Radiation increases the activity of oncolytic adenovirus cancer gene therapy vectors that overexpress the ADP (E3-11.6K) protein.
We have described three potential adenovirus type 5 (Ad5)-based replication-competent cancer gene therapy vectors named KD1, KD3, and VRX-007. All three vectors overexpress an Ad5 protein named Adenovirus Death Protein (ADP, also named E3-11.6 K protein). ADP is required for efficient lysis of Ad5-infected cells and spread of virus from cell to cell, and thus its overexpression increases the oncolytic activity of the vectors. KD1 and KD3 contain mutations in the Ad5 E1A gene that knock out binding of the E1A proteins to cellular p300/CBP and pRB; these mutations allow KD1 and KD3 to grow well in cancer cells but not in normal cells. VRX-007 has wild-type E1A. Here we report that radiation increases the oncolytic activity of KD1, KD3, and VRX-007. This increased activity was observed in cultured cells, and it was not because of radiation-induced replication of the vectors. The combination of radiation plus KD3 suppressed the growth of A549 lung adenocarcinoma xenografts in nude mice more efficiently than radiation alone or KD3 alone. The combination of ADP-overexpressing vectors and radiation may have potential in treating cancer.
Toth
Karoly
K
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Missouri 63104, USA. toth@slu.edu
Tarakanova
Vera
V
Doronin
Konstantin
K
Ward
Peter
P
Kuppuswamy
Mohan
M
Locke
Jacob E
JE
Dawson
Julie E
JE
Kim
Han J
HJ
Wold
William S M
WS
D000256:Adenoviridae / Q000235:genetics*; D017503:Adenovirus E3 Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004307:Dose-Response Relationship, Radiation; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000532:radiotherapy* / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
D017503:Adenovirus E3 Proteins; C099609:adenovirus death protein, Adenovirus