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Transcriptional effects of Lu-177-octreotate therapy using a priming treatment schedule on GOT1 tumor in nude mice

Journal article
Authors Johan Spetz
Britta Langen
Nils Rudqvist
Toshima Z Parris
Emman Shubbar
Johanna Dalmo
Bo Wängberg
Ola Nilsson
Khalil Helou
Eva Forssell-Aronsson
Published in Ejnmmi Research
Volume 9
Issue HIZUKA J, 1993, JOURNAL OF CELLULAR PHYSIOLOGY, V156, P112
ISSN 2191-219X
Publication year 2019
Published at Institute of Clinical Sciences, Department of Radiation Physics
Institute of Clinical Sciences, Department of Surgery
Institute of Clinical Sciences, Department of Oncology
Sahlgrenska Cancer Center
Institute of Biomedicine, Department of Pathology
Language en
Links dx.doi.org/10.1186/s13550-019-0500-...
Keywords GEPNET, NET, Radionuclide therapy, Radiation biology, Gene expression, Midgut carcinoid, PRRT, Lu-177-DOTATATE, receptor radionuclide therapy, up-regulation, neuroendocrine tumors, mouse-tissues, in-vivo, lu-177-dotatate, radiation, expression, dosimetry, cells, Radiology, Nuclear Medicine & Medical Imaging
Subject categories Cancer and Oncology

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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