Cheng Jin, Sauthoff Harald, Huang YaoQi, Kutler David I, Bajwa Sofia, Rom William N, Hay John G
Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, New York 10016, USA.
Mol Ther. 2007 Nov;15(11):1982-90. doi: 10.1038/sj.mt.6300264. Epub 2007 Jul 24.
The success of replicating adenoviruses for cancer therapy is limited by inefficient virus delivery and poor distribution within the tumor mass. Stromal matrix within the tumor may hinder the free cell-to-cell spread of the virus. In this study, in vitro cell culture experiments showed that collagen I blocked the passage of an adenoviral vector through a membrane. On the basis of reports of the effective collagen I-degrading activity of matrix metalloproteinase-8 (MMP-8), we constructed an adenovirus to express the MMP-8 transgene (AdMMP8). A549 cells infected in vitro with AdMMP8 did not show altered growth but were able to modify a fibrillar collagen substrate to allow viral diffusion. Further, AdMMP8 did not affect replication of the wild-type virus (Adwt300). Established human A549 lung cancer and BxPC-3 pancreatic cancer xenograft tumors that were injected with Adwt300 together with the non-replicating AdMMP8 virus showed significantly reduced growth compared with control tumors. Histochemical analysis showed reduced amounts of collagen within necrotic areas of MMP-8-injected tumors compared with controls. These results demonstrate that intra-tumoral expression of MMP-8 is a possible strategy for improving viral spread and improving the oncolytic activity of replicating adenovirus.
用于癌症治疗的腺病毒复制的成功受到病毒递送效率低下和在肿瘤块内分布不佳的限制。肿瘤内的基质可能会阻碍病毒在细胞间的自由传播。在本研究中，体外细胞培养实验表明，I型胶原可阻止腺病毒载体通过膜。基于基质金属蛋白酶-8（MMP-8）有效降解I型胶原活性的报道，我们构建了一种表达MMP-8转基因的腺病毒（AdMMP8）。体外感染AdMMP8的A549细胞生长未发生改变，但能够改变纤维状胶原底物以允许病毒扩散。此外，AdMMP8不影响野生型病毒（Adwt300）的复制。与对照肿瘤相比，注射Adwt300和非复制型AdMMP8病毒的已建立的人A549肺癌和BxPC-3胰腺癌异种移植肿瘤生长显著减缓。组织化学分析显示，与对照相比，注射MMP-8的肿瘤坏死区域内的胶原量减少。这些结果表明，肿瘤内表达MMP-8是改善病毒传播和提高复制型腺病毒溶瘤活性的一种可能策略。
