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Inhomogeneous activity distribution of 177Lu-DOTA0-Tyr3-octreotate and effects on somatostatin receptor expression in human carcinoid GOT1 tumors in nude mice

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Tumor Biology

Abstract

The aim of this study was to investigate the activity distribution in neouroendocrine tumors after diagnostic, or therapeutic, amounts of [177Lu-DOTA0-Tyr3]-octreotate and to investigate how the activity distribution influences the absorbed dose. Furthermore, the activity distribution of a second administration of radiolabeled octreotate was studied. Nude mice with subcutaneously grown human midgut carcinoid (GOT1) were injected intravenously with different amounts of 177Lu-octreotate. At different time points thereafter (4 h to 13 days), a second injection of [111In-DOTA0-Tyr3]-octreotate was given to estimate the somatostatin receptor (sstr) expression. The activity distribution in the tumors was then determined. Monte Carlo simulations with PENELOPE were performed for dosimetry. Fifty-one out of 58 investigated tumors showed a lower activity concentration in the peripheral part than in the central part of the tumor. The amount of activity injected, or time after administration, did neither influence the relative activity nor the sstr distribution in the tumor. After an initial down-regulation (at 4–24 h), there was an up-regulation of sstr (1.5–2 times, at 7–14 days). Monte Carlo simulations demonstrated an inhomogeneous absorbed dose distribution in the tumor using 177Lu, with twice as high absorbed dose centrally than peripherally. The high activity concentration centrally and the up-regulation of sstr demonstrated will facilitate fractionated therapy using radiolabeled somatostatin analogues if similar results will be obtained also in patients. The inhomogeneous activity distribution in the tumor has to be taken into account when the absorbed dose distribution in tumor is calculated.

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References

  1. De Jong M, Valkema R, Jamar F, Kvols LK, Kwekkeboom DJ, Breeman WA, Bakker WH, Smith C, Pauwels S, Krenning EP. Somatostatin receptor-targeted radionuclide therapy of tumors: preclinical and clinical findings. Semin Nucl Med. 2002;32(2):133–40.

    Article  PubMed  Google Scholar 

  2. Kwekkeboom DJ, Mueller-Brand J, Paganelli G, Anthony LB, Pauwels S, Kvols LK, O'Dorisio TM, Valkema R, Bodei L, Chinol M, Maecke HR, Krenning EP. Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs. J Nucl Med. 2005;46 Suppl 1:62S–6S.

    PubMed  CAS  Google Scholar 

  3. Kwekkeboom DJ, Teunissen JJ, Bakker WH, Kooij PP, de Herder WW, Feelders RA, van Eijck CH, Esser JP, Kam BL, Krenning EP. Radiolabeled somatostatin analog [177Lu-DOTA0, Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol. 2005;23(12):2754–62.

    Article  PubMed  CAS  Google Scholar 

  4. Swärd C, Bernhardt P, Ahlman H, Wangberg B, Forssel-Aronsson E, Larsson M, Svensson J, Rossi-Norrlund R, Kolby L. [177Lu-DOTA 0-Tyr 3]-octreotate treatment in patients with disseminated gastroenteropancreatic neuroendocrine tumors: the value of measuring absorbed dose to the kidney. World J Surg. 2010;34(6):1368–72.

    Article  PubMed  Google Scholar 

  5. Van Essen M, Krenning EP, De Jong M, Valkema R, Kwekkeboom DJ. Peptide receptor radionuclide therapy with radiolabelled somatostatin analogues in patients with somatostatin receptor positive tumours. Acta Oncol. 2007;46(6):723–34.

    Article  PubMed  Google Scholar 

  6. Andersson P, Forssell-Aronsson E, Johanson V, Wängberg B, Nilsson O, Fjälling M, Ahlman H. Internalization of indium-111 into human neuroendocrine tumor cells after incubation with indium-111-DTPA-D-Phe1-octreotide. J Nucl Med. 1996;37(12):2002–6.

    PubMed  CAS  Google Scholar 

  7. De Jong M, Bernard BF, De Bruin E, Van Gameren A, Bakker WH, Visser TJ, Macke HR, Krenning EP. Internalization of radiolabelled [DTPA0]octreotide and [DOTA0, Tyr3]octreotide: peptides for somatostatin receptor-targeted scintigraphy and radionuclide therapy. Nucl Med Commun. 1998;19(3):283–8.

    Article  PubMed  Google Scholar 

  8. Hofland LJ, van Koetsveld PM, Waaijers M, Lamberts SW. Internalisation of isotope-coupled somatostatin analogues. Digestion. 1996;57 Suppl 1:2–6.

    Article  PubMed  CAS  Google Scholar 

  9. Storch D, Behe M, Walter MA, Chen J, Powell P, Mikolajczak R, Macke HR. Evaluation of [99mTc/EDDA/HYNIC0]octreotide derivatives compared with [111In-DOTA0, Tyr3, Thr8]octreotide and [111In-DTPA0]octreotide: does tumor or pancreas uptake correlate with the rate of internalization? J Nucl Med. 2005;46(9):1561–9.

    PubMed  CAS  Google Scholar 

  10. Draznin B, Sherman N, Sussman K, Dahl R, Vatter A. Internalization and cellular processing of somatostatin in primary culture of rat anterior pituitary cells. Endocrinology. 1985;117(3):960–6.

    Article  PubMed  CAS  Google Scholar 

  11. Morel G, Pelletier G, Heisler S. Internalization and subcellular distribution of radiolabeled somatostatin-28 in mouse anterior pituitary tumor cells. Endocrinology. 1986;119(5):1972–9.

    Article  PubMed  CAS  Google Scholar 

  12. Behe M, Koller S, Püsken M, Gross M, Alfke H, Keil B. Irradiation-induced upregulation of somatostatin and gastrin receptors in vitro and in vivo. Eur J Nucl Med Mol Imaging. 2004;31:S237–8.

    Google Scholar 

  13. Oddstig J, Bernhardt P, Nilsson O, Ahlman H, Forssell-Aronsson E. Radiation-induced up-regulation of somatostatin receptor expression in small cell lung cancer in vitro. Nucl Med Biol. 2006;33(7):841–6.

    Article  PubMed  CAS  Google Scholar 

  14. Bernhardt P, Oddstig J, Kölby L, Nilsson O, Ahlman H, Forssell-Aronsson E. Effects of treatment with (177)Lu-DOTA-Tyr(3)-octreotate on uptake of subsequent injection in carcinoid-bearing nude mice. Cancer Biother Radiopharm. 2007;22(5):644–53.

    Article  PubMed  CAS  Google Scholar 

  15. Capello A, Krenning E, Bernard B, Reubi JC, Breeman W, de Jong M. 111In-labelled somatostatin analogues in a rat tumour model: somatostatin receptor status and effects of peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging. 2005;32(11):1288–95.

    Article  PubMed  CAS  Google Scholar 

  16. Melis M, Forrer F, Capello A, Bijster M, Bernard BF, Reubi JC, Krenning EP, De Jong M. Up-regulation of somatostatin receptor density on rat CA20948 tumors escaped from low dose [(177)Lu-DOTA(0), Tyr(3)]octreotate therapy. Q J Nucl Med Mol Imaging. 2007;51(4):324–33.

    PubMed  CAS  Google Scholar 

  17. Kölby L, Bernhardt P, Ahlman H, Wängberg B, Johanson V, Wigander A, Forssell-Aronsson E, Karlsson S, Ahren B, Stenman G, Nilsson O. A transplantable human carcinoid as model for somatostatin receptor-mediated and amine transporter-mediated radionuclide uptake. Am J Pathol. 2001;158(2):745–55.

    Article  PubMed  Google Scholar 

  18. Reubi JC, Schar JC, Waser B, Wenger S, Heppeler A, Schmitt JS, Macke HR. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000;27(3):273–82.

    Article  PubMed  CAS  Google Scholar 

  19. Reubi JC, Waser B, Schaer JC, Laissue JA. Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med. 2001;28(7):836–46.

    Article  PubMed  CAS  Google Scholar 

  20. de Jong M, Breeman WA, Bernard BF, Bakker WH, Schaar M, van Gameren A, Bugaj JE, Erion J, Schmidt M, Srinivasan A, Krenning EP. [177Lu-DOTA(0), Tyr3] octreotate for somatostatin receptor-targeted radionuclide therapy. Int J Cancer. 2001;92(5):628–33.

    Article  PubMed  Google Scholar 

  21. Schmitt A, Bernhardt P, Nilsson O, Ahlman H, Kölby L, Maecke HR, Forssell-Aronsson E. Radiation therapy of small cell lung cancer with 177Lu-DOTA-Tyr3-octreotate in an animal model. J Nucl Med. 2004;45(9):1542–8.

    PubMed  CAS  Google Scholar 

  22. Bernhardt P, Forssell-Aronsson E, Jacobsson L, Skarnemark G. Low-energy electron emitters for targeted radiotherapy of small tumours. Acta Oncol. 2001;40(5):602–8.

    Article  PubMed  CAS  Google Scholar 

  23. Uusijärvi HCN, Bernhardt P, Ferrer L, Bardiès M, Forssell-Aronsson E. Comparison of electron dose-point kernels in water generated by the Monte Carlo codes, PENELOPE, GEANT4, MCNPX, and ETRAN. Cancer Biother Radiopharm. 2009;24(4):461–7.

    Article  PubMed  Google Scholar 

  24. Salvat F, Fernándes-Varea J, Sempau J. PENELOPE-2006: a code system for Monte Carlo simulations of electron and photon transport. Paris: OECD Nuclear Energy Agency; 2006.

    Google Scholar 

  25. Browne E, Firestone R. Table of radioactive isotopes. New York: Wiley/Interscience; 1986.

    Google Scholar 

  26. Kölby L, Bernhardt P, Johanson V, Schmitt A, Ahlman H, Forssell-Aronsson E, Mäcke H, Nilsson O. Successful receptor-mediated radiation therapy of xenografted human midgut carcinoid tumour. Br J Cancer. 2005;93(10):1144–51.

    Article  PubMed  Google Scholar 

  27. Nordberg ESA, Persson M, Sundberg AL, Carlsson J, Glimelius B. Cellular uptake of radioiodine delivered by trastuzumab can be modified by the addition of epidermal growth factor. Eur J Nucl Med Mol Imaging. 2005;32(7):771–7.

    Article  PubMed  CAS  Google Scholar 

  28. Thurber GM, Schmidt MM, Wittrup KD. Factors determining antibody distribution in tumors. Trends Pharmacol Sci. 2008;29(2):57–61.

    PubMed  CAS  Google Scholar 

  29. Thurber GM, Zajic SC, Wittrup KD. Theoretic criteria for antibody penetration into solid tumors and micrometastases. J Nucl Med. 2007;48(6):995–9.

    Article  PubMed  CAS  Google Scholar 

  30. Williams L, Bares R, Fass J, Hauptmann S, Schumpelick V, Buell U. Uptake of radiolabeled anti-CEA antibodies in human colorectal primary tumors as a function of tumor mass. Eur J Nucl Med. 1993;20(4):345–7.

    Article  PubMed  CAS  Google Scholar 

  31. Williams L, Duda R, Proffitt R, Beatty B, Beatty D, Wong J, Shively J, Paxton R. Tumor uptake as a function of tumor mass: a mathematic model. J Nucl Med. 1988;29(1):103–9.

    PubMed  CAS  Google Scholar 

  32. Swärd C, Bernhardt P, Johanson V, Schmitt A, Ahlman H, Stridsberg M, Forssell-Aronsson E, Nilsson O, Kölby L. Comparison of [177Lu-DOTA0, Tyr3]-octreotate and [177Lu-DOTA0, Tyr3]-octreotide for receptor-mediated radiation therapy of the xenografted human midgut carcinoid tumor GOT1. Cancer Biother Radiopharm. 2008;23(1):114–20.

    Article  PubMed  Google Scholar 

  33. Forssell-Aronsson E, Bernhardt P, Nilsson O, Tisell LE, Wängberg B, Ahlman H. Biodistribution data from 100 patients i.v. injected with 111In-DTPA-D-Phe1-octreotide. Acta Oncol. 2004;43(5):436–42.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Ann Wikström and Lilian Karlsson at the Department of Radiation Physics for technical assistance, and Prof. Helmut Mäcke, Basel, for providing the DOTA-Tyr3-octreotate. This work was supported by grants from the Swedish National Cancer Society, the Swedish Research Council (5220), and King Gustav V Jubilee Clinic Cancer Research Foundation. The study was carried out within the European Cooperation in the Field of Science and Technology program COST BM0607.

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Authors and Affiliations

  1. Department of Radiation Physics, Lundberg Laboratory for Cancer Research, University of Gothenburg, Sahlgrenska University Hospital, 413 45, Gothenburg, Sweden

    Jenny Oddstig, Peter Bernhardt, Helena Lizana & Eva Forssell-Aronsson

  2. Department of Pathology, Lundberg Laboratory for Cancer Research, University of Gothenburg, Sahlgrenska University Hospital, 413 45, Gothenburg, Sweden

    Ola Nilsson

  3. Department of Surgery, Lundberg Laboratory for Cancer Research, University of Gothenburg, Sahlgrenska University Hospital, 413 45, Gothenburg, Sweden

    Håkan Ahlman & Lars Kölby

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  1. Jenny Oddstig
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Correspondence to Jenny Oddstig.

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Oddstig, J., Bernhardt, P., Lizana, H. et al. Inhomogeneous activity distribution of 177Lu-DOTA0-Tyr3-octreotate and effects on somatostatin receptor expression in human carcinoid GOT1 tumors in nude mice. Tumor Biol. 33, 229–239 (2012). https://doi.org/10.1007/s13277-011-0268-0

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  • DOI: https://doi.org/10.1007/s13277-011-0268-0

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