The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA.
Gene Ther. 2013 Mar;20(3):318-27. doi: 10.1038/gt.2012.42. Epub 2012 Jun 7.
Conditionally replicating adenoviruses (CRAd) are a promising class of gene therapy agents that can overcome already known glioblastoma (GBM) resistance mechanisms but have limited distribution upon direct intratumoral (i.t.) injection. Collagen bundles in the extracellular matrix (ECM) have an important role in inhibiting virus distribution. In fact, ECM pre-treatment with collagenases improves virus distributions to tumor cells. Matrix metalloproteinases (MMPs) are an endogenous class of collagenases secreted by tumor cells whose function can be altered by different drugs including anti-angiogenic agents, such as bevacizumab. In this study we hypothesized that upregulation of MMP activity during anti-angiogenic therapy can improve CRAd-S-pk7 distribution in GBM. We find that MMP-2 activity in human U251 GBM xenografts increases (*P=0.03) and collagen IV content decreases (*P=0.01) during vascular endothelial growth factor (VEGF-A) antibody neutralization. After proving that collagen IV inhibits CRAd-S-pk7 distribution in U251 xenografts (Spearman rho=-0.38; **P=0.003), we show that VEGF-blocking antibody treatment followed by CRAd-S-pk7 i.t. injection reduces U251 tumor growth more than each individual agent alone (***P<0.0001). Our data propose a novel approach to improve virus distribution in tumors by relying on the early effects of anti-angiogenic therapy.
条件复制型腺病毒（CRAd）是一种很有前途的基因治疗药物，能够克服胶质母细胞瘤（GBM）已有的耐药机制，但直接瘤内（i.t.）注射后分布有限。细胞外基质（ECM）中的胶原束在抑制病毒分布方面起着重要作用。事实上，ECM 用胶原酶预处理可以改善病毒向肿瘤细胞的分布。基质金属蛋白酶（MMPs）是肿瘤细胞分泌的内源性胶原酶类，其功能可以通过不同的药物改变，包括抗血管生成药物，如贝伐单抗。在这项研究中，我们假设在抗血管生成治疗过程中 MMP 活性的上调可以改善 CRAd-S-pk7 在 GBM 中的分布。我们发现，在血管内皮生长因子（VEGF-A）抗体中和期间，人 U251 GBM 异种移植中的 MMP-2 活性增加（*P=0.03），胶原 IV 含量减少（*P=0.01）。在证明胶原 IV 抑制 U251 异种移植中的 CRAd-S-pk7 分布后（Spearman rho=-0.38；**P=0.003），我们表明，VEGF 阻断抗体治疗后再进行 CRAd-S-pk7 i.t. 注射比单独使用每种药物更能减少 U251 肿瘤的生长（***P<0.0001）。我们的数据提出了一种通过依赖抗血管生成治疗的早期效应来改善肿瘤中病毒分布的新方法。
