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Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug
The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588367/ https://www.ncbi.nlm.nih.gov/pubmed/26501110 http://dx.doi.org/10.1016/j.ebiom.2015.08.013 |
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author | Sharpe, Martyn A. Livingston, Andrew D. Gist, Taylor L. Ghosh, Pardip Han, Junyan Baskin, David S. |
author_facet | Sharpe, Martyn A. Livingston, Andrew D. Gist, Taylor L. Ghosh, Pardip Han, Junyan Baskin, David S. |
author_sort | Sharpe, Martyn A. |
collection | PubMed |
description | The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P(+)-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models. |
format | Online Article Text |
id | pubmed-4588367 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-45883672015-10-23 Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug Sharpe, Martyn A. Livingston, Andrew D. Gist, Taylor L. Ghosh, Pardip Han, Junyan Baskin, David S. EBioMedicine Research Paper The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P(+)-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models. Elsevier 2015-08-08 /pmc/articles/PMC4588367/ /pubmed/26501110 http://dx.doi.org/10.1016/j.ebiom.2015.08.013 Text en © 2015 The Authors. Published by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Paper Sharpe, Martyn A. Livingston, Andrew D. Gist, Taylor L. Ghosh, Pardip Han, Junyan Baskin, David S. Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug |
title | Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug |
title_full | Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug |
title_fullStr | Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug |
title_full_unstemmed | Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug |
title_short | Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug |
title_sort | successful treatment of intracranial glioblastoma xenografts with a monoamine oxidase b-activated pro-drug |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588367/ https://www.ncbi.nlm.nih.gov/pubmed/26501110 http://dx.doi.org/10.1016/j.ebiom.2015.08.013 |
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