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 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.


RESULTS
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.
Pharmaceutics and Drug Delivery, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
Fabienne
F
Danhier
Pierre
P
Danhier
Nicolas
N
Magotteaux
Géraldine
G
De Preter
Bernard
B
Ucakar
Oussama
O
Karroum
Bénédicte
B
Jordan
Bernard
B
Gallez
Véronique
V
Préat
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods*; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008823:Micelles; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010313:Partial Pressure; D010477:Perfusion; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D013194:Staining and Labeling
D000970:Antineoplastic Agents; D008823:Micelles; D011838:Radiation-Sensitizing Agents; D017239:Paclitaxel; D010100:Oxygen