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

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) wi...

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Veröffentlicht in:Cancers 2022-08, Vol.14 (17), p.4244
Hauptverfasser: 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
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container_issue 17
container_start_page 4244
container_title Cancers
container_volume 14
creator 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
description 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.
doi_str_mv 10.3390/cancers14174244
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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. 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subjects Aminolevulinic acid
Blood-brain barrier
Brain cancer
Brain tumors
Cancer
Care and treatment
Cell adhesion & migration
Cell culture
Enzymes
Glioblastoma
Glioblastoma multiforme
Heme
Life Sciences
Methods
Oral administration
Patient outcomes
Patients
Porphyrins
Proteins
Protoporphyrin
Protoporphyrin IX
Radiation therapy
Radiosensitization
Radiotherapy
Santé publique et épidémiologie
Spheroids
Surgery
Tumors
title An Orthotopic Model of Glioblastoma Is Resistant to Radiodynamic Therapy with 5-AminoLevulinic Acid
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