| 1. |
- 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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| 2. |
- 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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| 3. |
- 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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