-H69 sections. Results Twelve days after177Lu-DOTA-Tyr3-octerotate treatment, the SCLC xenograft response was extensive. Twenty days after treatment, one of three analysed tumours displayed complete remission. The other two tumours showed 1/4 the cell density of untreated controls and cell nuclei were about three times larger than those of untreated controls. At 150 days after treatment, one of four mice exhibited complete remission. Treated tumours displayed increased TS1 antibody accumulation and high TS1 binding in necrotic patches. All seven human SCLC biopsies displayed necrotic areas with TS1 staining. Conclusions Radiation treatment with three injections of 30 MBq177Lu-DOTA-Tyr3-octreotate had pronounced effects on tumour cell density and cell nuclei, which indicated mitotic catastrophe. Despite these anti-tumour effects, two of three SCLC tumours recurred. Further studies should investigate the nature of tumour cell survival and develop more effective treatments. High TS1 accumulation in tumour sections in vitro after177Lu-DOTA-Tyr3-octerotate treatment indicated that TS1 might represent a promising secondary therapeutic strategy.
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| 2. |
- Josefsson, Anders, 1971, et al.
(författare)
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Microdosimetric analysis of 211At in thyroid models for man, rat and mouse.
- 2012
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Ingår i: EJNMMI research. - 2191-219X. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: The alpha particle emitter 211At is proposed for therapy of metastatic tumour disease. 211At is accumulated in the thyroid gland in a similar way as iodine. Dosimetric models of 211At in the thyroid are needed for radiation protection assessments for 1) patients receiving 211Atlabelled pharmaceuticals where 211At may be released in vivo and 2) personnel working with 211At. Before clinical trials, preclinical studies are usually made in mice and rats. The aims of this study were to develop thyroid models for mouse, rat and man, and to compare microdosimetric properties between the models. METHODS: A thyroid follicle model was constructed: a single layer of 6 to 10-mum thick follicle cells with centrally positioned 4 to 8 mum (diameter) spherical nuclei surrounded a 10 to 500 mum (diameter) spherical follicle lumen. Species-specific models were defined for mouse, rat and man. The source compartments for 211At were the follicle lumen, follicle cells and follicle cell nuclei. The target was the follicle cell nucleus. Simplified species-specific thyroid models were used to investigate the contribution from surrounding follicles. Monte Carlo simulations were performed using the general purpose radiation transport code MCNPX 2.6.0. RESULTS: When 211At was homogeneously distributed within the follicle lumen, the mean specific energies per decay, z, to the follicle cell nucleus were 2.0, 1.1 and 0.17 mGy for mouse, rat and man, respectively. Corresponding values for the single-hit mean specific energy per decay, z1, were 1.3, 0.61 and 0.37 Gy. Assuming a homogeneous 211At concentration in the follicle lumen, <0.5%, 7%, and 45% of the emitted alpha particles were fully stopped within the follicle lumen for the respective models. CONCLUSIONS: The results clearly show the influence of the follicle size, alpha particle range and 211At location within the thyroid follicle on the dosimetric parameters. Appropriate thyroid models are required for translation of dosimetric parameters between species.
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| 3. |
- Larsson, Maria, 1972, et al.
(författare)
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Estimation of absorbed dose to the kidneys in patients after treatment with 177Lu-octreotate: comparison between methods based on planar scintigraphy.
- 2012
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Ingår i: EJNMMI research. - 2191-219X. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Lu-[DOTA0, Tyr3]-octreotate (177Lu-octreotate) is used to treat neuroendocrine tumors with high somatostatin-receptor expression. 177Lu-octreotate is mainly excreted via the kidneys, but to some extent, accumulates in the kidney cortex due to, e.g., tubular reabsorption. Renal toxicity is one of the main limiting factors in 177Lu-octreotate treatment. Further knowledge of the biodistribution and dosimetry of 177Lu-octreotate in individual patients is needed. The aim of this study was to estimate the absorbed dose to the kidneys and compare the results obtained with planar imaging and different dosimetric methods: (1) conjugate-view (CV) method using patient-specific kidney sizes, (2) PA method, based on posterior images only, (3) CV method with reduced number of time points (CVreduced data), and (4) CV method using standard kidney sizes (CVstandard size). METHODS: Totally, 33 patients each received 3.4 to 8.2 GBq of 177Lu-octreotate up to five times, with infusion of lysine and arginine to block the renal uptake. Whole-body planar gamma camera images were acquired on days 0, 1, 2, and 7. The 177Lu concentration in the kidneys was determined by the CV method, and the absorbed dose was estimated with patient-specific organ sizes. Comparison to the CV method was made using posterior images only, together with the influence of the number of time points and with standard organ sizes. RESULTS: Large interindividual variations were found in the time-activity curve pattern and in the absorbed dose to the kidneys using the CV method: 0.33 to 2.4 Gy/GBq (mean 0.80 Gy/GBq, SD = 0.30). In the individual patient, the mean deviation of all subsequent kidney doses compared to that of the first administration was 1 % (SD 19 %) and 5 % (SD 23 %) for the right and left kidneys, respectively. Excluding data for day 7 resulted in large variations in the absorbed dose. CONCLUSION: Large interindividual variations in kidney dose were found, demonstrating the need for patient-specific dosimetry and treatment planning.
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| 4. |
- 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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| 5. |
- Schüler, Emil, et al.
(författare)
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Effects of internal low-dose irradiation from 131I on gene expression in normal tissues in Balb/c mice.
- 2011
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Ingår i: EJNMMI research. - 2191-219X. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- Background The aim of this study was to investigate the global gene expression response of normal tissues following internal low absorbed dose irradiation of 131I. Methods Balb/c mice were intravenously injected with 13 to 260 kBq of 131I and euthanized 24 h after injection. Kidneys, liver, lungs, and spleen were surgically removed. The absorbed dose to the tissues was 0.1 to 9.7 mGy. Total RNA was extracted, and Illumina MouseRef-8 Whole-Genome Expression BeadChips (Illumina, Inc., San Diego, California, USA) were used to compare the gene expression of the irradiated tissues to that of non-irradiated controls. The Benjamini-Hochberg method was used to determine differentially expressed transcripts and control for false discovery rate. Only transcripts with a modulation of 1.5-fold or higher, either positively or negatively regulated, were included in the analysis. Results The number of transcripts affected ranged from 260 in the kidney cortex to 857 in the lungs. The majority of the affected transcripts were specific for the different absorbed doses delivered, and few transcripts were shared between the different tissues investigated. The response of the transcripts affected at all dose levels was generally found to be independent of dose, and only a few transcripts showed increasing or decreasing regulation with increasing absorbed dose. Few biological processes were affected at all absorbed dose levels studied or in all tissues studied. The types of biological processes affected were clearly tissue-dependent. Immune response was the only biological process affected in all tissues, and processes affected in more than three tissues were primarily associated with the response to stimuli and metabolism. Conclusion Despite the low absorbed doses delivered to the tissues investigated, a surprisingly strong response was observed. Affected biological processes were primarily associated with the normal function of the tissues, and only small deviations from the normal metabolic activity in the tissues were induced.
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| 6. |
- Dalmo, Johanna, et al.
(författare)
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Evaluation of retinol binding protein 4 and carbamoylated haemoglobin as potential renal toxicity biomarkers in adult mice treated with Lu-177-octreotate
- 2014
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 4:59
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Tidskriftsartikel (refereegranskat)abstract
- Background: The kidneys are regarded as one of the main dose-limiting organs in the treatment of neuroendocrine tumours with Lu-177-[DOTA(0), Tyr(3)]-octreotate (Lu-177-octreotate), despite the successful use of kidney uptake blocking agents such as lysine and arginine. To avoid renal toxicity but still give each patient as high amount of Lu-177-octreotate as possible, there is a need for methods/biomarkers that indicate renal injury in an early stage of the treatment. The aim of this study was to investigate the potential of using urinary retinol binding protein 4 (RBP4) and carbamoylated haemoglobin (Hb) in blood as biomarkers of nephrotoxic effects on adult mice after Lu-177-octreotate treatment. Methods: Adult BALB/c nude mice were injected with 60 MBq or 120 MBq of Lu-177-octreotate or with saline (control). Urine was collected before injection and concentrations of urinary RBP4 and creatinine were determined 14 to 90 days after injection Blood samples were collected after 90 days, and carbamoylated N-terminal valine in Hb, formed from urea, was measured as valine hydantoin (VH) after detachment from Hb. Results: The RBP4 values increased with administered activity and time. For the 60 and 120 MBq groups, statistically significantly higher RBP4 levels (p <0.05) were found at day 60 and 90 compared to baseline, also at day 30 for 120 MBq group. For VH, the mean values were similar for the 60 MBq and control groups, while a small increase was observed for the 120 MBq group; but there were no statistically significant differences between any of the groups (p >0.05). No morphological changes in the kidney tissue were found. Conclusions: Urinary RBP4 is a promising new biomarker for radiation-induced renal toxicity. For the conditions used in this experiment, carbamoylated Hb (from urea) measured as VH may not be a sufficiently sensitive biomarker to be used for renal toxicity.
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| 7. |
- Dalmo, Johanna, et al.
(författare)
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Priming increases the anti-tumor effect and therapeutic window of 177Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1.
- 2017
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: 177Lu-[DOTA0, Tyr3]-octreotate (177Lu-octreotate) is used for treatment of patients with somatostatin receptor (SSTR) expressing neuroendocrine tumors. However, complete tumor remission is rarely seen, and optimization of treatment protocols is needed. In vitro studies have shown that irradiation can up-regulate the expression of SSTR1, 2 and 5, and increase 177Lu-octreotate uptake. The aim of the present study was to examine the anti-tumor effect of a 177Lu-octreotate priming dose followed 24 h later by a second injection of 177Lu-octreotate compared to a single administration of 177Lu-octreotate, performed on the human small intestine neuroendocrine tumor cell line, GOT1, transplanted to nude mice. RESULTS: Priming resulted in a 1.9 times higher mean absorbed dose to the tumor tissue per administered activity, together with a reduced mean absorbed dose for kidneys. Priming gave the best overall anti-tumor effects. Magnetic resonance imaging showed no statistically significant difference in tumor response between treatment with and without priming. Gene expression analysis demonstrated effects on cell cycle regulation. Biological processes associated with apoptotic cell death were highly affected in the biodistribution and dosimetry study, via differential regulation of, e.g., APOE, BAX, CDKN1A, and GADD45A. CONCLUSIONS: Priming had the best overall anti-tumor effects and also resulted in an increased therapeutic window. Results indicate that potential biomarkers for tumor regrowth may be found in the p53 or JNK signaling pathways. Priming administration is an interesting optimization strategy for 177Lu-octreotate therapy of neuroendocrine tumors, and further studies should be performed to determine the mechanisms responsible for the reported effects.
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| 8. |
- Josefsson, Anders, 1971, et al.
(författare)
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Dosimetric analysis of (123)I, (125)I and (131)I in thyroid follicle models.
- 2014
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Ingår i: EJNMMI research. - : Springer Science and Business Media LLC. - 2191-219X. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- RADIOIODINE IS ROUTINELY USED OR PROPOSED FOR DIAGNOSTIC AND THERAPEUTIC PURPOSES: (123)I, (125)I and (131)I for diagnostics and (125)I and (131)I for therapy. When radioiodine-labelled pharmaceuticals are administered to the body, radioiodide might be released into the circulation and taken up by the thyroid gland, which may then be an organ at risk. The aim of this study was to compare dosimetric properties for (123)I, (125)I and (131)I in previously developed thyroid models for man, rat and mouse.
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| 9. |
- Langen, Britta, et al.
(författare)
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Circadian rhythm influences genome-wide transcriptional responses to I-131 in a tissue-specific manner in mice
- 2015
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Circadian variation of gene expression is often neglected when ionizing radiation-induced effects are studied, whether in animal models or in cell culture. This study characterized diurnal variation of genome-wide transcriptional regulation and responses of potential biomarkers and signature genes in normal mouse tissues at 24 h after i.v. administration of I-131. Methods: Female BALB/c nude mice were i.v. injected with 90 kBq I-131 at 9: 00 a.m., 12: 00 p.m., or 3: 00 p.m. and killed after 24 h (n = 4/group). Paired control groups were mock-treated (n = 3-4/group). The kidneys, liver, lungs, spleen, and thyroid were excised, snap-frozen, and stored at -80 degrees C until extraction of total RNA. RNA microarray technology was used for genome-wide expression analysis. Enriched biological processes were categorized after cellular function. Signature genes for ionizing radiation and thyroid hormone-induced responses were taken from the literature. Absorbed dose was estimated using the Medical Internal Radiation Dose (MIRD) formalism. Results: The thyroid received an absorbed dose of 5.9 Gy and non-thyroid tissues received 0.75-2.2 mGy over 24 h. A distinct peak in the total number of significantly regulated transcripts was observed at 9: 00 a. m. in the thyroid, but 3 h later in the kidney cortex, kidney medulla, and liver. Transcriptional regulation in the lungs and spleen was marginal. Associated cellular functions generally varied in quality and response strength between morning, noon, and afternoon. In the thyroid, 25 genes were significantly regulated at all investigated times of day, and 24 thereof showed a distinct pattern of pronounced down-regulation at 9: 00 a. m. and comparatively weak up-regulation at later times. Eleven of these genes belonged to the species-specific kallikrein subfamily Klk1b. Responses in signature genes for thyroid hormone-induced responses were more frequent than for ionizing radiation, and trends persisted irrespective of time of day. Conclusion: Diurnal variation of genome-wide transcriptional responses to 90 kBq I-131 was demonstrated for the thyroid, kidney cortex and medulla, and liver, whereas variation was only marginal in the lungs and spleen. Overall, significant detection of potential biomarkers and signature genes was validated at each time of day, although direction of regulation and fold-change differed between morning, noon, and afternoon. These findings suggest that circadian rhythm should be considered in radiation research and that biological and analytical endpoints should be validated for circadian robustness.
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| 10. |
- Langen, Britta, et al.
(författare)
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Transcriptional response in normal mouse tissues after i.v. 211At administration - response related to absorbed dose, dose rate, and time
- 2015
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X .- 2191-219X. ; 5:1, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Background In cancer radiotherapy, knowledge of normal tissue responses and toxicity risks is essential in order to deliver the highest possible absorbed dose to the tumor while maintaining normal tissue exposure at non-critical levels. However, few studies have investigated normal tissue responses in vivo after 211At administration. In order to identify molecular biomarkers of ionizing radiation exposure, we investigated genome-wide transcriptional responses to (very) low mean absorbed doses from 211At in normal mouse tissues. Methods Female BALB/c nude mice were intravenously injected with 1.7 kBq 211At and killed after 1 h, 6 h, or 7 days or injected with 105 or 7.5 kBq and killed after 1 and 6 h, respectively. Controls were mock-treated. Total RNA was extracted from tissue samples of kidney cortex and medulla, liver, lungs, and spleen and subjected to microarray analysis. Enriched biological processes were categorized after cellular function based on Gene Ontology terms. Results Responses were tissue-specific with regard to the number of significantly regulated transcripts and associated cellular function. Dose rate effects on transcript regulation were observed with both direct and inverse trends. In several tissues, Angptl4, Per1 and Per2, and Tsc22d3 showed consistent transcript regulation at all exposure conditions. Conclusions This study demonstrated tissue-specific transcriptional responses and distinct dose rate effects after 211At administration. Transcript regulation of individual genes, as well as cellular responses inferred from enriched transcript data, may serve as biomarkers in vivo. These findings expand the knowledge base on normal tissue responses and may help to evaluate and limit side effects of radionuclide therapy. Keywords: Astatine-211; Ionizing radiation; Normal tissue response; Radionuclide therapy; Biomarke
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