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 19kDa- and E1B 55kDa-deleted oncolytic adenovirus (Ad-ΔE1B19/55). In combination with radiotherapy, greater cytotoxicity was observed for Ad-ΔE1B19/55 than for the single E1B 55kDa-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 19kDa 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 19kDa-deleted oncolytic Ad.
Bibliographical noteFunding Information:
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.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology