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Electron Paramagnetic Resonance Highlights That the Oxygen Effect Contributes to the Radiosensitizing Effect of Paclitaxel
BACKGROUND: Paclitaxel (PTX) is a potent anti-cancer chemotherapeutic agent and is widely used in the treatments of solid tumors, particularly of the breast and ovaries. An effective and safe micellar formulation of PTX was used to administer higher doses of PTX than Taxol® (the current commercializ...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395636/ https://www.ncbi.nlm.nih.gov/pubmed/22808261 http://dx.doi.org/10.1371/journal.pone.0040772 |
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author | Danhier, Fabienne Danhier, Pierre Magotteaux, Nicolas De Preter, Géraldine Ucakar, Bernard Karroum, Oussama Jordan, Bénédicte Gallez, Bernard Préat, Véronique |
author_facet | Danhier, Fabienne Danhier, Pierre Magotteaux, Nicolas De Preter, Géraldine Ucakar, Bernard Karroum, Oussama Jordan, Bénédicte Gallez, Bernard Préat, Véronique |
author_sort | Danhier, Fabienne |
collection | PubMed |
description | BACKGROUND: Paclitaxel (PTX) is a potent anti-cancer chemotherapeutic agent and is widely used in the treatments of solid tumors, particularly of the breast and ovaries. An effective and safe micellar formulation of PTX was used to administer higher doses of PTX than Taxol® (the current commercialized drug). We hypothesize that PTX-loaded micelles (M-PTX) may enhance tumor radiosensitivity by increasing the tumor oxygenation (pO(2)). Our goals were (i) to evaluate the contribution of the “oxygen effect” to the radiosensitizing effect of PTX; (ii) to demonstrate the therapeutic relevance of the combination of M-PTX and irradiation and (iii) to investigate the underlying mechanisms of the observed oxygen effect. METHODOLOGY AND PRINCIPAL FINDINGS: We used (PEG-p-(CL-co-TMC)) polymeric micelles to solubilize PTX. pO(2) was measured on TLT tumor-bearing mice treated with M-PTX (80 mg/kg) using electron paramagnetic resonance (EPR) oximetry. The regrowth delay following 10 Gy irradiation 24 h after M-PTX treatment was measured. The tumor perfusion was assessed by the patent blue staining. The oxygen consumption rate and the apoptosis were evaluated by EPR oximetry and the TUNEL assay, respectively. EPR oximetry experiments showed that M-PTX dramatically increases the pO(2) 24 h post treatment. Regrowth delay assays demonstrated a synergy between M-PTX and irradiation. M-PTX increased the tumor blood flow while cells treated with M-PTX consumed less oxygen and presented more apoptosis. CONCLUSIONS: M-PTX improved the tumor oxygenation which leads to synergy between this treatment and irradiation. This increased pO(2) can be explained both by an increased blood flow and an inhibition of O(2) consumption. |
format | Online Article Text |
id | pubmed-3395636 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33956362012-07-17 Electron Paramagnetic Resonance Highlights That the Oxygen Effect Contributes to the Radiosensitizing Effect of Paclitaxel Danhier, Fabienne Danhier, Pierre Magotteaux, Nicolas De Preter, Géraldine Ucakar, Bernard Karroum, Oussama Jordan, Bénédicte Gallez, Bernard Préat, Véronique PLoS One Research Article BACKGROUND: Paclitaxel (PTX) is a potent anti-cancer chemotherapeutic agent and is widely used in the treatments of solid tumors, particularly of the breast and ovaries. An effective and safe micellar formulation of PTX was used to administer higher doses of PTX than Taxol® (the current commercialized drug). We hypothesize that PTX-loaded micelles (M-PTX) may enhance tumor radiosensitivity by increasing the tumor oxygenation (pO(2)). Our goals were (i) to evaluate the contribution of the “oxygen effect” to the radiosensitizing effect of PTX; (ii) to demonstrate the therapeutic relevance of the combination of M-PTX and irradiation and (iii) to investigate the underlying mechanisms of the observed oxygen effect. METHODOLOGY AND PRINCIPAL FINDINGS: We used (PEG-p-(CL-co-TMC)) polymeric micelles to solubilize PTX. pO(2) was measured on TLT tumor-bearing mice treated with M-PTX (80 mg/kg) using electron paramagnetic resonance (EPR) oximetry. The regrowth delay following 10 Gy irradiation 24 h after M-PTX treatment was measured. The tumor perfusion was assessed by the patent blue staining. The oxygen consumption rate and the apoptosis were evaluated by EPR oximetry and the TUNEL assay, respectively. EPR oximetry experiments showed that M-PTX dramatically increases the pO(2) 24 h post treatment. Regrowth delay assays demonstrated a synergy between M-PTX and irradiation. M-PTX increased the tumor blood flow while cells treated with M-PTX consumed less oxygen and presented more apoptosis. CONCLUSIONS: M-PTX improved the tumor oxygenation which leads to synergy between this treatment and irradiation. This increased pO(2) can be explained both by an increased blood flow and an inhibition of O(2) consumption. Public Library of Science 2012-07-12 /pmc/articles/PMC3395636/ /pubmed/22808261 http://dx.doi.org/10.1371/journal.pone.0040772 Text en Danhier et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Danhier, Fabienne Danhier, Pierre Magotteaux, Nicolas De Preter, Géraldine Ucakar, Bernard Karroum, Oussama Jordan, Bénédicte Gallez, Bernard Préat, Véronique Electron Paramagnetic Resonance Highlights That the Oxygen Effect Contributes to the Radiosensitizing Effect of Paclitaxel |
title | Electron Paramagnetic Resonance Highlights That the Oxygen Effect Contributes to the Radiosensitizing Effect of Paclitaxel |
title_full | Electron Paramagnetic Resonance Highlights That the Oxygen Effect Contributes to the Radiosensitizing Effect of Paclitaxel |
title_fullStr | Electron Paramagnetic Resonance Highlights That the Oxygen Effect Contributes to the Radiosensitizing Effect of Paclitaxel |
title_full_unstemmed | Electron Paramagnetic Resonance Highlights That the Oxygen Effect Contributes to the Radiosensitizing Effect of Paclitaxel |
title_short | Electron Paramagnetic Resonance Highlights That the Oxygen Effect Contributes to the Radiosensitizing Effect of Paclitaxel |
title_sort | electron paramagnetic resonance highlights that the oxygen effect contributes to the radiosensitizing effect of paclitaxel |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395636/ https://www.ncbi.nlm.nih.gov/pubmed/22808261 http://dx.doi.org/10.1371/journal.pone.0040772 |
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