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- 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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- 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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- 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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- Spetz, Johan, et al.
(författare)
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Time-dependent transcriptional response of GOT1 human small intestine neuroendocrine tumor after 177Lu-octreotate therapy
- 2018
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051. ; 60, s. 11-18
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Patients with neuroendocrine tumors expressing somatostatin receptors are often treated with 177Lu-octreotate. Despite being highly effective in animal models, 177Lu-octreotate-based therapies in the clinical setting can be optimized further. The aims of the study were to identify and elucidate possible optimization venues for 177Lu-octreotate tumor therapy by characterizing transcriptional responses in the GOT1 small intestine neuroendocrine tumor model in nude mice. Methods: GOT1-bearing female BALB/c nude mice were intravenously injected with 15 MBq 177Lu-octreotate (non-curative amount) or mock-treated with saline solution. Animals were killed 1, 3, 7 or 41 d after injection. Total RNA was extracted from the tumor samples and profiled using Illumina microarray expression analysis. Differentially expressed genes were identified (treated vs. control) and pathway analysis was performed. Results: Distribution of differentially expressed transcripts indicated a time-dependent treatment response in GOT1 tumors after 177Lu-octreotate administration. Regulation of CDKN1A, BCAT1 and PAM at 1 d after injection was compatible with growth arrest as the initial response to treatment. Upregulation of APOE and BAX at 3 d, and ADORA2A, BNIP3, BNIP3L and HSPB1 at 41 d after injection suggests first activation and then inhibition of the intrinsic apoptotic pathway during tumor regression and regrowth, respectively. Conclusion: Transcriptional analysis showed radiation-induced apoptosis as an early response after 177Lu-octreotate administration, followed by pro-survival transcriptional changes in the tumor during the regrowth phase. Time-dependent changes in cell cycle and apoptosis-related processes suggest different time points after radionuclide therapy when tumor cells may be more susceptible to additional treatment, highlighting the importance of timing when administering multiple therapeutic agents. © 2017
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- Spetz, Johan, et al.
(författare)
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Transcriptional effects of 177Lu-octreotate therapy on GOT1 tumor in nude mice using conventional and priming treatment schedules
- 2015
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Ingår i: 15th International Congress of Radiation Research, Kyoto, Japan, May 25-29.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: 177Lu-octreotate can be used for therapy of somatostatin receptor expressing neuroendocrine tumors (NET). In GOT1 human small intestine NET transplanted to nude mice 177Lu-octreotate therapy has been successful with high cure rate. In clinical studies, on the other hand, the results have been moderate, and complete tumor remission is rarely seen. Previous studies have shown that a priming injection of 177Lu-octreotate 24 h before the main injection of 177Lu-octreotate resulted in higher SSTR expression, and increased absorbed dose, volume reduction and time to regrowth in GOT1 tumors in vivo. To our knowledge, the cellular effects of a priming treatment schedule have not yet been studied using a high throughput approach. Aim: To identify transcriptional changes responsible for the therapeutic differences in 177Lu-octreotate therapy of GOT1 tumors in nude mice with or without priming. Methods: GOT1 bearing BALB/c nude mice were treated with 15 MBq i.v. injected 177Lu-octreotate or 5 MBq of 177Lu-octreotate followed by additional 10 MBq of 177Lu-octreotate after 24 h. Animals were killed after 1, 3, 7 and 41 d and total RNA was extracted from excised tumor samples. Microarray analysis was performed on RNA from treated animals and untreated controls and differentially regulated transcripts were identified (change≥1.5-fold; adjusted P-value <0.01) using Nexus Expression 3.0. Results: Priming gave significantly greater treatment effects than without. Microarray analysis showed clear differences in transcriptional response, both with regard to treatment schedule and time-of-response. Higher influence on cell cycle arrest and physico-chemical environment was found 3 d after priming treatment compared to conventional treatment. Inhibition of apoptosis was found after 41 d without priming, but not after priming. Conclusions: Priming may be a promising method to optimize 177Lu-octreotate therapy in human malignant NET. Larger impact on cell cycle arrest and physico-chemical environment at earlier time points might influence the tumor volume reduction after priming. The prolonged time to tumor regrowth after priming may be explained by a lack of anti-apoptotic regulation at later time points.
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