Ectopic matrix metalloproteinase-9 expression in human brain tumor cells enhances oncolytic HSV vector infection.
Ectopic matrix metalloproteinase-9 expression in human brain tumor cells enhances oncolytic HSV vector infection.
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作者：
溶瘤HSV（oHSV）载体在复发性脑肿瘤患者的治疗中显示出前景，尽管几乎没有完全反应。有效治疗的障碍包括递送时有限的载体分布，这是注射的病毒粒子捕获在肿瘤细胞外基质（ECM）中的结果。为了增强病毒的传递和传播，我们研究了使用基质金属蛋白酶9（MMP 9）作为降解IV型胶原蛋白的手段，IV型胶原蛋白是正常脑组织中不存在的ECM和胶质瘤基底膜的主要成分。SK-N-AS神经母细胞瘤细胞被转导用于MMP 9的组成性、升高的表达，其在体外不增强肿瘤细胞迁移或在鼠异种移植脑肿瘤模型中不增强肿瘤进展。MMP 9表达增加了oHSV载体感染的肿瘤细胞球状体的分布，并在体内脑肿瘤的较大区域上提供了载体感染。这些结果表明，载体递送和体内分布可以通过损害ECM来改善，从而潜在地增强溶瘤功效。
Oncolytic HSV (oHSV) vectors have shown promise in the treatment of patients with recurrent brain tumors although few complete responses have accrued. Impediments to effective therapy include limited vector distribution on delivery, a consequence of injected virion particle trapping in the tumor extracellular matrix (ECM). To enhance virus delivery and spread, we investigated the use of the matrix metalloproteinase 9 (MMP9) as a means to degrade collagen type IV, a major component of the ECM and basement membranes of gliomas that is absent in normal brain tissue. SK-N-AS neuroblastoma cells were transduced for constitutive, elevated expression of MMP9, which did not enhance tumor cell migration in vitro or tumor progression in a murine xenograft brain tumor model. MMP9 expression afforded increased distribution of oHSV vector-infected tumor cell spheroids and afforded vector infection over larger areas of brain tumors in vivo. These results suggest that vector delivery and distribution in vivo can be improved by compromising the ECM, potentially enhancing oncolytic efficacy.
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DOI：
10.1073/pnas.95.7.3621
发表时间：
1998-03-31
影响因子：
11.1
作者：
Yoshizaki, T;Sato, H;Pagano, JS
通讯作者：
Pagano, JS
影响因子：
12.4
作者：
Niranjan, A;Moriuchi, S;Glorioso, JC
通讯作者：
Glorioso, JC
影响因子：
4.8
作者：
Kunapuli, P;Kasyapa, CS;Cowell, JK
通讯作者：
Cowell, JK
影响因子：
11.2
作者：
Bendrik, Christina;Robertson, Jennifer;Dabrosin, Charlotta
通讯作者：
Dabrosin, Charlotta
影响因子：
11.2
作者：
Deryugina, EI;Zijlstra, A;Quigley, JP
通讯作者：
Quigley, JP