| 1. |
- 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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| 2. |
- Larsson, Malin, et al.
(författare)
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Portable scintillation detector for lung activity measurements prior to V/PSPECT
- 2015
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Ingår i: Optimization in X-ray and Molecular Imaging, 28-30 May, 2015, Gothenburg, Sweden..
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Ventilation and perfusion SPECT (V/PSPECT) is a tomographic imaging method using 99mTc labeled carbon particles (technegas) and 99mTc-macro aggregated albumin (MAA), respectively, for examination of the lungs. The primary purpose of V/PSPECT is to diagnose pulmonary embolism (PE). Today in Sahlgrenska University Hospital, the gamma camera is used for determination of enough inhaled technegas before the ventilation SPECT, a sufficient activity in the lungs are 20- 30 MBq. To economize with camera time and eliminate the risk of contamination of the camera detector system it would be advantageous to use a portable detector in a preparation room to ensure an adequate count rate. The aim of this study was to find a method to use a portable scintillation detector for estimation of inhaled techegas in lung tissue before V/PSPECT and to validate the method for clinical use. A scintillation detector (SSL Radhound with SS404 Al probe, Southern Scientific UK, Gamma Data AB, UK), was positioned over and/or laterally of the patient lying on a bed in supine positon. The patient inhaled technegas and the countrate of the portable detector was compared to the total counts from the ventilation SPECT images. The scintillation detector count statistics showed potential to replace the gamma camera measurements of the inhaled lung activity. The detected counts by scintillation detector showed good correlation to the number of counts in the SPECT images. In conclusion, the scintillation measurements can replace the method using a gamma camera for the activity uptake measurement before ventilation SPECT in the clinic.
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| 3. |
- 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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| 4. |
- 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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| 5. |
- Spetz, Johan, et al.
(författare)
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Transcriptional effects of Lu-177-octreotate therapy using a priming treatment schedule on GOT1 tumor in nude mice
- 2019
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Ingår i: Ejnmmi Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background(177)Lu-octreotate is used for therapy of somatostatin receptor expressing neuroendocrine tumors with promising results, although complete tumor remission is rarely seen. Previous studies on nude mice bearing the human small intestine neuroendocrine tumor, GOT1, have shown that a priming injection of Lu-177-octreotate 24h before the main injection of Lu-177-octreotate resulted in higher Lu-177 concentration in tumor, resulting in increased absorbed dose, volume reduction, and time to regrowth. To our knowledge, the cellular effects of a priming treatment schedule have not yet been studied. The aim of this study was to identify transcriptional changes contributing to the enhanced therapeutic response of GOT1 tumors in nude mice to Lu-177-octreotate therapy with priming, compared with non-curative monotherapy.ResultsRNA microarray analysis was performed on tumor samples from GOT1-bearing BALB/c nude mice treated with a 5MBq priming injection of Lu-177-octreotate followed by a second injection of 10MBq of Lu-177-octreotate after 24h and killed after 1, 3, 7, and 41days after the last injection. Administered activity amounts were chosen to be non-curative, in order to facilitate the study of tumor regression and regrowth. Differentially regulated transcripts (RNA samples from treated vs. untreated animals) were identified (change 1.5-fold; adjusted p value <0.01) using Nexus Expression 3.0. Analysis of the biological effects of transcriptional regulation was performed using the Gene Ontology database and Ingenuity Pathway Analysis. Transcriptional analysis of the tumors revealed two stages of pathway regulation for the priming schedule (up to 1week and around 1month) which differed distinctly from cellular responses observed after monotherapy. Induction of cell cycle arrest and apoptotic pathways (intrinsic and extrinsic) was found at early time points after treatment start, while downregulation of pro-proliferative genes were found at a late time point.ConclusionsThe present study indicates increased cellular stress responses in the tumors treated with a priming treatment schedule compared with those seen after conventional Lu-177-octreotate monotherapy, resulting in a more profound initiation of cell cycle arrest followed by apoptosis, as well as effects on PI3K/AKT-signaling and unfolded protein response.
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