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Replication of an integrin targeted conditionally replicating adenovirus on primary ovarian cancer spheroids

Cancer Gene Therapy volume 10, pages 377–387 (2003)Cite this article

Abstract

Replication competent viruses hold promise for treatment of advanced cancers resistant to available therapeutic modalities. Although preliminary clinical results have substantiated their efficacy, preclinical development of these novel approaches is limited by assay substrates. The evaluation of candidate agents could be confounded by differences between primary tumor cells and tumor cell lines, as discordance in the levels of surface receptors relevant for viral entry has been reported. Since primary tumor cells are difficult to analyze ex vivo for longitudinal observation of virus replication, we developed three-dimensional aggregates or spheroids of unpassaged and purified ovarian cancer cells as a means for prolonging primary tumor cell viability and as a three-dimensional in vitro model for replicative viral infection. Ovarian cancer cells purified from ascites samples were sustained for 30 days while retaining the infection profile with tropism modified and unmodified adenoviruses (Ads). Cell line and primary cell spheroids were used to quantitate the replication and oncolytic potency of replicative Ads in preclinical testing for human ovarian cancer trials. Therefore, spheroids provide a method to sustain purified unpassaged primary ovarian cancer cells for extended periods and to allow evaluation of replicative viruses in a three-dimensional model.

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Acknowledgements

We gratefully acknowledge the excellent technical assistance of Jan Shultz, Sherri Coffman, and Mitzi Fincher. Gene transfer assays were performed in part at the UAB Gene Therapy Center Correlative Laboratories for Human Clinical Trials. This study was supported by the United States Public Health Service Training Grant T32 CA75930, the University of Alabama Health Services Foundation Interdisciplinary Corroborative Laboratory for Gene Therapy Clinical Trials, NIH grants CA74243, HL 63736, RO1 CA83821, IT32 CA75930, P50 CA83591, P50 CA89019, PC 99-1018, DAMD 17-00-1-0002, RO1 CA94084, RO1 CA93796, DAMD 17-98-1-8571, the Lustgarten Foundation LF043, the CapCure Foundation, the Damon Runyon-Walter Winchell Cancer Research Fund, the Sigrid Juselius Foundation, the Emil Aaltonen Foundation, the Maud Kuistila Foundation, and the Finnish Medical Foundation, the Academy of Finland, the Finnisha Cancer Society, Biocentrum Helsinki, University of Helsinki Internal Funds.

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  1. Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    John T Lam, Gerd J Bauerschmitz, Anna Kanerva, Shannon D Barker, Minghui Wang, Jerry L Blackwell, David T Curiel & Akseli Hemminki

  2. Division of Gynecology Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    J Michael Straughn, Mack N Barnes & Ronald D Alvarez

  3. Departments of Pathology, Cell Biology, and Surgery, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    Gene P Siegal

  4. Department of Oncology, Rational Drug Design, University of Helsinki, Helsinki University Central Hospital, Helsinki, 00014, Finland

    Akseli Hemminki

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Lam, J., Bauerschmitz, G., Kanerva, A. et al. Replication of an integrin targeted conditionally replicating adenovirus on primary ovarian cancer spheroids. Cancer Gene Ther 10, 377–387 (2003). https://doi.org/10.1038/sj.cgt.7700578

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