Transcriptional effects of 177Lu-octreotate therapy using a priming treatment schedule on GOT1 tumor in nude mice
Artikel i vetenskaplig tidskrift, 2019

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 177 Lu-octreotate 24 h before the main injection of 177 Lu-octreotate resulted in higher 177 Lu 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 177 Lu-octreotate therapy with priming, compared with non-curative monotherapy. Results: RNA microarray analysis was performed on tumor samples from GOT1-bearing BALB/c nude mice treated with a 5 MBq priming injection of 177 Lu-octreotate followed by a second injection of 10 MBq of 177 Lu-octreotate after 24 h and killed after 1, 3, 7, and 41 days 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 1 week and around 1 month) 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. Conclusions: The present study indicates increased cellular stress responses in the tumors treated with a priming treatment schedule compared with those seen after conventional 177 Lu-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.

GEPNET

Gene expression

PRRT

177 Lu-DOTATATE

NET

Radionuclide therapy

Radiation biology

Midgut carcinoid

Författare

Johan Spetz

Sahlgrenska universitetssjukhuset

Britta Langen

Sahlgrenska universitetssjukhuset

Institutionen för tillämpad fysik

Nils Rudqvist

Sahlgrenska universitetssjukhuset

Toshima Z Parris

Göteborgs universitet

E. Shubbar

Sahlgrenska universitetssjukhuset

Johanna Dalmo

Sahlgrenska universitetssjukhuset

Bo Wängberg

Göteborgs universitet

Ola Nilsson

Göteborgs universitet

Khalil Helou

Göteborgs universitet

Eva Forssell-Aronsson

Sahlgrenska universitetssjukhuset

EJNMMI Research

2191-219X (ISSN)

Vol. 9 28

Ämneskategorier

Cell- och molekylärbiologi

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

Cancer och onkologi

DOI

10.1186/s13550-019-0500-2

Mer information

Senast uppdaterat

2019-11-22