Synergism of peptide receptor-targeted Auger electron radiation therapy with anti-angiogenic compounds in a mouse model of neuroendocrine tumorsReport as inadecuate

Synergism of peptide receptor-targeted Auger electron radiation therapy with anti-angiogenic compounds in a mouse model of neuroendocrine tumors - Download this document for free, or read online. Document in PDF available to download.

EJNMMI Research

, 4:9

First Online: 16 February 2014Received: 27 November 2013Accepted: 31 January 2014DOI: 10.1186-2191-219X-4-9

Cite this article as: Wicki, A., Wild, D., Prêtre, V. et al. EJNMMI Res 2014 4: 9. doi:10.1186-2191-219X-4-9


BackgroundNeuroendocrine tumors are well vascularized and express specific cell surface markers, such as somatostatin receptors and the glucagon-like peptide-1 receptor GLP-1R. Using the Rip1Tag2 transgenic mouse model of pancreatic neuroendocrine tumors pNET, we have investigated the potential benefit of a combination of anti-angiogenic treatment with targeted internal radiotherapy.

MethodsLysAhx-DTPA-InNH2-exendin-4, a radiopeptide that selectively binds to GLP-1R expressed on insulinoma and other neuroendocrine tumor cells, was co-administered with oral vatalanib an inhibitor of vascular endothelial growth factor receptors VEGFR or imatinib a c-kit-PDGFR inhibitor. The control groups included single-agent kinase inhibitor treatments and LysAhx-DTPA-InNH2-exendin-4 monotherapy. For biodistribution, Rip1Tag2 mice were pre-treated with oral vatalanib or imatinib for 0, 3, 5, or 7 days at a dose of 100 mg-kg. Subsequently, LysAhx-DTPA-InNH2-exendin-4 was administered i.v., and the biodistribution was assessed after 4 h. For therapy, the mice were injected with 1.1 MBq LysAhx-DTPA-InNH2-exendin-4 and treated with vatalanib or imatinib 100 mg-kg orally for another 7 days. Tumor volume, tumor cell apoptosis and proliferation, and microvessel density were quantified.

ResultsCombination of LysAhx-DTPA-InNH2-exendin-4 and vatalanib was significantly more effective than single treatments p < 0.05 and reduced the tumor volume by 97% in the absence of organ damage. The pre-treatment of mice with vatalanib led to a reduction in the tumor uptake of LysAhx-DTPA-InNH2-exendin-4, indicating that concomitant administration of vatalanib and the radiopeptide was the best approach. Imatinib did not show a synergistic effect with LysAhx-DTPA-InNH2-exendin-4.

ConclusionThe combination of 1.1 MBq of LysAhx-DTPA-InNH2-exendin-4 with 100 mg-kg vatalanib had the same effect on a neuroendocrine tumor as the injection of 28 MBq of the radiopeptide alone but without any apparent side effects, such as radiation damage of the kidneys.

KeywordsGlucagon-like peptide receptor Neuroendocrine tumors Anti-angiogenesis Auger emitter Electronic supplementary materialThe online version of this article doi:10.1186-2191-219X-4-9 contains supplementary material, which is available to authorized users.

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Author: Andreas Wicki - Damian Wild - Vincent Prêtre - Rosalba Mansi - Annette Orleth - Jean-Claude Reubi - Christoph Rochlitz - C


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