Gene therapy for bladder cancer using E1B-55 kD-deleted adenovirus in combination with adenoviral vector encoding plasminogen kringles 1-5.
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.
Hsieh
J-L
JL
Institute of Basic Medical Sciences, National Cheng Kung University Medical College, 1 Dashiue Road, Tainan 701, Taiwan.
Wu
C-L
CL
Lai
M-D
MD
Lee
C-H
CH
Tsai
C-S
CS
Shiau
A-L
AL
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017501:Adenovirus E1B Proteins / Q000235:genetics*; D002470:Cell Survival; D017353:Gene Deletion; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D011994:Recombinant Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D014779:Virus Replication / Q000502:physiology*
D017501:Adenovirus E1B Proteins; D011994:Recombinant Proteins