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- Dalmo, Johanna, et al.
(författare)
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Potential renal toxicity biomarkers indicating radiation injury after 177Lu-octreotate treatment
- 2013
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Ingår i: Annual congress of the European association of nuclear medicine, october 19-23, 2013, Lyon, France. Posterwalk.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The kidneys are one of the most exposed non-tumor tissues and regarded as one of the main dose-limiting organs in peptide receptor radionuclide therapy (PRRT). [177Lu-DOTA0, Tyr3]-octreotate (177Lu-octreotate) has shown promising results in the treatment of somatostatin receptor overexpressing neuroendocrine tumors, but optimization is still needed. The ability to give each patient as much 177Lu-octreotate as possible without inducing nephrotoxicity is necessary for an efficient treatment. However, due to large inter-individual differences in uptake and retention in the kidneys, there is a need for efficient Methods that early can indicate renal injury. A possible way is to identify biomarkers for high risk of radiation nephrotoxicity. The aim of this study was to investigate the potential of using urinary retinol binding protein (RBP), and blood valinhydantoin (VH) as biomarkers of nephrotoxicity on adult mice after 177Lu-octreotate treatment. BALB/c nude mice (n=6/group) were i.v. injected with 60 MBq or 120 MBq of 177Lu-octreotate. The control group was mock treated with saline. Spot urine samples were collected before injection, and 14, 30, 60 and 90 days after injection. Analysis of RBP4 and creatinine was performed using Mouse RBP4 ELISA kit and Creatinine kit from R&D Systems, respectively. Erythrocytes were separated from whole blood samples collected 90 days after injection, and analysed for VH by LC-MS/MS. The ratio between VH and a volumetric standard was calculated. The RBP/creatinine level increased with time in both groups given 177Lu-octreotate, with earlier and higher response for the 120 MBq group. No clear change in VH level between the different groups was observed. The result show that RBP may be a promising new biomarker for radiation induced kidney toxicity. The presently used method based on VH was not sensitive enough to be used as kidney toxicity marker. Further studies on mice are ongoing to validate if RBP4 may be efficient in predicting late nephrotoxicity. In patients, RBP/creatinine levels are followed in urine samples after treatment with 177Lu-octreotate.
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| 2. |
- Montelius, Mikael, 1979, et al.
(författare)
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Tumour size measurement in a mouse model using high resolution MRI.
- 2012
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Ingår i: BMC medical imaging. - : Springer Science and Business Media LLC. - 1471-2342. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Animal models are frequently used to assess new treatment methods in cancer research. MRI offers a non-invasive in vivo monitoring of tumour tissue and thus allows longitudinal measurements of treatment effects, without the need for large cohorts of animals. Tumour size is an important biomarker of the disease development, but to our knowledge, MRI based size measurements have not yet been verified for small tumours (102-101g). The aim of this study was to assess the accuracy of MRI based tumour size measurements in small tumours on mice. METHODS: 2D and 3D T2-weighted RARE images of tumour bearing mice were acquired in vivo using a 7 T dedicated animal MR system. For the 3D images the acquired image resolution was varied. The images were exported to a PC workstation where the tumour mass was determined assuming a density of 1 g/cm3, using an in-house developed tool for segmentation and delineation. The resulting data were compared to the weight of the resected tumours after sacrifice of the animal using regression analysis. RESULTS: Strong correlations were demonstrated between MRI-and necropsy determined masses. In general, 3D acquisition was not a prerequisite for high accuracy. However, it was slightly more accurate than 2D when small (<0.2 g) tumours were assessed for inter-and intraobserver variation. In 3D images, the voxel sizes could be increased from 1603um3 to 2403um3 without affecting the results significantly, thus reducing acquisition time substantially. CONCLUSIONS: 2D MRI was sufficient for accurate tumour size measurement, except for small tumours (<0.2g) where 3D acquisition was necessary to reduce interobserver variation. Acquisition times between 15 and 50 minutes, depending on tumour size, were sufficient for accurate tumour volume measurement. Hence, it is possible to include further MR investigations of the tumour, such as tissue perfusion, diffusion or metabolic composition in the same MR session.
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| 3. |
- 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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| 7. |
- 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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| 10. |
- 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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