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Validation of tissue-specific promoter-driven tumor-targeting trans-splicing ribozyme system as a multifunctional cancer gene therapy device in vivo

Cancer Gene Therapy volume 16, pages 113–125 (2009)Cite this article

Abstract

A trans-splicing ribozyme that can specifically reprogram human telomerase reverse transcriptase (hTERT) RNA was previously suggested as a useful tool for tumor-targeted gene therapy. In this study, we applied transcriptional targeting with the RNA replacement approach to target liver cancer cells by combining a liver-selective promoter with an hTERT-mediated cancer-specific ribozyme. To validate effects of this system in vivo, we constructed an adenovirus encoding for the hTERT-targeting trans-splicing ribozyme under the control of a liver-selective phosphoenolpyruvate carboxykinase promoter. We observed that intratumoral injection of this virus produced selective and efficient regression of tumors that had been subcutaneously inoculated with hTERT-positive liver cancer cells in mice. Importantly, the trans-splicing reaction worked equally well in a nude mouse model of hepatocarcinoma-derived peritoneal carcinomatosis, inducing the highly specific expression of a transgene, and moreover, the efficient regression of the hTERT-positive liver tumors with minimal liver toxicity when systemically delivered with the adenovirus. In addition to the observed hTERT-dependent therapeutic gene induction, significant reductions in the levels of hTERT RNA (∼75%) were also observed. In conclusion, this study demonstrates that a cancer-specific RNA replacement approach using trans-splicing ribozyme with a tissue-selective promoter represents a promising strategy for cancer treatment.

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Acknowledgements

We thank Kazuhiro Oka (Baylor College of Medicine, Houston, TX, USA) for his kind donation of liver-specific promoter constructs. This work was supported by the Korea Science & Engineering Foundation grants (R01-2004-000-10436-0, M10534000004-06N3400-00410, and for the Medical Research Center for Cancer Molecular Therapy at Dong-A University), and grants from the Health 21 R&D Project (03-PJ1-PG3-21000-0008) and from the National R&D Program for Cancer Control by Korean Ministry of Health & Welfare. MS Song, G Ban, and YS Won are recipients of Brain Korea 21 fellowship.

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Author notes

  1. M-S Song and J-S Jeong: The first two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Yongin, Republic of Korea

    M-S Song, G Ban, J-H Lee, Y-S Won & S-W Lee

  2. Department of Pathology, Medical Research Center for Cancer Molecular Therapy, Dong-A University College of Medicine, Busan, Republic of Korea

    J-S Jeong & K-S Cho

  3. Molecular Imaging and Therapy Branch, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea

    I-H Kim

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  1. M-S Song
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Correspondence to I-H Kim or S-W Lee.

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Supplementary Information accompanies the paper on Cancer Gene Therapy website (http://www.nature.com/cgt)

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Song, MS., Jeong, JS., Ban, G. et al. Validation of tissue-specific promoter-driven tumor-targeting trans-splicing ribozyme system as a multifunctional cancer gene therapy device in vivo. Cancer Gene Ther 16, 113–125 (2009). https://doi.org/10.1038/cgt.2008.64

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