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Pasireotide Therapy of Multiple Endocrine Neoplasia Type 1–Associated Neuroendocrine Tumors in Female Mice Deleted for an Men1 Allele Improves Survival and Reduces Tumor Progression
Pasireotide, a somatostatin analog, is reported to have anti-proliferative effects in neuroendocrine tumors (NETs). We therefore assessed the efficacy of pasireotide for treating pancreatic and pituitary NETs that develop in a mouse model of multiple endocrine neoplasia type 1 (MEN1). Men1(+/−) mice...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Endocrine Society
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870877/ https://www.ncbi.nlm.nih.gov/pubmed/26990064 http://dx.doi.org/10.1210/en.2015-1965 |
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author | Walls, Gerard V. Stevenson, Mark Soukup, Benjamin S. Lines, Kate E. Grossman, Ashley B. Schmid, Herbert A. Thakker, Rajesh V. |
author_facet | Walls, Gerard V. Stevenson, Mark Soukup, Benjamin S. Lines, Kate E. Grossman, Ashley B. Schmid, Herbert A. Thakker, Rajesh V. |
author_sort | Walls, Gerard V. |
collection | PubMed |
description | Pasireotide, a somatostatin analog, is reported to have anti-proliferative effects in neuroendocrine tumors (NETs). We therefore assessed the efficacy of pasireotide for treating pancreatic and pituitary NETs that develop in a mouse model of multiple endocrine neoplasia type 1 (MEN1). Men1(+/−) mice were treated from age 12 mo with 40 mg/kg pasireotide long-acting release formulation, or PBS, intramuscularly monthly for 9 mo. The Men1(+/−) mice had magnetic resonance imaging at 12 and 21 mo, and from 20 mo oral 5-bromo-2-deoxyuridine for 1 mo, to assess tumor development and proliferation, respectively. NETs were collected at age 21 mo, and proliferation and apoptosis assessed by immunohistochemistry and TUNEL assays, respectively. Pasireotide-treated Men1(+/−) mice had increased survival (pasireotide, 80.9% vs PBS, 65.2%; P < .05), with fewer mice developing pancreatic NETs (pasireotide, 86.9% vs PBS, 96.9%; P < .05) and smaller increases in pituitary NET volumes (pre-treated vs post-treated, 0.803 ± 0.058 mm(3) vs 2.872 ± 0.728 mm(3) [pasireotide] compared with 0.844 ± 0.066 mm(3) vs 8.847 ±1.948 mm(3) [PBS]; P < .01). In addition, pasireotide-treated mice had fewer pancreatic NETs compared with PBS-treated mice (2.36 ± 0.25 vs 3.72 ± 0.32, respectively; P < .001), with decreased proliferation in pancreatic NETs (pasireotide, 0.35 ± 0.03% vs PBS, 0.78 ± 0.08%; P < .0001) and pituitary NETs (pasireotide, 0.73 ±0.07% vs PBS, 1.81 ± 0.15%; P < .0001), but increased apoptosis in pancreatic NETs (pasireotide, 0.42 ± 0.05% vs PBS, 0.19 ± 0.03%; P < .001) and pituitary NETs (pasireotide, 14.75 ± 1.58% vs PBS, 2.35 ± 0.44%; P < .001). Thus, pasireotide increased survival and inhibited pancreatic and pituitary NET growth, thereby indicating its potential as an anti-proliferative and pro-apoptotic therapy. |
format | Online Article Text |
id | pubmed-4870877 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Endocrine Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-48708772016-05-25 Pasireotide Therapy of Multiple Endocrine Neoplasia Type 1–Associated Neuroendocrine Tumors in Female Mice Deleted for an Men1 Allele Improves Survival and Reduces Tumor Progression Walls, Gerard V. Stevenson, Mark Soukup, Benjamin S. Lines, Kate E. Grossman, Ashley B. Schmid, Herbert A. Thakker, Rajesh V. Endocrinology Original Research Pasireotide, a somatostatin analog, is reported to have anti-proliferative effects in neuroendocrine tumors (NETs). We therefore assessed the efficacy of pasireotide for treating pancreatic and pituitary NETs that develop in a mouse model of multiple endocrine neoplasia type 1 (MEN1). Men1(+/−) mice were treated from age 12 mo with 40 mg/kg pasireotide long-acting release formulation, or PBS, intramuscularly monthly for 9 mo. The Men1(+/−) mice had magnetic resonance imaging at 12 and 21 mo, and from 20 mo oral 5-bromo-2-deoxyuridine for 1 mo, to assess tumor development and proliferation, respectively. NETs were collected at age 21 mo, and proliferation and apoptosis assessed by immunohistochemistry and TUNEL assays, respectively. Pasireotide-treated Men1(+/−) mice had increased survival (pasireotide, 80.9% vs PBS, 65.2%; P < .05), with fewer mice developing pancreatic NETs (pasireotide, 86.9% vs PBS, 96.9%; P < .05) and smaller increases in pituitary NET volumes (pre-treated vs post-treated, 0.803 ± 0.058 mm(3) vs 2.872 ± 0.728 mm(3) [pasireotide] compared with 0.844 ± 0.066 mm(3) vs 8.847 ±1.948 mm(3) [PBS]; P < .01). In addition, pasireotide-treated mice had fewer pancreatic NETs compared with PBS-treated mice (2.36 ± 0.25 vs 3.72 ± 0.32, respectively; P < .001), with decreased proliferation in pancreatic NETs (pasireotide, 0.35 ± 0.03% vs PBS, 0.78 ± 0.08%; P < .0001) and pituitary NETs (pasireotide, 0.73 ±0.07% vs PBS, 1.81 ± 0.15%; P < .0001), but increased apoptosis in pancreatic NETs (pasireotide, 0.42 ± 0.05% vs PBS, 0.19 ± 0.03%; P < .001) and pituitary NETs (pasireotide, 14.75 ± 1.58% vs PBS, 2.35 ± 0.44%; P < .001). Thus, pasireotide increased survival and inhibited pancreatic and pituitary NET growth, thereby indicating its potential as an anti-proliferative and pro-apoptotic therapy. Endocrine Society 2016-05 2016-03-18 /pmc/articles/PMC4870877/ /pubmed/26990064 http://dx.doi.org/10.1210/en.2015-1965 Text en https://creativecommons.org/licenses/by/4.0/ This article has been published under the terms of the Creative Commons Attribution License (CC-BY; https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s). |
spellingShingle | Original Research Walls, Gerard V. Stevenson, Mark Soukup, Benjamin S. Lines, Kate E. Grossman, Ashley B. Schmid, Herbert A. Thakker, Rajesh V. Pasireotide Therapy of Multiple Endocrine Neoplasia Type 1–Associated Neuroendocrine Tumors in Female Mice Deleted for an Men1 Allele Improves Survival and Reduces Tumor Progression |
title | Pasireotide Therapy of Multiple Endocrine Neoplasia Type 1–Associated Neuroendocrine Tumors in Female Mice Deleted for an Men1 Allele Improves Survival and Reduces Tumor Progression |
title_full | Pasireotide Therapy of Multiple Endocrine Neoplasia Type 1–Associated Neuroendocrine Tumors in Female Mice Deleted for an Men1 Allele Improves Survival and Reduces Tumor Progression |
title_fullStr | Pasireotide Therapy of Multiple Endocrine Neoplasia Type 1–Associated Neuroendocrine Tumors in Female Mice Deleted for an Men1 Allele Improves Survival and Reduces Tumor Progression |
title_full_unstemmed | Pasireotide Therapy of Multiple Endocrine Neoplasia Type 1–Associated Neuroendocrine Tumors in Female Mice Deleted for an Men1 Allele Improves Survival and Reduces Tumor Progression |
title_short | Pasireotide Therapy of Multiple Endocrine Neoplasia Type 1–Associated Neuroendocrine Tumors in Female Mice Deleted for an Men1 Allele Improves Survival and Reduces Tumor Progression |
title_sort | pasireotide therapy of multiple endocrine neoplasia type 1–associated neuroendocrine tumors in female mice deleted for an men1 allele improves survival and reduces tumor progression |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870877/ https://www.ncbi.nlm.nih.gov/pubmed/26990064 http://dx.doi.org/10.1210/en.2015-1965 |
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