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Identification of the Human IAI.3B Promoter Element and Its Use in the Construction of a Replication-selective Adenovirus for Ovarian Cancer Therapy¹

Departments of Obstetrics and Gynecology [K. H., M. Iw., H. Y., M. It.], Neurosurgery [S. K.] and Dermatology [K. Y., Y. S., K. H.], School of Medicine, Ehime University, Ehime 791-0295; Division of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871 [M. O.]; Division of Pathology, Chiba Cancer Center Research Institute, Chiba 260-8717 [M. T.]; and Department of Developmental Genetics, National Institute of Genetics, Shizuoka 411-8540 [S. H.] Japan

Little is known concerning promoters or gene therapy specific for ovarian cancer. To explore the potential use of IAI.3B isolated from ovarian cancer cells in gene therapy for ovarian cancer, we identified the promoter region of the IAI.3B gene and created a replication-selective adenovirus, AdE3-IAI.3B, driven by the promoter. Transient transfection experiments showed that the DNA segment located between -1816 and -1 bp resulted in preferential expression in ovarian cancer cells with negligible expression in squamous cell carcinoma and normal cells. The promoter activity of IAI.3B was almost the same as that of cytomegalovirus and an order of magnitude higher than those of midkine and cyclooxygenase-2 in ovarian cancer cells. AdE3-IAI.3B replicated as efficiently as the wild-type adenovirus and caused extensive cell killing in a panel of ovarian cancer cells in vitro. In contrast, squamous cell carcinoma and normal cells were not able to support AdE3-IAI.3B replication. In animal studies, AdE3-IAI.3B administered to flank and i.p. xenografts of ovarian cancer cells led to a significant therapeutic effect. These results demonstrate the usefulness of the IAI.3B promoter for generation of ovarian cancer-specific adenoviral vectors and provide a potential for the development of ovarian cancer-specific oncolytic viral therapies.

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