{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:19:37Z","timestamp":1790720377253,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T00:00:00Z","timestamp":1641254400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["no. 21073"],"award-info":[{"award-number":["no. 21073"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002794","name":"Swedish Cancer Society","doi-asserted-by":"publisher","award":["no. 3427"],"award-info":[{"award-number":["no. 3427"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011759","name":"Swedish Radiation Safety Authority","doi-asserted-by":"publisher","award":["SSM"],"award-info":[{"award-number":["SSM"]}],"id":[{"id":"10.13039\/501100011759","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Radionuclide treatment of patients with neuroendocrine tumors has advanced in the last decades with favorable results using 177Lu-octreotate. However, the gap between the high cure rate in animal studies vs. patient studies indicates a potential to increase the curation of patients. The aim of this study was to investigate the tumor response for different fractionation schemes with 177Lu-octreotate. BALB\/c mice bearing a human small-intestine neuroendocrine GOT1 tumor were either mock treated with saline or injected intravenously with a total of 30\u2013120 MBq of 177Lu-octreotate: 1 \u00d7 30, 2 \u00d7 15, 1 \u00d7 60, 2 \u00d7 30, 1 \u00d7 120, 2 \u00d7 60, or 3 \u00d7 40 MBq. The tumor volume was measured twice per week until the end of the experiment. The mean tumor volume for mice that received 2 \u00d7 15 = 30 and 1 \u00d7 30 MBq 177Lu-octreotate was reduced by 61% and 52%, respectively. The mean tumor volume was reduced by 91% and 44% for mice that received 2 \u00d7 30 = 60 and 1 \u00d7 60 MBq 177Lu-octreotate, respectively. After 120 MBq 177Lu-octreotate, given as 1\u20133 fractions, the mean tumor volume was reduced by 91\u201397%. Multiple fractions resulted in delayed regrowth and prolonged overall survival by 20\u201325% for the 120 MBq groups and by 45% for lower total activities, relative to one fraction. The results indicate that fractionation and hyperfractionation of 177Lu-octreotate are beneficial for tumor reduction and prolongs the time to regrowth.<\/jats:p>","DOI":"10.3390\/cancers14010235","type":"journal-article","created":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T20:42:16Z","timestamp":1641415336000},"page":"235","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Hyperfractionated Treatment with 177Lu-Octreotate Increases Tumor Response in Human Small-Intestine Neuroendocrine GOT1 Tumor Model"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5470-1377","authenticated-orcid":false,"given":"Mikael","family":"Elvborn","sequence":"first","affiliation":[{"name":"Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden"},{"name":"Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emman","family":"Shubbar","sequence":"additional","affiliation":[{"name":"Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden"},{"name":"Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7558-4368","authenticated-orcid":false,"given":"Eva","family":"Forssell-Aronsson","sequence":"additional","affiliation":[{"name":"Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden"},{"name":"Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden"},{"name":"Department of Medical Physics and Biomedical Engineering, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,4]]},"reference":[{"key":"ref_1","unstructured":"LUTATHERA\u00ae (2021, November 09). Summary of Product Characteristics European Medicines Agency: European Public Assessment Report (EPAR); 2018 [Updated 27 January 2021]. Available online: http:\/\/www.ema.europa.eu."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2124","DOI":"10.1200\/JCO.2007.15.2553","article-title":"Treatment with the radiolabeled somatostatin analog [177Lu-DOTA 0,Tyr3]octreotate: Toxicity, efficacy, and survival","volume":"26","author":"Kwekkeboom","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1056\/NEJMoa1607427","article-title":"Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors","volume":"376","author":"Strosberg","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"R53","DOI":"10.1677\/ERC-09-0078","article-title":"Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors","volume":"17","author":"Kwekkeboom","year":"2010","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/0360-3016(91)90171-Y","article-title":"Tolerance of normal tissue to therapeutic irradiation","volume":"21","author":"Emami","year":"1991","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.1200\/JCO.2005.08.066","article-title":"Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors","volume":"23","author":"Kwekkeboom","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1007\/s00259-018-3945-z","article-title":"Prospective observational study of (177)Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): Feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity","volume":"45","author":"Lundin","year":"2018","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/2191-219X-2-49","article-title":"Estimation of absorbed dose to the kidneys in patients after treatment with 177Lu-octreotate: Comparison between methods based on planar scintigraphy","volume":"2","author":"Larsson","year":"2012","journal-title":"EJNMMI Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1007\/s00268-009-0387-6","article-title":"[177Lu-DOTA 0-Tyr 3]-octreotate treatment in patients with disseminated gastroenteropancreatic neuroendocrine tumors: The value of measuring absorbed dose to the kidney","volume":"34","author":"Bernhardt","year":"2010","journal-title":"World J. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1002\/1097-0215(20010601)92:5<628::AID-IJC1244>3.0.CO;2-L","article-title":"[177Lu-DOTA0,Tyr3]octreotate for somatostatin receptor-targeted radionuclide therapy","volume":"92","author":"Breeman","year":"2001","journal-title":"Int. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1038\/sj.bjc.6602845","article-title":"Successful receptor-mediated radiation therapy of xenografted human midgut carcinoid tumour","volume":"93","author":"Bernhardt","year":"2005","journal-title":"Br. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"288","DOI":"10.2967\/jnumed.116.177584","article-title":"NAMPT Inhibitor GMX1778 Enhances the Efficacy of 177Lu-DOTATATE Treatment of Neuroendocrine Tumors","volume":"58","author":"Elf","year":"2017","journal-title":"J. Nucl. Med."},{"key":"ref_13","first-page":"1542","article-title":"Radiation therapy of small cell lung cancer with 177Lu-DOTA-Tyr3-octreotate in an animal model","volume":"45","author":"Schmitt","year":"2004","journal-title":"J. Nucl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"250","DOI":"10.2174\/1871520611009030250","article-title":"New medical strategies for midgut carcinoids","volume":"10","author":"Nilsson","year":"2010","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1159\/000336086","article-title":"Radionuclide therapy via SSTR: Future aspects from experimental animal studies","volume":"97","author":"Spetz","year":"2013","journal-title":"Neuroendocrinology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3109\/0284186X.2015.1027001","article-title":"The amount of injected 177Lu-octreotate strongly influences biodistribution and dosimetry in C57BL\/6N mice","volume":"55","year":"2016","journal-title":"Acta Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/S0969-8051(02)00417-1","article-title":"Biodistribution of 111in-DTPA-D-Phe1-octreotide in tumor-bearing nude mice: Influence of amount injected and route of administration","volume":"30","author":"Bernhardt","year":"2003","journal-title":"Nucl. Med. Biol."},{"key":"ref_18","first-page":"2002","article-title":"Internalization of indium-111 into human neuroendocrine tumor cells after incubation with indium-111-DTPA-D-Phe1-octreotide","volume":"37","author":"Andersson","year":"1996","journal-title":"J. Nucl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1210\/jc.2008-1919","article-title":"Differential effects of octreotide and pasireotide on somatostatin receptor internalization and trafficking in vitro","volume":"94","author":"Lesche","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1055\/s-0032-1311603","article-title":"Specific binding and uptake of 131I-MIBG and 111In-octreotide in metastatic paraganglioma--tools for choice of radionuclide therapy","volume":"44","author":"Spetz","year":"2012","journal-title":"Horm. Metab. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"936","DOI":"10.2967\/jnumed.108.061457","article-title":"Highly efficient in vivo agonist-induced internalization of sst2 receptors in somatostatin target tissues","volume":"50","author":"Waser","year":"2009","journal-title":"J. Nucl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1210\/er.2000-0001","article-title":"The pathophysiological consequences of somatostatin receptor internalization and resistance","volume":"24","author":"Hofland","year":"2003","journal-title":"Endocr. Rev."},{"key":"ref_23","first-page":"231","article-title":"Differences in biodistribution between 99mTc-depreotide, 111In-DTPA-octreotide, and 177Lu-DOTA-Tyr3-octreotate in a small cell lung cancer animal model","volume":"20","author":"Schmitt","year":"2005","journal-title":"Cancer Biother. Radiopharm."},{"key":"ref_24","first-page":"623","article-title":"Effect of dose and specific activity on tissue distribution of indium-111-pentetreotide in rats","volume":"36","author":"Breeman","year":"1995","journal-title":"J. Nucl. Med."},{"key":"ref_25","first-page":"174","article-title":"Biodistribution of 177Lu-octreotate and 111In-minigastrin in female nude mice transplanted with human medullary thyroid carcinoma GOT2","volume":"27","author":"Dalmo","year":"2012","journal-title":"Oncol. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/2191-219X-3-82","article-title":"Does PRRT with standard activities of 177Lu-octreotate really achieve relevant somatostatin receptor saturation in target tumor lesions? Insights from intra-therapeutic receptor imaging in patients with metastatic gastroenteropancreatic neuroendocrine tumors","volume":"3","author":"Sabet","year":"2013","journal-title":"EJNMMI Res."},{"key":"ref_27","unstructured":"Andersson, P., Forssell-Aronsson, E., Gr\u00e9tarsd\u00f3ttir, J., Johanson, V., W\u00e4ngberg, B., Nilsson, O., Fj\u00e4lling, M., and Ahlman, H. (1996, January 7\u201310). Biokinetics and dosimetry after repeated injections of 111In-DTPA-D-Phe1-octreotide. Proceedings of the Sixth International Radiopharmaceutical Dosimetry Symposium, ORISE 99-0164, Gatlinburg, TN, USA."},{"key":"ref_28","first-page":"644","article-title":"Effects of treatment with (177)Lu-DOTA-Tyr(3)-octreotate on uptake of subsequent injection in carcinoid-bearing nude mice","volume":"22","author":"Bernhardt","year":"2007","journal-title":"Cancer Biother. Radiopharm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s13277-011-0268-0","article-title":"Inhomogeneous activity distribution of 177Lu-DOTA0-Tyr3-octreotate and effects on somatostatin receptor expression in human carcinoid GOT1 tumors in nude mice","volume":"33","author":"Oddstig","year":"2012","journal-title":"Tumour Biol."},{"key":"ref_30","first-page":"759","article-title":"Radiation induces up-regulation of somatostatin receptors 1, 2, and 5 in small cell lung cancer in vitro also at low absorbed doses","volume":"26","author":"Oddstig","year":"2011","journal-title":"Cancer Biother. Radiopharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.nucmedbio.2006.07.010","article-title":"Radiation-induced up-regulation of somatostatin receptor expression in small cell lung cancer in vitro","volume":"33","author":"Oddstig","year":"2006","journal-title":"Nucl. Med. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13550-016-0247-y","article-title":"Priming increases the anti-tumor effect and therapeutic window of (177)Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1","volume":"7","author":"Dalmo","year":"2017","journal-title":"EJNMMI Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s13550-019-0500-2","article-title":"Transcriptional effects of (177)Lu-octreotate therapy using a priming treatment schedule on GOT1 tumor in nude mice","volume":"9","author":"Spetz","year":"2019","journal-title":"EJNMMI Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/S0002-9440(10)64017-5","article-title":"A transplantable human carcinoid as model for somatostatin receptor-mediated and amine transporter-mediated radionuclide uptake","volume":"158","author":"Bernhardt","year":"2001","journal-title":"Am. J. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.2967\/jnumed.120.243543","article-title":"Peptide Receptor Radionuclide Therapy with (67)Cu-CuSarTATE Is Highly Efficacious Against a Somatostatin-Positive Neuroendocrine Tumor Model","volume":"61","author":"Cullinane","year":"2020","journal-title":"J. Nucl. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Romiani, A., Spetz, J., Shubbar, E., Lind, D.E., Hallberg, B., Palmer, R.H., and Forssell-Aronsson, E. (2021). Neuroblastoma xenograft models demonstrate the therapeutic potential of (177)Lu-octreotate. BMC Cancer, 21.","DOI":"10.1186\/s12885-021-08551-8"},{"key":"ref_37","first-page":"324","article-title":"Up-regulation of somatostatin receptor density on rat CA20948 tumors escaped from low dose [177Lu-DOTA0,Tyr3]octreotate therapy","volume":"51","author":"Melis","year":"2007","journal-title":"Q. J. Nucl. Med. Mol. Imaging"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1097\/MNM.0000000000000685","article-title":"Early efficacy of and toxicity from lutetium-177-DOTATATE treatment in patients with progressive metastatic NET","volume":"38","author":"Pencharz","year":"2017","journal-title":"Nucl. Med. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Carpizo, D.R., and Harris, C.R. (2021). Genetic Drivers of Ileal Neuroendocrine Tumors. Cancers, 13.","DOI":"10.3390\/cancers13205070"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1196\/annals.1294.031","article-title":"GOT1 xenografted to nude mice: A unique model for in vivo studies on SSTR-mediated radiation therapy of carcinoid tumors","volume":"1014","author":"Nilsson","year":"2004","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e4060","DOI":"10.1002\/nbm.4060","article-title":"Multiparametric MR for non-invasive evaluation of tumour tissue histological characteristics after radionuclide therapy","volume":"32","author":"Montelius","year":"2019","journal-title":"NMR Biomed."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/1\/235\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:00:06Z","timestamp":1760364006000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/1\/235"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,4]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["cancers14010235"],"URL":"https:\/\/doi.org\/10.3390\/cancers14010235","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,4]]}}}