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.

Abstract

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.

• Authors: Hideaki Miyake, Kazuki Yamanaka, Mototsugu Muramaki, Isao Hara, Martin E Gleave
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 7 Issue 2 Pg. 171-9 (Feb 2005) ISSN: 1522-8002 [Print] United States
• PMID: 15802022 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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, genetics, pharmacology)
• Humans
• Lymphatic Metastasis (prevention & control)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Chaperones (antagonists & inhibitors, genetics, pharmacology)
• Oligodeoxyribonucleotides, Antisense (therapeutic use)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Urinary Bladder Neoplasms (genetics, pathology, therapy)