Combination gene therapy of lung cancer with conditionally replicating adenovirus and adenovirus-herpes simplex virus thymidine kinase

  • Authors:
    • Jin Young Oh
    • Mi Young Park
    • Dal Rae Kim
    • Jung Hee Lee
    • Seon-Hui Shim
    • Jin-Haeng Chung
    • Ho-Il Yoon
    • Jae Ho Lee
    • Myung-Whun Sung
    • Yeon-soo Kim
    • Choon-taek Lee
  • View Affiliations

  • Published online on: March 1, 2010     https://doi.org/10.3892/ijmm_00000354
  • Pages: 369-376
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Abstract

A major obstacle to the success of gene therapy strategies that directly target cancer cells is the low gene transfer rate. To address this problem, we had previously proposed a combination adenoviral gene therapy containing a conditionally replicating adenovirus (CRAD) expressing mutant E1 (Δ24RGD), and a replication-defective E1-deleted adenovirus to enhance the efficiency of gene transfer. Suicide/pro-drug gene therapy has an important additional benefit to the therapy of cancer. This relates to the transfer and expression of non-mammalian genes encoding enzymes that convert non-toxic pro-drugs into cellular toxins. We investigated the interaction between CRAD (Δ24RGD) and a replication-defective E1-deleted adenovirus (ad-HSTK) containing a suicide gene (HSTK: herpes simplex virus thymidine kinase gene) with respect to therapeutic gene production and tumor cell killing efficacy. Combined transduction of CRAD and ad-HSTK increased the transduction efficiency of HSTK and increased its sensitivity to ganciclovir (GCV) more efficiently than ad-HSTK alone. Transfer of medium of CRAD and ad-HSTK co-transduced cells induced the transfer of HSTK (media transferable bystander effect), and enhanced its sensitivity to GCV. In an animal tumor model, combined intratumoral injection of CRAD and ad-HSTK followed by GCV administration induced prolonged expression of HSTK and stronger growth suppression of established lung cancer xenografts than single injections. These data demonstrate that the selective replication of ad-HSTK due to the presence of mutant E1, produced by a Δ24RGD and HSTK/GCV suicide gene system, resulted in a striking improvement in anti-tumor effects in vitro and in vivo.

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March 2010
Volume 25 Issue 3

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Oh JY, Park MY, Kim DR, Lee JH, Shim S, Chung J, Yoon H, Lee JH, Sung M, Kim Y, Kim Y, et al: Combination gene therapy of lung cancer with conditionally replicating adenovirus and adenovirus-herpes simplex virus thymidine kinase. Int J Mol Med 25: 369-376, 2010
APA
Oh, J.Y., Park, M.Y., Kim, D.R., Lee, J.H., Shim, S., Chung, J. ... Lee, C. (2010). Combination gene therapy of lung cancer with conditionally replicating adenovirus and adenovirus-herpes simplex virus thymidine kinase. International Journal of Molecular Medicine, 25, 369-376. https://doi.org/10.3892/ijmm_00000354
MLA
Oh, J. Y., Park, M. Y., Kim, D. R., Lee, J. H., Shim, S., Chung, J., Yoon, H., Lee, J. H., Sung, M., Kim, Y., Lee, C."Combination gene therapy of lung cancer with conditionally replicating adenovirus and adenovirus-herpes simplex virus thymidine kinase". International Journal of Molecular Medicine 25.3 (2010): 369-376.
Chicago
Oh, J. Y., Park, M. Y., Kim, D. R., Lee, J. H., Shim, S., Chung, J., Yoon, H., Lee, J. H., Sung, M., Kim, Y., Lee, C."Combination gene therapy of lung cancer with conditionally replicating adenovirus and adenovirus-herpes simplex virus thymidine kinase". International Journal of Molecular Medicine 25, no. 3 (2010): 369-376. https://doi.org/10.3892/ijmm_00000354