To establish a more effective therapeutic strategy against advanced
bladder cancer, we investigated the effects of combined treatment with antisense (AS)
oligodeoxynucleotide (ODN) targeting the anti-apoptotic gene
clusterin and adenoviral-mediated p53 gene transfer (Ad5CMV-p53) using the human
bladder cancer KoTCC-1 model.
Clusterin expression in KoTCC-1 cells was highly upregulated by Ad5CMV-p53 treatment; however, AS
clusterin ODN treatment further suppressed
clusterin expression in KoTCC-1 cells after Ad5CMV-p53 treatment. AS
clusterin ODN treatment synergistically enhanced the cytotoxic effect of Ad5CMV-p53, and DNA fragmentation characteristic of apoptosis was observed only after combined treatment with AS
clusterin ODN and Ad5CMV-p53, but not
after treatment with either agent alone. Administration of AS
clusterin ODN and Ad5CMV-p53 into nude mice resulted in a significant inhibition of KoTCC-1
tumor growth as well as
lymph node metastases compared to administration of either agent alone. Furthermore, combined treatment with AS
clusterin ODN, Ad5CMV-p53, and
cisplatin completely eradicated KoTCC-1
tumors and
lymph node metastases in 60% and 100% of mice, respectively. These findings suggest that combined treatment with AS
clusterin ODN and Ad5CMV-p53 could be a novel strategy to inhibit
bladder cancer progression, and that further additional use of a chemotherapeutic agent may substantially enhance the efficacy of this combined regimen.