Selectivity of a replication-competent adenovirus for human breast carcinoma cells expressing the MUC1 antigen.
The DF3/MUC1 gene is aberrantly overexpressed in human breast and other carcinomas. Previous studies have demonstrated that the DF3/MUC1 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 of E1A 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.
Kurihara
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Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Brough
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DE
Kovesdi
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Kufe
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DW
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D001943:Breast Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000628:therapy; D002455:Cell Division; D003587:Cytomegalovirus / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006651:Histocytochemistry; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018396:Mucin-1 / Q000032:analysis / Q000235:genetics*; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D014779:Virus Replication / Q000235:genetics*
D017500:Adenovirus E1A Proteins; D014408:Biomarkers, Tumor; D018396:Mucin-1; D014409:Tumor Necrosis Factor-alpha