AUTHOR=Fruytier Anne-Catherine , Le Duff Cecile S. , Po Chrystelle , Magat Julie , Bouzin Caroline , Neveu Marie-Aline , Feron Olivier , Jordan Benedicte F. , Gallez Bernard 

TITLE=The Blood Flow Shutdown Induced by Combretastatin A4 Impairs Gemcitabine Delivery in a Mouse Hepatocarcinoma

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 7 - 2016

YEAR=2016

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2016.00506

DOI=10.3389/fphar.2016.00506

ISSN=1663-9812

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 hours after CA4 treatment, using DCE-MRI, a significant decrease in the perfusion-relevant parameters Ktrans and 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 using ex vivo fluorine 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.