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Enhanced combined tumor-specific oncolysis and suicide gene therapy for prostate cancer using M6 promoter

Cancer Gene Therapy volume 16, pages 73–82 (2009)Cite this article

Abstract

Enzyme pro-drug suicide gene therapy has been hindered by inefficient viral delivery and gene transduction. To further explore the potential of this approach, we have developed AdIU1, a prostate-restricted replicative adenovirus (PRRA) armed with the herpes simplex virus thymidine kinase (HSV-TK). In our previous Ad-OC-TK/ACV phase I clinical trial, we demonstrated safety and proof of principle with a tissue-specific promoter-based TK/pro-drug therapy using a replication-defective adenovirus for the treatment of prostate cancer metastases. In this study, we aimed to inhibit the growth of androgen-independent (AI), PSA/PSMA-positive prostate cancer cells by AdIU1. In vitro the viability of an AI- PSA/PSMA-expressing prostate cancer cell line, CWR22rv, was significantly inhibited by treatment with AdIU1 plus GCV (10 μg ml−1), compared with AdIU1 treatment alone and also cytotoxicity was observed following treatment with AdIU1 plus GCV only in PSA/PSMA-positive CWR22rv and C4-2 cells, but not in the PSA/PSMA-negative cell line, DU-145. In vivo assessment of AdIU1 plus GCV treatment revealed a stronger therapeutic effect against CWR22rv tumors in nude mice than treatment with AdIU1 alone, AdE4PSESE1a alone or in combination with GCV. Our results demonstrate the therapeutic potential of specific-oncolysis and suicide gene therapy for AI-PSA/PSMA-positive prostate cancer gene therapy.

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Acknowledgements

We thank M Black, Department of pharmaceutical Sciences, Washington State University for providing the TK-polyclonal antibody. These studies were supported by NIH K08 CA079544-01A2 and DOD DAMD 17-03-1-0077.

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Authors and Affiliations

  1. Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA

    M Ahn, S-J Lee, X Li, J A Jiménez, Y-P Zhang, K-H Bae, C Kao & T A Gardner

  2. Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, USA

    M Ahn, S-J Lee, X Li, J A Jiménez, Y-P Zhang, K-H Bae, C Kao & T A Gardner

  3. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA

    J A Jiménez, C Kao & T A Gardner

  4. Department of Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    Y Mohammadi

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Correspondence to T A Gardner.

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Ahn, M., Lee, SJ., Li, X. et al. Enhanced combined tumor-specific oncolysis and suicide gene therapy for prostate cancer using M6 promoter. Cancer Gene Ther 16, 73–82 (2009). https://doi.org/10.1038/cgt.2008.59

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