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...

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Main Authors: Fabienne Danhier, Pierre Danhier, Nicolas Magotteaux, Géraldine De Preter, Bernard Ucakar, Oussama Karroum, Bénédicte Jordan, Bernard Gallez, Véronique Préat
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2012-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3395636?pdf=render
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author Fabienne Danhier
Pierre Danhier
Nicolas Magotteaux
Géraldine De Preter
Bernard Ucakar
Oussama Karroum
Bénédicte Jordan
Bernard Gallez
Véronique Préat
author_facet Fabienne Danhier
Pierre Danhier
Nicolas Magotteaux
Géraldine De Preter
Bernard Ucakar
Oussama Karroum
Bénédicte Jordan
Bernard Gallez
Véronique Préat
author_sort Fabienne Danhier
collection DOAJ
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.
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spelling doaj.art-6c2fc95f033647f5968e4dac4dc873e42022-12-22T00:14:29ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0177e4077210.1371/journal.pone.0040772Electron paramagnetic resonance highlights that the oxygen effect contributes to the radiosensitizing effect of paclitaxel.Fabienne DanhierPierre DanhierNicolas MagotteauxGéraldine De PreterBernard UcakarOussama KarroumBénédicte JordanBernard GallezVéronique PréatBACKGROUND: 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.http://europepmc.org/articles/PMC3395636?pdf=render
spellingShingle Fabienne Danhier
Pierre Danhier
Nicolas Magotteaux
Géraldine De Preter
Bernard Ucakar
Oussama Karroum
Bénédicte Jordan
Bernard Gallez
Véronique Préat
Electron paramagnetic resonance highlights that the oxygen effect contributes to the radiosensitizing effect of paclitaxel.
PLoS ONE
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
url http://europepmc.org/articles/PMC3395636?pdf=render
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