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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 gene expression in GOT1 midgut carcinoid in nude mice
- 2012
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Ingår i: 58th Annual Meeting of the Radiation Research Society, San Juan, Puerto Rico, September 30 - October 3, 2012.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Radionuclide therapy using the somatostatin analog 177Lu-octreotate is promising for treatment of malignant neuroendocrine tumors, e.g. carcinoids and endocrine pancreatic tumors, with high expression of somatostatin receptors. Little is known about molecular mechanisms after irradiation of neuroendocrine tumors. The aim of this study was to investigate the regulation of gene expression in the human midgut carcinoma cell line GOT1. Female GOT1 bearing BALB/c nude mice were intravenously injected with 7 MBq 177Lu-octreotate. After 24 hours, all animals were sacrificed and tumors were excised. Radioactivity measurements were performed on the tumor tissues and absorbed doses were determined to about 2 Gy. Total RNA was extracted from the tumors and processed using Illumina MouseRef-8 Whole-Genome Expression Beadchips. Nexus Expression 2.0 was used for data analysis of both regulated genes and biological processes. The data was compared with that of a control group receiving only NaCl solution intravenously. Analysis revealed a strong up-regulation of four genes after irradiation, compared to controls. These genes were identified and classified using Gene Ontology terms. Two of the genes (CXCL9, encoding a cytokine and the SERPINA3, encoding a serpin peptidase inhibitor) were found to be associated with e.g. immune and inflammatory response, while the other two (ACTA1, encoding actin and MYL1, encoding myosin light chain 1/3) were associated with e.g. muscle contraction. ACTA1 was also found to be associated to cell growth. These preliminary results show that 177Lu-octreotate caused a significant impact on gene expression of a few genes in GOT1 tumors, especially on genes associated with immune response. These interesting results show that the effects of 177Lu-octreotate on tumor tissue needs to be studied further and studies on absorbed dose- and time relationships are ongoing.
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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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