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Gene therapy for bladder cancer using E1B-55 kD-deleted adenovirus in combination with adenoviral vector encoding
1Institute of Basic Medical Sciences, National Cheng Kung University Medical College, 1 Dashiue Road, Tainan 701, Taiwan.
Abstract:
Mutations or loss of heterozygosity of p53 are detected in approximately 50% of bladder cancers. E1B-55 kD-deleted adenovirus has been shown to kill tumour cells with defective p53 function while sparing normal cells. Here, we examined the cytolytic effect and replication of E1B-55 kD-deleted adenovirus, designated Ad5WS1, on human bladder cancer cell lines with various p53 status. Ad5WS1 caused more severe cytolytic effect and replicated more efficiently in J82 and TCC-SUP bladder cancer cells carrying mutant p53 compared with TSGH-8301 and BFTC-905 bladder cancer cells retaining wild-type p53. Introduction of dominant negative p53 into BFTC-905 cells rendered them more susceptible to Ad5WS1-induced cytolysis. Furthermore, cells susceptible to lysis caused by Ad5WS1 were not attributable to their greater infectability by adenovirus. Finally, Ad5WS1 suppressed the growth of TCC-SUP bladder tumour xenografts, which could be augmented when combined with replication-defective adenoviral vector encoding kringles 1-5 of plasminogen (K1-5), an angiogenic inhibitor. Taken together, our results show that E1B-55 kD-deleted adenovirus replicates and hence lyses bladder cancer cells with mutant p53 much more efficient than those with wild-type p53. Thus, E1B-deleted adenovirus may have therapeutic potential, especially in combination with adenoviral vector expressing K1-5, for the treatment of bladder cancer.
Insights
E1B-55 kD-deleted adenovirus effectively kills bladder cancer cells with mutant p53, sparing normal cells. This oncolytic virus shows therapeutic potential, especially when combined with angiogenesis inhibitors for bladder cancer treatment.
Area of Science:
- Oncolytic virology
- Cancer biology
- Molecular oncology
Background:
- TP53 mutations are common in bladder cancer, affecting tumor suppressor function.
- E1B-55 kD-deleted adenoviruses selectively target and kill tumor cells with defective p53.
- Targeting p53 pathways offers a promising strategy for bladder cancer therapy.
Purpose of the Study:
- To evaluate the efficacy of E1B-55 kD-deleted adenovirus (Ad5WS1) against human bladder cancer cells with varying p53 statuses.
- To investigate the replication and cytolytic potential of Ad5WS1 in bladder cancer models.
- To assess the therapeutic potential of Ad5WS1, alone and in combination with other agents, for bladder cancer treatment.
Main Methods:
- Assessing Ad5WS1-induced cytolysis and viral replication in bladder cancer cell lines with wild-type and mutant p53.
- Introducing dominant-negative p53 into cells to confirm p53-dependent susceptibility.
- Evaluating Ad5WS1 efficacy in suppressing bladder tumor xenografts, with and without combination therapy.
Main Results:
- Ad5WS1 demonstrated significantly enhanced cytolytic effects and replication in bladder cancer cells harboring mutant p53 compared to those with wild-type p53.
- Cells engineered to express dominant-negative p53 showed increased susceptibility to Ad5WS1-mediated lysis.
- Ad5WS1 suppressed tumor growth in vivo, with synergistic effects observed when combined with an adenoviral vector expressing kringles 1-5 (K1-5).
Conclusions:
- E1B-55 kD-deleted adenovirus exhibits selective oncolytic activity against p53-mutated bladder cancer cells.
- Ad5WS1 demonstrates significant therapeutic potential for bladder cancer, particularly when used in combination with K1-5 for enhanced anti-tumor and anti-angiogenic effects.