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Two-step amplification of the human PPT sequence provides specific gene expression in an immunocompetent murine prostate cancer model

Cancer Gene Therapy volume 14, pages 233–240 (2007)Cite this article

Abstract

The recombinant prostate-specific PPT sequence comprises a prostate-specific antigen enhancer, a PSMA enhancer and a TARP promoter. It is transcriptionally active in human prostate cancer cells both in the presence and absence of testosterone. However, in experimental murine prostate cancer, it has no detectable transcriptional activity. Herein, we describe that the PPT sequence in combination with a two-step transcriptional amplification (TSTA) system becomes active also in murine prostate cancer cells. An adenovirus with TSTA-amplified PPT-controlled expression of the luciferase reporter gene, Ad[PPT/TSTA-Luc], has up to 100-fold higher prostate-specific transcriptional activity than a non-amplified PPT-based adenovirus, Ad[PPT-Luc], in human cells. In addition, Ad[PPT/TSTA-Luc] confers prostate-specific transgene expression in murine cells, with an activity that is approximately 23% of Ad[CMV-Luc] in the transgenic adenocarcinoma of the mouse prostate (TRAMP)-C2 cells. Moreover, to visualize luciferase expression in living mice a charge-coupled device camera was used. Ad[PPT/TSTA-Luc] yielded approximately 30-fold higher transgene expression than Ad[PPT-Luc] in LNCaP tumor xenografts. Importantly, Ad[PPT/TSTA-Luc] also showed activity in murine TRAMP-C2 tumors, whereas Ad[PPT-Luc] activity was undetectable. These results highlight that the recombinant PPT sequence is active in murine prostate cancer cells when augmented by a TSTA system. This finding opens up for preclinical studies with prostate-specific therapeutic gene expression in immunocompetent mice.

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Acknowledgements

This work was supported by funding from the Swedish Cancer Society (Grant 4419-B05-06XBC), the Swedish Research Council (Grant K2005-31X-15270-01A), the Knut and Alice Wallenberg Foundation and the European Community on behalf of GIANT (Grant LSHB-CT-2004-512087). ME is a recipient of the Göran Gustafsson's Foundation Award.

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  1. H Dzojic and W-S Cheng: These authors contributed equally to this work.

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  1. Clinical Immunology Division, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

    H Dzojic, W-S Cheng & M Essand

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  1. H Dzojic
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  2. W-S Cheng
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  3. M Essand
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Correspondence to M Essand.

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Dzojic, H., Cheng, WS. & Essand, M. Two-step amplification of the human PPT sequence provides specific gene expression in an immunocompetent murine prostate cancer model. Cancer Gene Ther 14, 233–240 (2007). https://doi.org/10.1038/sj.cgt.7701007

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