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Tumor-specific gene expression in hepatic metastases by a replication-activated adenovirus vector

Nature Medicine volume 7, pages 240–243 (2001)Cite this article

Abstract

Clinical applications of tumor gene therapy require tumor-specific delivery or expression of therapeutic genes in order to maximize the oncolytic index and minimize side effects1,2. This study demonstrates activation of transgene expression exclusively in hepatic metastases after systemic application of a modified first-generation (E1A/E1B-deleted) adenovirus vector (AdE1−) in mouse tumor models. The discrimination between tumors and normal liver tissue is based on selective DNA replication of AdE1− vectors in tumor cells. This new AdE1− based vector system uses homologous recombination between inverted repeats to mediate precise rearrangements within the viral genome. As a result of these rearrangements, a promoter is brought into conjunction with a reporter gene creating a functional expression cassette. Genomic rearrangements are dependent upon viral DNA replication, which in turn occurs specifically in tumor cells. In a mouse tumor model with liver metastases derived from human tumor cells, a single systemic administration of replication activated AdE1− vectors achieved transgene expression in every metastasis, whereas no extra-tumoral transgene induction was observed. Here we provide a new concept for tumor-specific gene expression that is also applicable for other conditionally replicating adenovirus vectors.

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Figure 1: Replication of AdE1− in human tumor cells, primary human cells, and mouse liver.
Figure 2: Activation of transgene expression in vitro upon adenovirus vector replication.
Figure 3: Tumor-specific β-gal expression from Ad.IR-BG in hepatic metastases derived from human tumor cells.

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Acknowledgements

We thank D. Russell and T. Moeller for primary human cells and M. Steinwaerder for technical assistance and help with digital images. This work was supported by a grant from the Cystic Fibrosis Foundation and by Grant R01 CA80192 from the National Cancer Institute of the National Institutes of Health.

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Authors and Affiliations

  1. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA

    Dirk S. Steinwaerder, Cheryl A. Carlson, Zong-Yi Li, Shaoheng Ni & André Lieber

  2. Department of Pathology, University of Washington, Seattle, Washington, USA

    Cheryl A. Carlson

  3. Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, USA

    Desiree L. Otto

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  1. Dirk S. Steinwaerder
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  6. André Lieber
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Correspondence to André Lieber.

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Steinwaerder, D., Carlson, C., Otto, D. et al. Tumor-specific gene expression in hepatic metastases by a replication-activated adenovirus vector. Nat Med 7, 240–243 (2001). https://doi.org/10.1038/84696

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