Systemic Delivery of Oncolytic Adenoviruses Targeting Transforming Growth Factor-β Inhibits Established Bone Metastasis in a Prostate Cancer Mouse Model
Systemic Delivery of Oncolytic Adenoviruses Targeting Transforming Growth Factor-β Inhibits Established Bone Metastasis in a Prostate Cancer Mouse Model
复制标题
DOI：
10.1089/hum.2012.040
复制
发表时间：
2012-08-01
影响因子：
4.2
通讯作者：
Seth, Prem
中科院分区：
文献类型：
--
作者：
Hu, Zebin;Gupta, Janhavi;Seth, Prem
我们已经检查了Ad。sT - RFc和TAd。sT β RFc是两种表达可溶性转化生长因子- β受体II与人Fc融合的溶瘤病毒（sTGF β RIIFc），可用于治疗前列腺癌骨转移。PC-3和DU-145前列腺肿瘤细胞与Ad的孵育。sT - RFc和TAd。sT β RFc产生sTGF β RIIFc和病毒复制；sTGF β RIIFc可抑制tgf - β介导的SMAD2和SMAD3磷酸化。广告(E1)。sT β RFc是一种E1（-）腺病毒，产生sTGF β RIIFc，但在肿瘤细胞中无法复制。为了检测腺病毒载体的抗肿瘤反应，将PC-3-luc细胞注射到裸鼠左心室。第9天，小鼠进行全身生物发光成像（BLI）。后肢肿瘤小鼠于第10、13和17天通过尾静脉注射病毒载体（每只小鼠每次注射2.5 x 10（10）个病毒颗粒，每次注射体积为0.1 ml），并每周进行BLI和x射线摄影，直到第53天。广告。sT RFc, TAd。sT β RFc和Ad（E1-）。sT β RFc对肿瘤生长有显著抑制作用；然而,广告。sT β RFc是所有载体中最有效的。只有广告。sT - RFc和TAd。sT β RFc抑制肿瘤诱导的高钙血症。离体骨的组织形态学和同步加速器显微计算机断层扫描分析显示Ad。sT β RFc诱导肿瘤负荷、破骨细胞数量、骨小梁和皮质骨破坏显著减少。这些研究表明，Ad。sT - RFc和TAd。sT β RFc可作为前列腺癌骨转移的潜在新疗法。
We have examined whether Ad.sT beta RFc and TAd.sT beta RFc, two oncolytic viruses expressing soluble transforming growth factor-beta receptor II fused with human Fc (sTGF beta RIIFc), can be developed to treat bone metastasis of prostate cancer. Incubation of PC-3 and DU-145 prostate tumor cells with Ad.sT beta RFc and TAd.sT beta RFc produced sTGF beta RIIFc and viral replication; sTGF beta RIIFc caused inhibition of TGF-beta-mediated SMAD2 and SMAD3 phosphorylation. Ad(E1-).sT beta RFc, an E1(-) adenovirus, produced sTGF beta RIIFc but failed to replicate in tumor cells. To examine the antitumor response of adenoviral vectors, PC-3-luc cells were injected into the left heart ventricle of nude mice. On day 9, mice were subjected to whole-body bioluminescence imaging (BLI). Mice bearing hind-limb tumors were administered viral vectors via the tail vein on days 10, 13, and 17 (2.5 x 10(10) viral particles per injection per mouse, each injection in a 0.1-ml volume), and subjected to BLI and X-ray radiography weekly until day 53. Ad.sT beta RFc, TAd.sT beta RFc, and Ad(E1-).sT beta RFc caused significant inhibition of tumor growth; however, Ad.sT beta RFc was the most effective among all the vectors. Only Ad.sT beta RFc and TAd.sT beta RFc inhibited tumor-induced hypercalcemia. Histomorphometric and synchrotron micro-computed tomographic analysis of isolated bones indicated that Ad.sT beta RFc induced significant reduction in tumor burden, osteoclast number, and trabecular and cortical bone destruction. These studies suggest that Ad.sT beta RFc and TAd.sT beta RFc can be developed as potential new therapies for prostate cancer bone metastasis.