Fruytier Anne-Catherine, Le Duff Cecile S, Po Chrystelle, Magat Julie, Bouzin Caroline, Neveu Marie-Aline, Feron Olivier, Jordan Benedicte F, Gallez Bernard
Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université Catholique de Louvain Brussels, Belgium.
Institute of Condensed Matter and Nanosciences, Université Catholique de Louvain Louvain-la-Neuve, Belgium.
Front Pharmacol. 2016 Dec 23;7:506. doi: 10.3389/fphar.2016.00506. eCollection 2016.
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 K 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 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.
在最近的临床研究中，血管破坏剂（VDAs）主要与化疗联合使用。然而，联合治疗中一个常常被忽视的问题是VDAs导致化疗药物在肿瘤内分布的受损。本文所展示的工作研究了康普瑞汀A4（CA4）诱导的血流阻断对吉西他滨进入小鼠肝癌的摄取的影响。CA4治疗后2小时，使用动态对比增强磁共振成像（DCE-MRI），与对照组相比，治疗组中与灌注相关的参数K和Vp显著降低。组织学研究确实证实了血流阻断。在第三个实验中，如在另一个使用氟核磁共振波谱的实验中所评估的，发现治疗组肿瘤中的吉西他滨总摄取量显著更低。治疗组肿瘤中活性代谢物三磷酸吉西他滨的量也更低。总之，VDAs诱导的血流阻断会对肿瘤中小的细胞毒性药物的递送产生负面影响。本研究概述了在设计联合用药时监测肿瘤血管功能的重要性。
