title: Priming increases the anti-tumor effect and therapeutic window of177Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1.
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 increase177Lu-octreotate uptake. The aim of the present study was to examine the anti-tumor effect of a177Lu-octreotate priming dose followed 24 h later by a second injection of177Lu-octreotate compared to a single administration of177Lu-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 for177Lu-octreotate therapy of neuroendocrine tumors, and further studies should be performed to determine the mechanisms responsible for the reported effects.
authors.affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden. johanna.dalmo@vgregion.se.
authors.forename: Johanna
authors.initials: J
authors.lastname: Dalmo
authors.affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Spetz
authors.affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Montelius
authors.affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
authors.forename: Britta
authors.initials: B
authors.lastname: Langen
authors.affiliation: Department of Pathology, Institute of Biomedicine, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Arvidsson
authors.affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Johansson
authors.affiliation: Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
authors.forename: Toshima Z
authors.initials: TZ
authors.lastname: Parris
authors.affiliation: Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
authors.forename: Khalil
authors.initials: K
authors.lastname: Helou
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Wängberg
authors.affiliation: Department of Pathology, Institute of Biomedicine, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Nilsson
authors.affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Ljungberg
authors.affiliation: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, SE-413 45, Gothenburg, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Forssell-Aronsson
keywords: 177Lu-DOTATATE; Fractionated radionuclide therapy; Gene expression; MRI; Neuroendocrine tumor; Radiation biology; Somatostatin receptors; Xenograft model