Abstract
The inability to repair DNA double-strand breaks (DSB) leads to radiosensitization, such that ionizing radiation combined with molecular inhibition of cellular DSB processing may greatly affect treatment of human cancer. As a variety of viral products interact with the DNA repair machinery, oncolytic virotherapy may improve the therapeutic window of conventional radiotherapy. Here, we describe the mechanistic basis for synergy of irradiation and OBP-301 (Telomelysin), an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 infection led to E1B55kDa viral protein expression that degraded the complex formed by Mre11, Rad50, and NBS1, which senses DSBs. Subsequently, the phosphorylation of cellular ataxia-telangiectasia mutated protein was inhibited, disrupting the signaling pathway controlling DNA repair. Thus, tumor cells infected with OBP-301 could be rendered sensitive to ionizing radiation. Moreover, by using noninvasive whole-body imaging, we showed that intratumoral injection of OBP-301 followed by regional irradiation induces a substantial antitumor effect, resulting from tumor cell-specific radiosensitization, in an orthotopic human esophageal cancer xenograft model. These results illustrate the potential of combining oncolytic virotherapy and ionizing radiation as a promising strategy in the management of human cancer.
| Original language | English |
|---|---|
| Pages (from-to) | 9339-9348 |
| Number of pages | 10 |
| Journal | Cancer Research |
| Volume | 70 |
| Issue number | 22 |
| DOIs | |
| Publication status | Published - Nov 15 2010 |
Fingerprint
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Telomerase-dependent oncolytic adenovirus sensitizes human cancer cells to ionizing radiation via inhibition of DNA repair machinery. / Kuroda, Shinji; Fujiwara, Toshiya; Shirakawa, Yasuhiro; Yamasaki, Yasumoto; Yano, Shuuya; Uno, Futoshi; Tazawa, Hiroshi; Hashimoto, Yuuri; Watanabe, Yuichi; Noma, Kazuhiro; Urata, Yasuo; Kagawa, Shunsuke; Fujiwara, Toshiyoshi.
In: Cancer Research, Vol. 70, No. 22, 15.11.2010, p. 9339-9348.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Telomerase-dependent oncolytic adenovirus sensitizes human cancer cells to ionizing radiation via inhibition of DNA repair machinery
AU - Kuroda, Shinji
AU - Fujiwara, Toshiya
AU - Shirakawa, Yasuhiro
AU - Yamasaki, Yasumoto
AU - Yano, Shuuya
AU - Uno, Futoshi
AU - Tazawa, Hiroshi
AU - Hashimoto, Yuuri
AU - Watanabe, Yuichi
AU - Noma, Kazuhiro
AU - Urata, Yasuo
AU - Kagawa, Shunsuke
AU - Fujiwara, Toshiyoshi
PY - 2010/11/15
Y1 - 2010/11/15
N2 - The inability to repair DNA double-strand breaks (DSB) leads to radiosensitization, such that ionizing radiation combined with molecular inhibition of cellular DSB processing may greatly affect treatment of human cancer. As a variety of viral products interact with the DNA repair machinery, oncolytic virotherapy may improve the therapeutic window of conventional radiotherapy. Here, we describe the mechanistic basis for synergy of irradiation and OBP-301 (Telomelysin), an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 infection led to E1B55kDa viral protein expression that degraded the complex formed by Mre11, Rad50, and NBS1, which senses DSBs. Subsequently, the phosphorylation of cellular ataxia-telangiectasia mutated protein was inhibited, disrupting the signaling pathway controlling DNA repair. Thus, tumor cells infected with OBP-301 could be rendered sensitive to ionizing radiation. Moreover, by using noninvasive whole-body imaging, we showed that intratumoral injection of OBP-301 followed by regional irradiation induces a substantial antitumor effect, resulting from tumor cell-specific radiosensitization, in an orthotopic human esophageal cancer xenograft model. These results illustrate the potential of combining oncolytic virotherapy and ionizing radiation as a promising strategy in the management of human cancer.
AB - The inability to repair DNA double-strand breaks (DSB) leads to radiosensitization, such that ionizing radiation combined with molecular inhibition of cellular DSB processing may greatly affect treatment of human cancer. As a variety of viral products interact with the DNA repair machinery, oncolytic virotherapy may improve the therapeutic window of conventional radiotherapy. Here, we describe the mechanistic basis for synergy of irradiation and OBP-301 (Telomelysin), an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 infection led to E1B55kDa viral protein expression that degraded the complex formed by Mre11, Rad50, and NBS1, which senses DSBs. Subsequently, the phosphorylation of cellular ataxia-telangiectasia mutated protein was inhibited, disrupting the signaling pathway controlling DNA repair. Thus, tumor cells infected with OBP-301 could be rendered sensitive to ionizing radiation. Moreover, by using noninvasive whole-body imaging, we showed that intratumoral injection of OBP-301 followed by regional irradiation induces a substantial antitumor effect, resulting from tumor cell-specific radiosensitization, in an orthotopic human esophageal cancer xenograft model. These results illustrate the potential of combining oncolytic virotherapy and ionizing radiation as a promising strategy in the management of human cancer.
UR - http://www.scopus.com/inward/record.url?scp=78549274429&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78549274429&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-10-2333
DO - 10.1158/0008-5472.CAN-10-2333
M3 - Article
C2 - 21045143
AN - SCOPUS:78549274429
VL - 70
SP - 9339
EP - 9348
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 22
ER -