Abstract
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.
Highlights
Urothelial carcinoma of the bladder is the second most common genitourinary malignancy and the second most common cause of genitourinary cancer-related death [1]
The promoter driving survivin expression in bladder cancer cells was evaluated using reporter constructs in which the promoter was placed upstream of the luciferase gene
These results led us to explore whether the regulatory elements mediating survivin expression may be utilized to construct a replicationcompetent adenovirus under the control of the survivin promoter
Summary
Urothelial carcinoma of the bladder is the second most common genitourinary malignancy and the second most common cause of genitourinary cancer-related death [1]. 70 to 80% of patients with urothelial carcinoma of the bladder present with non-muscle invasive bladder cancer (NMIBC). The standard treatment for NMIBC is transurethral resection (TUR) with or without intravesical therapy; approximately 70% of patients develop recurrence after initial treatment, with up to 30% of patients progressing to muscle-invasive disease. Radical cystectomy with urinary tract reconstruction provides for the optimal control of high-risk NMIBC and muscle-invasive bladder cancer. Advances in reconstruction techniques of the lower urinary tract have decreased the lifestyle changes associated with radical cystectomy, significant quality of life alterations occur after radical surgery [2,3,4,5,6,7]. The intravesical route has demonstrated significant advantages because the virus comes in direct contact with the bladder cancer and eliminates the need for systemic administration. Efficient delivery and selectivity remain major hurdles to this type of treatment
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