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An Orthotopic Model of Glioblastoma Is Resistant to Radiodynamic Therapy with 5-AminoLevulinic Acid

SIMPLE SUMMARY: Radiosensitization of glioblastoma is a major ambition to increase the survival of this incurable cancer. Before surgery, oral administration of 5-aminolevulinic acid leads to the accumulation of fluorescent protoporphyrin IX, preferentially in the cancer cells rather than in the nor...

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Autores principales: Dupin, Charles, Sutter, Jade, Amintas, Samuel, Derieppe, Marie-Alix, Lalanne, Magalie, Coulibaly, Soule, Guyon, Joris, Daubon, Thomas, Boutin, Julian, Blouin, Jean-Marc, Richard, Emmanuel, Moreau-Gaudry, François, Bedel, Aurélie, Vendrely, Véronique, Dabernat, Sandrine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454704/
https://www.ncbi.nlm.nih.gov/pubmed/36077783
http://dx.doi.org/10.3390/cancers14174244
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author Dupin, Charles
Sutter, Jade
Amintas, Samuel
Derieppe, Marie-Alix
Lalanne, Magalie
Coulibaly, Soule
Guyon, Joris
Daubon, Thomas
Boutin, Julian
Blouin, Jean-Marc
Richard, Emmanuel
Moreau-Gaudry, François
Bedel, Aurélie
Vendrely, Véronique
Dabernat, Sandrine
author_facet Dupin, Charles
Sutter, Jade
Amintas, Samuel
Derieppe, Marie-Alix
Lalanne, Magalie
Coulibaly, Soule
Guyon, Joris
Daubon, Thomas
Boutin, Julian
Blouin, Jean-Marc
Richard, Emmanuel
Moreau-Gaudry, François
Bedel, Aurélie
Vendrely, Véronique
Dabernat, Sandrine
author_sort Dupin, Charles
collection PubMed
description SIMPLE SUMMARY: Radiosensitization of glioblastoma is a major ambition to increase the survival of this incurable cancer. Before surgery, oral administration of 5-aminolevulinic acid leads to the accumulation of fluorescent protoporphyrin IX, preferentially in the cancer cells rather than in the normal brain. This property is used to optimize the resection of the tumor under fluorescent light. Protoporphyrin IX may also carry radiosensitization activity. To test this hypothesis, we designed a robust murine preclinical model of glioblastoma with tumors implanted into the brain of mice treated by fractionated radiotherapy, as for humans. Despite the specific accumulation of porphyrins in glioblastoma, there was no radiosensitization. We confirmed these results in in vitro 3D patient-derived spheroids. Radiosensitization by molecules such as porphyrins needs more exploration for application in glioblastoma treatment. ABSTRACT: Radiosensitization of glioblastoma is a major ambition to increase the survival of this incurable cancer. The 5-aminolevulinic acid (5-ALA) is metabolized by the heme biosynthesis pathway. 5-ALA overload leads to the accumulation of the intermediate fluorescent metabolite protoporphyrin IX (PpIX) with a radiosensitization potential, never tested in a relevant model of glioblastoma. We used a patient-derived tumor cell line grafted orthotopically to create a brain tumor model. We evaluated tumor growth and tumor burden after different regimens of encephalic multifractionated radiation therapy with or without 5-ALA. A fractionation scheme of 5 × 2 Gy three times a week resulted in intermediate survival [48–62 days] compared to 0 Gy (15–24 days), 3 × 2 Gy (41–47 days) and, 5 × 3 Gy (73–83 days). Survival was correlated to tumor growth. Tumor growth and survival were similar after 5 × 2 Gy irradiations, regardless of 5-ALA treatment (RT group (53–67 days), RT+5-ALA group (40–74 days), HR = 1.57, p = 0.24). Spheroid growth and survival were diminished by radiotherapy in vitro, unchanged by 5-ALA pre-treatment, confirming the in vivo results. The analysis of two additional stem-like patient-derived cell lines confirmed the absence of radiosensitization by 5-ALA. Our study shows for the first time that in a preclinical tumor model relevant to human glioblastoma, treated as in clinical routine, 5-ALA administration, although leading to important accumulation of PpIX, does not potentiate radiotherapy.
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spelling pubmed-94547042022-09-09 An Orthotopic Model of Glioblastoma Is Resistant to Radiodynamic Therapy with 5-AminoLevulinic Acid Dupin, Charles Sutter, Jade Amintas, Samuel Derieppe, Marie-Alix Lalanne, Magalie Coulibaly, Soule Guyon, Joris Daubon, Thomas Boutin, Julian Blouin, Jean-Marc Richard, Emmanuel Moreau-Gaudry, François Bedel, Aurélie Vendrely, Véronique Dabernat, Sandrine Cancers (Basel) Article SIMPLE SUMMARY: Radiosensitization of glioblastoma is a major ambition to increase the survival of this incurable cancer. Before surgery, oral administration of 5-aminolevulinic acid leads to the accumulation of fluorescent protoporphyrin IX, preferentially in the cancer cells rather than in the normal brain. This property is used to optimize the resection of the tumor under fluorescent light. Protoporphyrin IX may also carry radiosensitization activity. To test this hypothesis, we designed a robust murine preclinical model of glioblastoma with tumors implanted into the brain of mice treated by fractionated radiotherapy, as for humans. Despite the specific accumulation of porphyrins in glioblastoma, there was no radiosensitization. We confirmed these results in in vitro 3D patient-derived spheroids. Radiosensitization by molecules such as porphyrins needs more exploration for application in glioblastoma treatment. ABSTRACT: Radiosensitization of glioblastoma is a major ambition to increase the survival of this incurable cancer. The 5-aminolevulinic acid (5-ALA) is metabolized by the heme biosynthesis pathway. 5-ALA overload leads to the accumulation of the intermediate fluorescent metabolite protoporphyrin IX (PpIX) with a radiosensitization potential, never tested in a relevant model of glioblastoma. We used a patient-derived tumor cell line grafted orthotopically to create a brain tumor model. We evaluated tumor growth and tumor burden after different regimens of encephalic multifractionated radiation therapy with or without 5-ALA. A fractionation scheme of 5 × 2 Gy three times a week resulted in intermediate survival [48–62 days] compared to 0 Gy (15–24 days), 3 × 2 Gy (41–47 days) and, 5 × 3 Gy (73–83 days). Survival was correlated to tumor growth. Tumor growth and survival were similar after 5 × 2 Gy irradiations, regardless of 5-ALA treatment (RT group (53–67 days), RT+5-ALA group (40–74 days), HR = 1.57, p = 0.24). Spheroid growth and survival were diminished by radiotherapy in vitro, unchanged by 5-ALA pre-treatment, confirming the in vivo results. The analysis of two additional stem-like patient-derived cell lines confirmed the absence of radiosensitization by 5-ALA. Our study shows for the first time that in a preclinical tumor model relevant to human glioblastoma, treated as in clinical routine, 5-ALA administration, although leading to important accumulation of PpIX, does not potentiate radiotherapy. MDPI 2022-08-31 /pmc/articles/PMC9454704/ /pubmed/36077783 http://dx.doi.org/10.3390/cancers14174244 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dupin, Charles
Sutter, Jade
Amintas, Samuel
Derieppe, Marie-Alix
Lalanne, Magalie
Coulibaly, Soule
Guyon, Joris
Daubon, Thomas
Boutin, Julian
Blouin, Jean-Marc
Richard, Emmanuel
Moreau-Gaudry, François
Bedel, Aurélie
Vendrely, Véronique
Dabernat, Sandrine
An Orthotopic Model of Glioblastoma Is Resistant to Radiodynamic Therapy with 5-AminoLevulinic Acid
title An Orthotopic Model of Glioblastoma Is Resistant to Radiodynamic Therapy with 5-AminoLevulinic Acid
title_full An Orthotopic Model of Glioblastoma Is Resistant to Radiodynamic Therapy with 5-AminoLevulinic Acid
title_fullStr An Orthotopic Model of Glioblastoma Is Resistant to Radiodynamic Therapy with 5-AminoLevulinic Acid
title_full_unstemmed An Orthotopic Model of Glioblastoma Is Resistant to Radiodynamic Therapy with 5-AminoLevulinic Acid
title_short An Orthotopic Model of Glioblastoma Is Resistant to Radiodynamic Therapy with 5-AminoLevulinic Acid
title_sort orthotopic model of glioblastoma is resistant to radiodynamic therapy with 5-aminolevulinic acid
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454704/
https://www.ncbi.nlm.nih.gov/pubmed/36077783
http://dx.doi.org/10.3390/cancers14174244
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