Development of replication-competent adenovirus for bladder cancer by controlling adenovirus E1a and E4 gene expression with the survivin promoter
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Ho Kyung Seo1, Jeong Bin Seo2, Jae-Kook Nam3, Kyung-Chae Jeong4, Seung-Pil Shin3, In-Hoo Kim5, Sang Don Lee2 and Sang-Jin Lee3
1 Center for Prostate Cancer, Gyeonggi-do, Biomedical Research Institute, Pusan National University and Research Institute for Convergence of Biomedical Science and Technology, Pusan
2 Pusan National University and Biomedical Research Institute, Pusan National University and Research Institute for Convergence of Biomedical Science and Technology, Pusan
3 Genitourinary Cancer Branch, Research Institute National Cancer Center, Gyeonggi-do, Korea
4 Biomolecular Function Research Branch, Research Institute National Cancer Center, Gyeonggi-do, Korea
5 Molecular Imaging and Therapy Branch, Research Institute National Cancer Center, Gyeonggi-do, Korea
Sang-Jin Lee, email:
Sang-Don Lee, email:
Keywords: bladder cancer, gene therapy, adenovirus, survivin
Received: April 6, 2014 Accepted: June 29, 2014 Published: June 30, 2014
Survivin is a member of the inhibitors of apoptosis protein family. Here, we examined survivin expression and confirmed abundant survivin expression in bladder cancer cells. This expression pattern indicated that the transcriptional regulatory elements that control survivin expression could be utilized to discriminate cancer from normal cells. We therefore generated a novel adenovirus termed Ad5/35E1apsurvivinE4 with the following characteristics: 1) E1A and E4 protein expression was dependent on survivin promoter activity; 2) the green fluorescence protein gene was inserted into the genome under the control of the CMV promoter; 3) most of the E3 sequences were deleted, but the construct was still capable of expressing the adenovirus death protein with potent cytotoxic effects; and 4) the fiber knob was from serotype 35 adenovirus. As expected from the abundant survivin expression observed in bladder cancer cells, Ad5/35E1apsurvivinE4 replicated better in cancer cells than in normal cells by a factor of 106 to 102. Likewise, Ad5/35E1apsurvivinE4 exerted greater cytotoxic effects on all bladder cancer cell lines tested. Importantly, Ad5/35E1apsurvivinE4 inhibited the growth of Ku7-Luc orthotopic xenografts in nude mice. Taken together, Ad5/35E1apsurvivinE4 indicates that the survivin promoter may be utilized for the development of a replication-competent adenovirus to target bladder cancers.
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