Therapeutic efficacy of adenoviral-mediated p53 gene transfer is synergistically enhanced by combined use of antisense oligodeoxynucleotide targeting clusterin gene in a human bladder cancer model

Neoplasia. 2005 Feb;7(2):171-9. doi: 10.1593/neo.04478.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Cisplatin / therapeutic use
  • Clusterin
  • Combined Modality Therapy
  • Disease Models, Animal
  • Drug Synergism*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Transfer Techniques
  • Genetic Therapy*
  • Genetic Vectors
  • Glycoproteins / antagonists & inhibitors
  • Glycoproteins / genetics
  • Glycoproteins / pharmacology*
  • Humans
  • Lymphatic Metastasis / prevention & control
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Chaperones / antagonists & inhibitors
  • Molecular Chaperones / genetics
  • Molecular Chaperones / pharmacology*
  • Oligodeoxyribonucleotides, Antisense / therapeutic use*
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / therapy*


  • Antineoplastic Agents
  • CLU protein, human
  • Clu protein, mouse
  • Clusterin
  • Glycoproteins
  • Molecular Chaperones
  • Oligodeoxyribonucleotides, Antisense
  • Tumor Suppressor Protein p53
  • Cisplatin