Selectivity of a replication-competent adenovirus for human breast carcinoma cells expressing the MUC1 antigen
Selectivity of a replication-competent adenovirus for human breast carcinoma cells expressing the MUC1 antigen
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DOI：
10.1172/jci9180
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发表时间：
2000-09-01
影响因子：
15.9
通讯作者：
Kufe, DW
中科院分区：
文献类型：
--
作者：
Kurihara, T;Brough, DE;Kufe, DW
DF 3/MUC 1基因在人乳腺癌和其他癌症中异常过表达。先前的研究已经证明DF 3/MUC 1 I启动子/增强子赋予MUC 1阳性乳腺癌细胞中多种转基因的选择性表达。在这项研究中，我们表明，腺病毒载体（Ad.DF3-E1），其中DF 3/MUC 1启动子驱动E1 A的表达选择性复制MUC 1阳性乳腺癌细胞。我们还表明，Ad.DF3-E1感染人乳腺癌裸鼠移植瘤与肿瘤生长的抑制。与沿着注射轨迹感染的无复制能力的腺病毒载体相反，在整个肿瘤异种移植物中可检测到Ad.DF3-E1感染。为了产生具有并入治疗产品的能力的Ad.DF3-E1载体，我们将巨细胞病毒（CMV）启动子插入TNF cDNA的上游。Ad.DF3-E1/CMV-TNF感染与表达MUC 1的细胞中TNF的选择性复制和产生相关。此外，治疗MUC 1阳性，但不是MUC 1阴性，异种移植物与单次注射的Ad.DF3-E1/CMV-TNF是有效的，在诱导稳定的肿瘤消退。这些研究结果表明，DF 3/MUC 1启动子赋予的能力，选择性复制的Ad.DF3-E1 MUC 1阳性乳腺肿瘤细胞中，这种载体的抗肿瘤活性是增强的TNF cDNA的整合。
The DF3/MUC1 gene is aberrantly overexpressed in human breast and other carcinomas. Previous studies have demonstrated that the DF3/MUC1I promoter/enhancer confers selective expression of diverse transgenes in MUC1-positive breast cancer cells. In this study, we show that an adenoviral vector (Ad.DF3-E1) in which the DF3/MUC1 promoter drives expression ofE1A selectively replicates in MUC1-positive breast cancer cells. We also show that Ad.DF3-E1 infection of human breast tumor xenografts in nude mice is associated with inhibition of tumor growth. In contrast to a replication-incompetent adenoviral vector that infects along the injection track, Ad.DF3-E1 infection was detectable throughout the tumor xenografts. To generate an Ad.DF3-E1 vector with the capacity for incorporating therapeutic products, we inserted the cytomegalovirus (CMV) promoter upstream of the TNF cDNA. Infection with Ad.DF3-E1/CMV-TNF was associated with selective replication and production of TNF in cells that express MUC1. Moreover, treatment of MUC1-positive, but not MUC1-negative, xenografts with a single injection of Ad.DF3-E1/CMV-TNF was effective in inducing stable tumor regression These findings demonstrate that the DF3/MUC1 promoter confers competence for selective replication of Ad.DF3-E1 in MUC1-positive breast tumor cells, and that the antitumor activity of this vector is potentiated by integration of the TNF cDNA.