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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C et al. Cancer statistics, 2006. CA Cancer J Clin 2006; 56: 106–130.
Cheon J, Kim HK, Moon DG, Yoon DK, Cho JH, Koh SK . Adenovirus-mediated suicide-gene therapy using the herpes simplex virus thymidine kinase gene in cell and animal models of human prostate cancer: changes in tumour cell proliferative activity. BJU Int 2000; 85: 759–766.
van der Poel HG, McCadden J, Verhaegh GW, Kruszewski M, Ferrer F, Schalken JA et al. A novel method for the determination of basal gene expression of tissue-specific promoters: an analysis of prostate-specific promoters. Cancer Gene Ther 2001; 8: 927–935.
Latham JP, Searle PF, Mautner V, James ND . Prostate-specific antigen promoter/enhancer driven gene therapy for prostate cancer: construction and testing of a tissue-specific adenovirus vector. Cancer Res 2000; 60: 334–341.
Steiner MS, Gingrich JR . Gene therapy for prostate cancer: where are we now? J Urol 2000; 164: 1121–1136.
O’Keefe DS, Uchida A, Bacich DJ, Watt FB, Martorana A, Molloy PL et al. Prostate-specific suicide gene therapy using the prostate-specific membrane antigen promoter and enhancer. Prostate 2000; 45: 149–157.
Xing Y, Lu G, Xiao Y, Zeng F, Zhang Q, Xiong P et al. Bystander effect mediated by herpes simplex virus-thymidine kinase/ganciclovir approach on prostatic cancer cells and its regulation. Zhonghua Yi Xue Za Zhi 2002; 82: 1484–1487.
Park HS, Cheon J, Cho HY, Ko YH, Bae JH, Moon DG et al. In vivo characterization of a prostate-specific antigen promoter-based suicide gene therapy for the treatment of benign prostatic hyperplasia. Gene Therapy 2003; 10: 1129–1134.
Ko SC, Cheon J, Kao C, Gotoh A, Shirakawa T, Sikes RA et al. Osteocalcin promoter-based toxic gene therapy for the treatment of osteosarcoma in experimental models. Cancer Res 1996; 56: 4614–4619.
Springer CJ, Niculescu-Duvaz I . Prodrug-activating systems in suicide gene therapy. J Clin Invest 2000; 105: 1161–1167.
Denny WA . Prodrugs for Gene-Directed Enzyme-Prodrug Therapy (Suicide Gene Therapy). J Biomed Biotechnol 2003; 2003: 48–70.
Schepelmann S, Springer CJ . Viral vectors for gene-directed enzyme prodrug therapy. Curr Gene Ther 2006; 6: 647–670.
Yu DC, Sakamoto GT, Henderson DR . Identification of the transcriptional regulatory sequences of human kallikrein 2 and their use in the construction of calydon virus 764, an attenuated replication competent adenovirus for prostate cancer therapy. Cancer Res 1999; 59: 1498–1504.
Matsubara S, Wada Y, Gardner TA, Egawa M, Park MS, Hsieh CL et al. A conditional replication-competent adenoviral vector, Ad-OC-E1a, to cotarget prostate cancer and bone stroma in an experimental model of androgen-independent prostate cancer bone metastasis. Cancer Res 2001; 61: 6012–6019.
DeWeese TL, van der Poel H, Li S, Mikhak B, Drew R, Goemann M et al. A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy. Cancer Res 2001; 61: 7464–7472.
Sadeghi H, Hitt MM . Transcriptionally targeted adenovirus vectors. Curr Gene Ther 2005; 5: 411–427.
Wu L, Matherly J, Smallwood A, Adams JY, Billick E, Belldegrun A et al. Chimeric PSA enhancers exhibit augmented activity in prostate cancer gene therapy vectors. Gene Therapy 2001; 8: 1416–1426.
Diamandis EP, Yousef GM . Human tissue kallikreins: a family of new cancer biomarkers. Clin Chem 2002; 48: 1198–1205.
Hsieh CL, Gardner TA, Miao L, Balian G, Chung LW . Cotargeting tumor and stroma in a novel chimeric tumor model involving the growth of both human prostate cancer and bone stromal cells. Cancer Gene Ther 2004; 11: 148–155.
Kubo H, Gardner TA, Wada Y, Koeneman KS, Gotoh A, Yang L et al. Phase I dose escalation clinical trial of adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase in localized and metastatic hormone-refractory prostate cancer. Hum Gene Ther 2003; 14: 227–241.
Rodriguez R, Schuur ER, Lim HY, Henderson GA, Simons JW, Henderson DR . Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells. Cancer Res 1997; 57: 2559–2563.
Galanis E, Vile R, Russell SJ . Delivery systems intended for in vivo gene therapy of cancer: targeting and replication competent viral vectors. Crit Rev Oncol Hematol 2001; 38: 177–192.
Freytag SO, Rogulski KR, Paielli DL, Gilbert JD, Kim JH . A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene, and radiotherapy. Hum Gene Ther 1998; 9: 1323–1333.
Freytag SO, Khil M, Stricker H, Peabody J, Menon M, DePeralta-Venturina M et al. Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer Res 2002; 62: 4968–4976.
Freytag SO, Stricker H, Pegg J, Paielli D, Pradhan DG, Peabody J et al. Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer. Cancer Res 2003; 63: 7497–7506.
Edwards SJ, Dix BR, Myers CJ, Dobson-Le D, Huschtscha L, Hibma M et al. Evidence that replication of the antitumor adenovirus ONYX-015 is not controlled by the p53 and p14(ARF) tumor suppressor genes. J Virol 2002; 76: 12483–12490.
Rothmann T, Hengstermann A, Whitaker NJ, Scheffner M, zur Hausen H . Replication of ONYX-015, a potential anticancer adenovirus, is independent of p53 status in tumor cells. J Virol 1998; 72: 9470–9478.
O’Shea CC, Johnson L, Bagus B, Choi S, Nicholas C, Shen A et al. Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell 2004; 6: 611–623.
O’Shea CC, Soria C, Bagus B, McCormick F . Heat shock phenocopies E1B-55 K late functions and selectively sensitizes refractory tumor cells to ONYX-015 oncolytic viral therapy. Cancer Cell 2005; 8: 61–74.
Lee SJ, Kim HS, Yu R, Lee K, Gardner TA, Jung C et al. Novel prostate-specific promoter derived from PSA and PSMA enhancers. Mol Ther 2002; 6: 415–421.
Li X, Zhang YP, Kim HS, Bae KH, Stantz KM, Lee SJ et al. Gene therapy for prostate cancer by controlling adenovirus E1a and E4 gene expression with PSES enhancer. Cancer Res 2005; 65: 1941–1951.
Lee SJ, Lee K, Yang X, Jung C, Gardner T, Kim HS et al. NFATc1 with AP-3 site binding specificity mediates gene expression of prostate-specific-membrane-antigen. J Mol Biol 2003; 330: 749–760.
Hallenbeck PL, Chang YN, Hay C, Golightly D, Stewart D, Lin J et al. A novel tumor-specific replication-restricted adenoviral vector for gene therapy of hepatocellular carcinoma. Hum Gene Ther 1999; 10: 1721–1733.
Kim JH, Kim SH, Brown SL, Freytag SO . Selective enhancement by an antiviral agent of the radiation-induced cell killing of human glioma cells transduced with HSV-tk gene. Cancer Res 1994; 54: 6053–6056.
Kim JH, Kim SH, Kolozsvary A, Brown SL, Kim OB, Freytag SO . Selective enhancement of radiation response of herpes simplex virus thymidine kinase transduced 9L gliosarcoma cells in vitro and in vivo by antiviral agents. Int J Radiat Oncol Biol Phys 1995; 33: 861–868.
Rogulski KR, Wing MS, Paielli DL, Gilbert JD, Kim JH, Freytag SO . Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization. Hum Gene Ther 2000; 11: 67–76.
Rogulski KR, Freytag SO, Zhang K, Gilbert JD, Paielli DL, Kim JH et al. In vivo antitumor activity of ONYX-015 is influenced by p53 status and is augmented by radiotherapy. Cancer Res 2000; 60: 1193–1196.
Freytag SO, Paielli D, Wing M, Rogulski K, Brown S, Kolozsvary A et al. Efficacy and toxicity of replication-competent adenovirus-mediated double suicide gene therapy in combination with radiation therapy in an orthotopic mouse prostate cancer model. Int J Radiat Oncol Biol Phys 2002; 54: 873–885.
Small EJ, Carducci MA, Burke JM, Rodriguez R, Fong L, van Ummersen L et al. A phase I trial of intravenous CG7870, a replication-selective, prostate-specific antigen-targeted oncolytic adenovirus, for the treatment of hormone-refractory, metastatic prostate cancer. Mol Ther 2006; 14: 107–117.
Dilley J, Reddy S, Ko D, Nguyen N, Rojas G, Working P et al. Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity. Cancer Gene Ther 2005; 12: 715–722.
Chen Y, DeWeese T, Dilley J, Zhang Y, Li Y, Ramesh N et al. CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity. Cancer Res 2001; 61: 5453–5460.
Wang JQ, Zheng QH, Fei X, Mock BH, Hutchins GD . Novel radiosynthesis of PET HSV-tk gene reporter probes [18F]FHPG and [18F]FHBG employing dual Sep-Pak SPE techniques. Bioorg Med Chem Lett 2003; 13: 3933–3938.
Lambright ES, Amin K, Wiewrodt R, Force SD, Lanuti M, Propert KJ et al. Inclusion of the herpes simplex thymidine kinase gene in a replicating adenovirus does not augment antitumor efficacy. Gene Therapy 2001; 8: 946–953.
Morris JC, Wildner O . Therapy of head and neck squamous cell carcinoma with an oncolytic adenovirus expressing HSV-tk. Mol Ther 2000; 1: 56–62.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/cgt.2008.59
Keywords
This article is cited by
-
In vitro and in vivo double-enhanced suicide gene therapy mediated by generation 5 polyamidoamine dendrimers for PC-3 cell line
World Journal of Surgical Oncology (2012)
-
Adenovirus-mediated hypoxia-targeted gene therapy using HSV thymidine kinase and bacterial nitroreductase prodrug-activating genes in vitro and in vivo
Cancer Gene Therapy (2011)
-
Antitumor activity of Ad-IU2, a prostate-specific replication-competent adenovirus encoding the apoptosis inducer, TRAIL
Cancer Gene Therapy (2010)
-
Side populations of glioblastoma cells are less sensitive to HSV-TK/GCV suicide gene therapy system than the non-side population
In Vitro Cellular & Developmental Biology - Animal (2010)