Low-dose radiation enhances survivin-mediated virotherapy against malignant glioma stem cells.
To improve the efficacy and selectivity of virotherapy for malignant glioma, we designed a strategy to amplify adenoviral replication in conjunction with radiotherapy using a radioinducible promoter. First, we compared the radiation-inducible activity of FLT-1, vascular endothelial growth factor, DR5, Cox2, and survivin. We then examined the capacity of the optimal promoter to modulate transgene expression followed by E1A activity in vitro and in vivo in a glioma stem cell model. In the presence of radiation, survivin mRNA activity increased 10-fold. Luciferase transgene expression was dose dependent and optimal at 2 Gy. A novel oncolytic adenovirus, CRAd-Survivin-pk7, showed significant toxicity and replication against a panel of passaged and primary CD133(+) glioma stem cells. On delivery of radiation, the toxicity associated with CRAd-Survivin-pk7 increased by 20% to 50% (P < 0.05). At the same time, the level of E1A activity increased 3- to 10-fold. In vivo, treatment of U373MG CD133(+) stem cells with CRAd-Survivin-pk7 and radiation significantly inhibited tumor growth (P < 0.05). At the same time, the level of E1A activity was 100-fold increased versus CRAd-Survivin-pk7 alone. Selected genes linked to radioinducible promoters whose expression can be regulated by ionizing radiation may improve the therapeutic ratio of virotherapy. In this study, we have identified a new radioinducible promoter, survivin, which greatly enhances the activity of an oncolytic adenovirus in the presence of low-dose radiotherapy.
Nandi
Suvobroto
S
The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA.
Ulasov
Ilya V
IV
Tyler
Matthew A
MA
Sugihara
Adam Quasar
AQ
Molinero
Luciana
L
Han
Yu
Y
Zhu
Zeng B
ZB
Lesniak
Maciej S
MS
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001932:Brain Neoplasms / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism*; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy / Q000379:methods*; D010455:Peptides; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D013234:Stem Cells / Q000378:metabolism*; D000077022:Survivin
D000071916:AC133 Antigen; D015703:Antigens, CD; C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; D006023:Glycoproteins; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D000077022:Survivin