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Combination of gemcitabine and Ad5/3-Δ24, a tropism modified conditionally replicating adenovirus, for the treatment of ovarian cancer

Gene Therapy volume 12, pages 1198–1205 (2005)Cite this article

Abstract

Conditionally replicating adenoviruses (CRAds) represent a novel approach for the treatment of cancers resistant to conventional therapies. The efficacy of CRAds might be further improved by using chemotherapeutic agents in a multimodal antitumor approach. We have evaluated the use of Ad5/3-Δ24, a serotype 3 receptor targeted Rb/p16 pathway selective CRAd, in combination with gemcitabine against human ovarian adenocarcinoma. The combination of these agents showed synergistic cell killing in vitro compared to single treatments. However, the effect was dependent on dose and sequencing of the agents. Our results also indicate that gemcitabine reduces the initial rate of Ad5/3-Δ24 replication without affecting the total amount of virus produced. Possible reasons for synergy between Ad5/3-Δ24 and gemcitabine include the chemosensitizing activity of E1A and/or altered replication kinetics. In an orthotopic murine model of peritoneally disseminated ovarian cancer, the combination increased the survival of mice over either agent alone, and almost 60% of treated mice were cured. Sequencing of the agents was critical for toxicity versus efficacy. Mice remained free from intraperitoneal disease, but some succumbed to treatment-related hepatic or bone marrow toxicity. This suggests that improved efficacy may uncover treatment-related toxicity, which needs to be monitored closely in clinical trials.

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Acknowledgements

We thank Eli Lilly and Co. for providing gemcitabine. This work was supported by the Academy of Finland, Helsinki University Central Hospital Research Funds, University of Helsinki Internal Funds, Sohlberg Foundation, Emil Aaltonen Foundation, Biocentrum Helsinki, Sigrid Juselius Foundation, Ida Montin Foundation, Finnish Cancer Society, Finnish Oncology Association, Instrumentarium Research Fund, Research and Science Foundation Farmos, City of Kotka Research Funds, and Regional Funds of the Finnish Cultural Foundation.

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Authors and Affiliations

  1. Cancer Gene Therapy Group, Rational Drug Design Program, University of Helsinki, Helsinki, Finland

    M Raki, A Kanerva, T Ranki, M Sarkioja, L Kangasniemi & A Hemminki

  2. Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland

    M Raki, A Kanerva, T Ranki, M Sarkioja, L Kangasniemi & A Hemminki

  3. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland

    A Kanerva

  4. Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland

    A Ristimaki

  5. Molecular and Cancer Biology Research Program, University of Helsinki, Helsinki, Finland

    A Ristimaki

  6. Comprehensive Cancer Center, Biostatistics and Bioinformatics Unit, University of Alabama at Birmingham, Birmingham, AL, USA

    R A Desmond & D-T Chen

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Raki, M., Kanerva, A., Ristimaki, A. et al. Combination of gemcitabine and Ad5/3-Δ24, a tropism modified conditionally replicating adenovirus, for the treatment of ovarian cancer. Gene Ther 12, 1198–1205 (2005). https://doi.org/10.1038/sj.gt.3302517

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