Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Department of Radiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Cancer Lett. 2022 Sep 28;544:215801. doi: 10.1016/j.canlet.2022.215801. Epub 2022 Jun 19.
Delivery of therapeutic agents in pancreatic cancer (PC) is impaired due to its hypovascular and desmoplastic tumor microenvironment. The Endothelin (ET)-axis is the major regulator of vasomotor tone under physiological conditions and is highly upregulated in multiple cancers. We investigated the effect of dual endothelin receptor antagonist bosentan on perfusion and macromolecular transport in a PC cell-fibroblast co-implantation tumor model using Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI). Following bosentan treatment, the contrast enhancement ratio and wash-in rates in tumors were two- and nine times higher, respectively, compared to the controls, whereas the time to peak was significantly shorter (7.29 ± 1.29 min v/s 22.08 ± 5.88 min; p = 0.04). Importantly, these effects were tumor selective as the magnitudes of change for these parameters were much lower in muscles. Bosentan treatment also reduced desmoplasia and improved intratumoral distribution of high molecular weight FITC-dextran. Overall, these findings support that targeting the ET-axis can serve as a potential strategy to selectively enhance tumor perfusion and improve the delivery of therapeutic agents in pancreatic tumors.
由于胰腺癌细胞（PC）的血管稀少和纤维性肿瘤微环境，治疗药物的递送受到了损害。内皮素（ET）轴是生理条件下血管舒缩的主要调节剂，在多种癌症中高度上调。我们使用动态对比增强磁共振成像（DCE-MRI）研究了双重内皮素受体拮抗剂波生坦对 PC 细胞-成纤维细胞共植入肿瘤模型中的灌注和大分子转运的影响。与对照组相比，博生坦治疗后肿瘤的对比增强比和洗脱率分别高 2 倍和 9 倍，而达峰时间明显缩短（7.29 ± 1.29 分钟比 22.08 ± 5.88 分钟；p = 0.04）。重要的是，这些作用具有肿瘤选择性，因为这些参数的变化幅度在肌肉中要低得多。博生坦治疗还减少了纤维增生并改善了高分子量 FITC-右旋糖酐在肿瘤内的分布。总的来说，这些发现支持靶向 ET 轴可以作为一种潜在的策略，选择性地增强肿瘤灌注并改善胰腺肿瘤中治疗药物的递送。
