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Feasibility of experimental BT4C glioma models for somatostatin receptor 2-targeted therapies.

AbstractUNLABELLED:
Somatostatin receptor subtype 2 (sstr2) is regarded as a potential target in malignant gliomas for new therapeutic approaches. Therefore, visualizing and quantifying tumor sstr2 expression in vivo would be highly relevant for the future development of sstr2-targeted therapies. The purpose of this study was to evaluate sstr2 status in experimental BT4C malignant gliomas.
METHODS:
Rat BT4C malignant glioma cells were injected into BDIX rat brain or subcutaneously into nude mice. Tumor uptake of [(68)Ga]DOTA-(Tyr(3))-Octreotide ([(68)Ga]DOTATOC), a somatostatin analog binding to sstr2, was studied by positron emission tomography/computed tomography (PET/CT). Additionally, subcutaneous tumor-bearing mice underwent PET imaging with 5-deoxy-5-[(18)F]fluororibose-NOC ([(18)F]FDR-NOC), a novel glycosylated peptide tracer also targeting sstr2. Ex vivo tissue radioactivity measurements, autoradiography and immunohistochemistry were performed to study sstr2 expression.
RESULTS:
Increased tumor uptake of [(68)Ga]DOTATOC was detected at autoradiography with mean tumor-to-brain ratio of 68 ± 30 and tumor-to-muscle ratio of 9.2 ± 3.8 for rat glioma. High tumor-to-muscle ratios were also observed in subcutaneous tumor-bearing mice after injection with [(68)Ga]DOTATOC and [(18)F]FDR-NOC with both autoradiography (6.7 ± 1.5 and 4.3 ± 0.8, respectively) and tissue radioactivity measurements (6.5 ± 0.8 and 4.8 ± 0.6, respectively). Furthermore, sstr2 immunohistochemistry showed positive staining in both tumor models. However, surprisingly low tumor signal compromised PET imaging. Mean SUVmax for rat gliomas was 0.64 ± 0.28 from 30 to 60 min after [(68)Ga]DOTATOC injection. The majority of subcutaneous tumors were not visualized by [(68)Ga]DOTATOC or [(18)F]FDR-NOC PET.
CONCLUSIONS:
Experimental BT4C gliomas show high expression of sstr2. Weak signal in PET imaging, however, suggests only limited benefit of [(68)Ga]DOTATOC or [(18)F]FDR-NOC PET/CT in this tumor model for in vivo imaging of sstr2 status.
AuthorsAida Kiviniemi, Maria Gardberg, Anu Autio, Xiang-Guo Li, Vanina D Heuser, Heidi Liljenbäck, Meeri Käkelä, Henri Sipilä, Jere Kurkipuro, Seppo Ylä-Herttuala, Juhani Knuuti, Heikki Minn, Anne Roivainen
JournalActa oncologica (Stockholm, Sweden) (Acta Oncol) Vol. 53 Issue 8 Pg. 1125-34 (Aug 2014) ISSN: 1651-226X [Electronic] England
PMID24957558 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 68Ga-octreotide, DOTA(0)-Tyr(3)-
  • Neoplasm Proteins
  • Organometallic Compounds
  • Radiopharmaceuticals
  • Receptors, Somatostatin
  • somatostatin receptor 2
  • Fluorodeoxyglucose F18
  • Octreotide
Topics
  • Animals
  • Autoradiography
  • Brain (metabolism, radionuclide imaging)
  • Cell Line, Tumor
  • Fluorodeoxyglucose F18 (pharmacokinetics)
  • Glioma (metabolism, radionuclide imaging)
  • Male
  • Mice
  • Mice, Nude
  • Muscle, Skeletal (metabolism, radionuclide imaging)
  • Neoplasm Proteins (metabolism)
  • Neoplasm Transplantation (methods)
  • Octreotide (analogs & derivatives, pharmacokinetics)
  • Organometallic Compounds (pharmacokinetics)
  • Positron-Emission Tomography (methods)
  • Radiopharmaceuticals (pharmacokinetics)
  • Rats
  • Receptors, Somatostatin (metabolism)
  • Tomography, X-Ray Computed (methods)

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