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Antisense Smo under the control of the PTCH1 promoter delivered by an adenoviral vector inhibits the growth of human pancreatic cancer

Gene Therapy volume 13, pages 1587–1594 (2006)Cite this article

Abstract

Hedgehog (Hh) signaling pathway is crucial in growth and patterning during embryonic development. Recent data have shown an association of its activation with cancer formation and maintenance. A ligand-dependent activation, where Hh components (SHH, PTCH1, Smo and GLi1) are aberrantly expressed with PTCH1 being a negative feedback regulator, is a newly identified mechanism for pancreatic carcinogenesis. In this study, we developed a cell-specific cytotoxic model for the treatment of human pancreatic cancer (HPC) in which expression of antisense Smo (SAS) was under the control of the PTCH1 promoter (ptch/p) delivered by an adenoviral vector (Ad-ptch/p-SAS). We observed that the cell-specific cytotoxicity in HPC cells depended on the expressions of inherent PTCH1, Smo and GLi1 in the target cells in which the Hh pathway was presumed to be activated. Fluorescence-activated cell sorting analysis indicated that the cell death was apoptosis. Western blot showed that Smo protein in the infected cells significantly decreased. Furthermore, an in vivo experiment demonstrated that such Hh activity-cell-specific cytotoxicity was achieved by daily intratumoral injection of Ad-ptch/p-SAS (109 plaque-forming unit) for 5 days. Our study suggests that targeting at the Hh signaling pathway may be an effective novel gene therapeutic strategy alone or in combination with other agents for the treatment of pancreatic cancer.

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Acknowledgements

This project was supported in part by a grant from the National Natural Science Foundation of China (Nos. 30370646 and 30370647).

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Authors and Affiliations

  1. Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China

    J Gao, Z Li, Z Chen, J Shao, L Zhang, G Xu, Z Tu & Y Gong

Authors
  1. J Gao
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  2. Z Li
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  3. Z Chen
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  4. J Shao
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  5. L Zhang
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  6. G Xu
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  7. Z Tu
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Correspondence to Z Li.

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Gao, J., Li, Z., Chen, Z. et al. Antisense Smo under the control of the PTCH1 promoter delivered by an adenoviral vector inhibits the growth of human pancreatic cancer. Gene Ther 13, 1587–1594 (2006). https://doi.org/10.1038/sj.gt.3302816

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