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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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- Druid, Malin, et al.
(författare)
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Late age- and dose-related effects on the proteome of thyroid tissue in rats after 131I exposure.
- 2024
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Ingår i: Radiation. - 2673-592X. ; 4:2, s. 149-166
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Tidskriftsartikel (refereegranskat)abstract
- The physiological process of iodine uptake in the thyroid is used for 131I treatment of thyroid diseases. Children are more sensitive to radiation compared to adults and may react differently to 131I exposure. The aims of this study were to evaluate the effects on thyroid protein expression in young and adult rats one year after 131I injection and identify potential biomarkers related to 131I exposure, absorbed dose, and age. Twelve Sprague Dawley rats (young and adults) were i.v. injected with 50 kBq or 500 kBq 131I and killed twelve months later. Twelve untreated rats were used as age-matched controls. Quantitative proteomics, statistical analysis, and evaluation of biological effects were performed. The effects of irradiation were most prominent in young rats. Protein biomarker candidates were proposed related to age, absorbed dose, thyroid function, and cancer, and a panel was proposed for 131I exposure. In conclusion, the proteome of rat thyroid was differentially regulated twelve months after low-intermediate dose exposure to 131I in both young and adult rats. Several biomarker candidates are proposed for 131I exposure, age, and many of them are known to be related to thyroid function or thyroid cancer. Further research on human samples is needed for validation. Data are avaiable via ProteomeXchange with identifier PXD024786.
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- Langen, Britta, et al.
(författare)
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Data convolution and circadian rhythm impact identification of biomarker genes for ionizing radiation exposure in vivo: concept study on 131I exposure in mouse thyroid
- 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
- Background: Expression microarrays have been used increasingly for biomarker discovery of genes related to ionizing radiation (IR) exposure, particularly in vivo. However, diurnal variation of gene expression and data convolution from mixed cell populations can hinder biomarker discovery. For one, candidate biomarker genes may underlie circadian rhythmicity and their expression may oscillate affecting their robustness or indicative potential. For the other, significant responses from a specific cell type can be hidden in expression data from mixed cell populations creating bias in results or even precluding biomarker discovery. Aim: To identify biomarkers of IR exposure in thyroid tissue and asses their robustness with regard to circadian rhythm and data convolution. Methods: Female BALB/c nude mice (n=3–4/group) were i.v. injected with 90 kBq 131I, or mock-treated, at 9am, 12pm, or 3pm and killed after 24h. Total RNA was extracted from excised thyroids and subjected to microarray analysis (Illumina platform). Data were processed with Nexus Expression v3.0 (cut-off adjusted P <0.01; log2 ratio ≥0.58). Enriched biological processes (P value <0.05) were categorized after cellular function according to Gene Ontology terms. Data was deconvoluted by cell frequency of follicular cells and C-cells with csSAM using R/Bioconductor. Thyroid mean absorbed dose was calculated as 5.9 Gy using the MIRD formalism. Results: Twenty-five genes responded to 131I in thyroid irrespective of time of day, notably members of the kallikrein (KLK1) gene family, but direction of regulation and fold-change differed distinctly. All KLK1 transcripts were detected in at least one deconvoluted data set, while five additional KLK1 transcripts were detected upon deconvolution. Deconvolution also increased the detection rate of significant transcript regulation and regulated biological processes: DNA integrity, gene expression integrity, and cellular stress were negative in convoluted data, but showed distinct responses in both follicular cells and C-cells. Conclusions: The KLK1 gene family is a promising biomarker candidate that shows robustness of detection. Circadian rhythm and convolution affected the quality and quantity of detected transcriptional responses and we advocate their consideration in the in vivo setting.
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