Abstract
We have previously shown that a dual system for controlling gene expression that relies both on transcriptional regulation and DNA recombination mediated by the site-directed recombinase, Flp, effectively controls the expression of a gene encoding diphtheria toxin (DT-A). In this study, we investigated the use of a chimeric modified enhancer/promoter sequence of the human prostate-specific antigen (PSA) gene to regulate DT-A expression in human prostate cancer cells in culture, in xenografts derived from these cells, and in autochthonous tumors in TRAMP mice. Following adenoviral delivery of DNA encoding PSA promoter-driven Flp recombinase and DT-A, we demonstrate that this transcriptional/DNA recombination control strategy effectively activates DT-A expression in a manner that correlates with the amount of PSA and androgen in cells. Significantly, the size of xenografts was reduced by 50%, and tumor cells in TRAMP mice died following intratumoral injection of DT-A viruses. Direct injection of virally-delivered DT-A into normal mouse prostates resulted in a dramatic reduction in the size of the gland. Our results suggest that the PSA promoter-driven Flp recombinase regulatory system will allow for targeted death of PSA-expressing cells. When combined with newly developed strategies for targeted gene delivery, this approach holds promise as an effective systemically-administered therapy for metastatic prostate cancer.
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
American Cancer Society. Facts and figures. http://www.cancer.org.
Collier RJ . Diphtheria toxin: mode of action and structure. Bacteriol Rev 1975; 39: 54–85.
Maxwell IH, Maxwell F, Glode LM . Regulated expression of a diphtheria toxin A-chain gene transfected into human cells: possible strategy for inducing cancer cell suicide. Cancer Res 1986; 46: 4660–4664.
Peng W, Verbitsky A, Bao Y, Sawicki JA . Regulated expression of diphtheria toxin in prostate cancer cells. Mol Therapy 2002; 6: 537–545.
Wu L et al. Chimeric PSA enhancers exhibit augmented activity in prostate cancer gene therapy vectors. Gene Ther 2001; 8: 1416–1426.
Greenberg NM et al. Prostate cancer in a transgenic mouse. Proc Natl Acad Sci USA 1995; 92: 3439–3443.
Shirakawa T et al. In vivo suppression of osteosarcoma pulmonary metastasis with intravenous osteocalcin promoter-based toxic gene therapy. Cancer Gene Ther 1998; 5: 274–280.
Lee EJ, Jameson JL . Cell-specific Cre-mediated activation of the diphtheria toxin gene in pituitary tumor cells: potential for cytotoxic gene therapy. Human Gene Ther 2002; 13: 533–542.
Coen JJ, Zietman AL, Thakral H, Shipley WU . Radical radiation for localized prostate cancer: local persistence of disease results in a late wave of metastases. J Clin Oncol 2002; 20: 3199–3205.
Han M et al. Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. J Urol 2003; 169: 517–523.
Smaletz O, Scher HI . Outcome predictions for patients with metastatic prostate cancer. Semin Urol Oncol 2002; 20: 155–163.
Anderson DG et al. A polymer library approach to suicide gene therapy for cancer. Proc Natl Acad Sci USA 2004; 101: 16028–16033.
Dibler MS, An Hahrton G . Suicide gene therapy: possible implications in haematopoietic disorders. J Intern Med 2001; 249: 359–367.
Schlemmer HP et al. Alterations of intratumoral pharmacokinetics of 5-fluorouracil in head and neck carcinoma during simultaneous radiochemotherapy. Cancer Res 1999; 59: 2363–2369.
Vassaux G, Marin-Duque P . Use of suicide genes for cancer gene therapy: study of the different approaches. Expert Opin Biol Ther 2004; 4: 519–530.
Thomson JM, Parrott WA . pMECA: a cloning plasmid with 44 unique restriction sites that allows selection of recombinants based on colony size. BioTechn 1998; 24: 922–928.
Acknowledgements
We thank Cheryl Hobbs for helpful comments on the manuscript, Lisa Laury-Kleintop for assistance with fluorescent microscopy, and Gwendolyn Gilliard for excellent technical assistance. We are grateful to Lily Wu (UCLA) for a plasmid containing the PSE-BC promoter, Michael Carey (UCLA) for pBCVP2G5-lucNSN, Susan Dymecki (Harvard) for pFRT2neolacZ, A Francis Stewart (EMBL, Heidelberg) for p22EDT1, J Miyazaki (Kyoto U) for pCX-EGFP, and R Rodriguez (Johns Hopkins U) for 293DTRP#2 cells. This work was supported by NIH Grant CA90841 (JAS).
Author information
Authors and Affiliations
Additional information
Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)
Supplementary information
Rights and permissions
About this article
Cite this article
Peng, W., Chen, J., Huang, YH. et al. Tightly-regulated suicide gene expression kills PSA-expressing prostate tumor cells. Gene Ther 12, 1573–1580 (2005). https://doi.org/10.1038/sj.gt.3302580
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3302580
Keywords
This article is cited by
-
Neomorphic DNA-binding enables tumor-specific therapeutic gene expression in fusion-addicted childhood sarcoma
Molecular Cancer (2022)
-
Rad51 Promoter-Targeted Gene Therapy Is Effective for In Vivo Visualization and Treatment of Cancer
Molecular Therapy (2012)
-
A tunable dual‐promoter integrator for targeting of cancer cells
Molecular Systems Biology (2010)
-
Rapid Optimization of Gene Delivery by Parallel End-modification of Poly(β-amino ester)s
Molecular Therapy (2007)
-
Rapid Optimization of Gene Delivery by Parallel End-modification of Poly(β-amino ester)s
Molecular Therapy (2007)