Al-Mahrouki Azza A, Iradji Sara, Tran William Tyler, Czarnota Gregory J
Physical Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
Dis Model Mech. 2014 Mar;7(3):363-72. doi: 10.1242/dmm.012922. Epub 2014 Jan 30.
Tumor radiation resistance poses a major obstacle in achieving an optimal outcome in radiation therapy. In the current study, we characterize a novel therapeutic approach that combines ultrasound-driven microbubbles with radiation to increase treatment responses in a prostate cancer xenograft model in mice. Tumor response to ultrasound-driven microbubbles and radiation was assessed 24 hours after treatment, which consisted of radiation treatments alone (2 Gy or 8 Gy) or ultrasound-stimulated microbubbles only, or a combination of radiation and ultrasound-stimulated microbubbles. Immunohistochemical analysis using in situ end labeling (ISEL) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) revealed increased cell death within tumors exposed to combined treatments compared with untreated tumors or tumors exposed to radiation alone. Several biomarkers were investigated to evaluate cell proliferation (Ki67), blood leakage (factor VIII), angiogenesis (cluster of differentiation molecule CD31), ceramide-formation, angiogenesis signaling [vascular endothelial growth factor (VEGF)], oxygen limitation (prolyl hydroxylase PHD2) and DNA damage/repair (γH2AX). Results demonstrated reduced vascularity due to vascular disruption by ultrasound-stimulated microbubbles, increased ceramide production and increased DNA damage of tumor cells, despite decreased tumor oxygenation with significantly less proliferating cells in the combined treatments. This combined approach could be a feasible option as a novel enhancing approach in radiation therapy.
肿瘤放射抗性是实现放射治疗最佳效果的主要障碍。在本研究中，我们描述了一种新的治疗方法，该方法将超声驱动的微泡与放射相结合，以增强小鼠前列腺癌异种移植模型中的治疗反应。在治疗后24小时评估肿瘤对超声驱动微泡和放射的反应，治疗包括单独的放射治疗（2 Gy或8 Gy）、仅超声刺激的微泡，或放射与超声刺激微泡的组合。使用原位末端标记（ISEL）和末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）的免疫组织化学分析显示，与未治疗的肿瘤或仅接受放射治疗的肿瘤相比，联合治疗的肿瘤内细胞死亡增加。研究了几种生物标志物以评估细胞增殖（Ki67）、血液渗漏（因子VIII）、血管生成（分化簇分子CD31）、神经酰胺形成、血管生成信号传导[血管内皮生长因子（VEGF）]、氧限制（脯氨酰羟化酶PHD2）和DNA损伤/修复（γH2AX）。结果表明，尽管联合治疗中肿瘤氧合减少且增殖细胞显著减少，但超声刺激的微泡导致血管破坏，从而使血管密度降低，肿瘤细胞的神经酰胺生成增加且DNA损伤增加。这种联合方法作为放射治疗中的一种新的增强方法可能是一种可行的选择。
