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 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.