Complete regression of human malignant mesothelioma xenografts following local injection of midkine promoter-driven oncolytic adenovirus.
Complete regression of human malignant mesothelioma xenografts following local injection of midkine promoter-driven oncolytic adenovirus.
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DOI：
10.1002/jgm.1486
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发表时间：
2010-08
影响因子：
3.5
通讯作者：
Okamura, Haruki
中科院分区：
文献类型：
--
作者：
Kubo, Shuji;Kawasaki, Yoshiko;Yamaoka, Norie;Tagawa, Masatoshi;Kasahara, Noriyuki;Terada, Nobuyuki;Okamura, Haruki
恶性间皮瘤是一种高度侵袭性的肿瘤，预后较差。间皮瘤的常规疗法通常无法治愈，迫切需要新的治疗模式。我们假设肿瘤特异性中期因子（Mdk）启动子可以赋予溶瘤腺病毒转录靶向，从而有效治疗恶性间皮瘤。我们通过定量 RT-PCR 分析了六种人间皮瘤细胞系中 Mdk 的表达，并通过荧光素酶报告基因测定测试了 Mdk 启动子活性。基于这些数据，我们构建了一种复制选择性溶瘤腺病毒，命名为AdMdk-E1-iresTK，它包含Mdk启动子驱动的腺病毒E1基因和HSV胸苷激酶（TK）自杀基因，以及CMV启动子驱动的绿色荧光蛋白（GFP）标记基因。在体外对正常细胞与间皮瘤细胞中病毒复制和细胞溶解的选择性进行了表征，并在体内研究了瘤内扩散和抗肿瘤功效。 Mdk 启动子活性在正常细胞中受到限制，但在间皮瘤细胞系中高度激活。 AdMdk-E1-iresTK 可有效复制、产生病毒后代并在多种间皮瘤细胞系中传播。 AdMdk-E1-iresTK 的裂解扩散介导了对这些间皮瘤细胞的有效杀伤，并且通过前体药物更昔洛韦处理，其体外杀细胞作用显着增强。瘤内注射 AdMdk-E1-iresTK 导致无胸腺小鼠 MESO4 和 MSTO 人间皮瘤异种移植物完全消退。体内荧光成像显示 AdMdk-E1-iresTK 衍生信号在肿瘤内扩散，该信号在肿瘤根除后消失。这些数据表明，Mdk 启动子对病毒复制的转录靶向代表了一种有前景的溶瘤病毒治疗 Mdk 表达上调的癌症（包括恶性间皮瘤）的总体策略。
Malignant mesothelioma is a highly aggressive tumor with poor prognosis. Conventional therapies for mesothelioma are generally non-curative, and new treatment paradigms are urgently needed. We hypothesized that the tumor-specific midkine (Mdk) promoter could confer transcriptional targeting to oncolytic adenoviruses for effective treatment of malignant mesothelioma. We analyzed Mdk expression by quantitative RT-PCR in six human mesothelioma cell lines, and tested Mdk promoter activity by luciferase reporter assay. Based on these data, we constructed a replication-selective oncolytic adenovirus, designated AdMdk-E1-iresTK, which contains an Mdk promoter-driven adenoviral E1 gene and HSV-thymidine kinase (TK) suicide gene, and CMV promoter-driven green fluorescent protein (GFP) marker gene. Selectivity of viral replication and cytolysis were characterized in normal vs. mesothelioma cells in vitro, and intratumoral spread and antitumor efficacy were investigated in vivo. Mdk promoter activity was restricted in normal cells, but highly activated in mesothelioma cell lines. AdMdk-E1-iresTK was seen to efficiently replicate, produce viral progeny, and spread in multiple mesothelioma cell lines. Lytic spread of AdMdk-E1-iresTK mediated efficient killing of these mesothelioma cells, and its in vitro cytocidal effect was significantly enhanced by treatment with the prodrug, ganciclovir. Intratumoral injection of AdMdk-E1-iresTK caused complete regression of MESO4 and MSTO human mesothelioma xenografts in athymic mice. In vivo fluorescence imaging demonstrated intratumoral spread of AdMdk-E1-iresTK-derived signals, which vanished after tumor eradication. These data indicate that transcriptional targeting of viral replication by the Mdk promoter represents a promising general strategy for oncolytic virotherapy of cancers with upregulated Mdk expression, including malignant mesothelioma.
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影响因子：
8.8
作者：
Maeda, S.;Shinchi, H.;Kurahara, H.;Mataki, Y.;Noma, H.;Maemura, K.;Aridome, K.;Yokomine, T.;Natsugoe, S.;Aikou, T.;Takao, S.
通讯作者：
Takao, S.
DOI：
10.1006/bbrc.1995.2661
发表时间：
1995-11-13
影响因子：
3.1
作者：
KOJIMA, S;INUI, T;MURAMATSU, T
通讯作者：
MURAMATSU, T
影响因子：
3.8
作者：
GRAHAM, FL;SMILEY, J;NAIRN, R
通讯作者：
NAIRN, R
影响因子：
2.7
作者：
Qi, MS;Ikematsu, S;Kadomatsu, K
通讯作者：
Kadomatsu, K
影响因子：
1.8
作者：
Fiegel, Henning C.;Kaifi, Jussuf T.;Till, Holger
通讯作者：
Till, Holger