title: The Blood Flow Shutdown Induced by Combretastatin A4 Impairs Gemcitabine Delivery in a Mouse Hepatocarcinoma.
abstract: In recent clinical studies, vascular disrupting agents (VDAs) are mainly used in combination with chemotherapy. However, an often overlooked concern in treatment combination is the VDA-induced impairment of chemotherapy distribution in the tumor. The work presented here investigated the impact of blood flow shutdown induced by Combretastatin A4 (CA4) on gemcitabine uptake into mouse hepatocarcinoma. At 2 h after CA4 treatment, using DCE-MRI, a significant decrease in the perfusion-relevant parameters Ktransand Vp were observed in treated group compared with the control group. The blood flow shutdown was indeed confirmed by a histology study. In a third experiment, the total gemcitabine uptake was found to be significantly lower in treated tumors, as assessed in a separate experiment usingex vivofluorine nuclear magnetic resonance spectroscopy. The amount of active metabolite gemcitabine triphosphate was also lower in treated tumors. In conclusion, the blood flow shutdown induced by VDAs can impact negatively on the delivery of small cytotoxic agents in tumors. The present study outlines the importance of monitoring the tumor vascular function when designing drug combinations.
authors.affiliation: Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université Catholique de Louvain Brussels, Belgium.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Fruytier
authors.affiliation: Institute of Condensed Matter and Nanosciences, Université Catholique de Louvain Louvain-la-Neuve, Belgium.
authors.forename: Cecile S
authors.initials: CS
authors.lastname: Le Duff
authors.affiliation: Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université Catholique de Louvain Brussels, Belgium.
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Po
authors.affiliation: Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université Catholique de Louvain Brussels, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Magat
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pole of Pharmacology, Angiogenesis and Cancer Research Laboratory, Université Catholique de Louvain Brussels, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bouzin
authors.affiliation: Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université Catholique de Louvain Brussels, Belgium.
authors.forename: Marie-Aline
authors.initials: MA
authors.lastname: Neveu
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pole of Pharmacology, Angiogenesis and Cancer Research Laboratory, Université Catholique de Louvain Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
authors.affiliation: Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université Catholique de Louvain Brussels, Belgium.
authors.forename: Benedicte F
authors.initials: BF
authors.lastname: Jordan
authors.affiliation: Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université Catholique de Louvain Brussels, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Gallez
keywords: 19F NMR; DCE-MRI; drug delivery; tumor perfusion; vascular disrupting agent