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Double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus in combination with radiotherapy elicits an enhanced anti-tumor effect

Gene Therapy volume 16, pages 1111–1121 (2009)Cite this article

Abstract

Radiation therapy, a mainstay for anti-tumor therapeutic regimens for a variety of tumor types, triggers tumor cell apoptotic pathways by either directly eliciting DNA damage or indirectly inducing the formation of oxygen radicals. In an effort to augment radiation therapy, we generated a double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus (Ad−ΔE1B19/55). In combination with radiotherapy, greater cytotoxicity was observed for Ad−ΔE1B19/55 than for the single E1B 55 kDa-deleted oncolytic Ad (Ad−ΔE1B55). Consistent with this observation, higher levels of p53, phospho-p53, phospho-Chk1, phospho-Chk2, PI3K (phosphatidylinositol-3-kinase), phospho-AKT, cytochrome c, and cleavage of PARP (poly (ADP-ribose) polymerase) and caspase-3 were observed in cells treated with Ad−ΔE1B19/55 compared with those treated with Ad−ΔE1B55, indicating that the E1B 19 kDa present in Ad−ΔE1B55 may partially block radiation-induced apoptosis. A significant therapeutic benefit was also observed in vivo when oncolytic Ads and radiation were combined. Tumors treated with Ad−ΔE1B19/55 and radiation showed large areas of necrosis and apoptosis with the corresponding induction of p53. Finally, consistent with in vitro observations, the combination of Ad−ΔE1B19/55 and radiation was more efficacious than the combination of Ad−ΔE1B55 and radiation. Taken together, these results present a strong therapeutic rationale for combining radiation therapy with E1B 19 kDa-deleted oncolytic Ad.

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Acknowledgements

This work was supported by grants from the Ministry of Commerce, Industry and Energy (10030051, Dr C-O Yun), the Korea Science and Engineering Foundation (KOSEF) (R04-2004-000-10011-0, R01-2006-000-10084-0, R15-2004-024-02001-0, M10416130002-04N1613-00210, Dr C-O Yun), and through its National Nuclear Technology Program. Jaesung Kim, Ji Young Yoo and A-Rum Yoon are graduate students sponsored by the Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea. Pyung-Hwan Kim is a graduate student sponsored by the graduate program for Nanomedical Science, Yonsei University, Seoul, South Korea.

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Author notes

  1. J Kim and P-H Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Brain Korea 21 Project for Medical Sciences, Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea

    J Kim, J Y Yoo, A-R Yoon, H J Choi, I-W Kim, J-H Kim & C-O Yun

  2. Graduate Program for Nanomedical Science, Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea

    P-H Kim, J Y Yoo & C-O Yun

  3. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea

    H J Choi & J-H Kim

  4. Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea

    J Seong

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

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Kim, J., Kim, PH., Yoo, J. et al. Double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus in combination with radiotherapy elicits an enhanced anti-tumor effect. Gene Ther 16, 1111–1121 (2009). https://doi.org/10.1038/gt.2009.72

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