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.
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.
Miyake
Hideaki
H
Department of Urology, Hyogo Medical Center for Adults, Akashi 673-8558, Japan. hideakimiyake@hotmail.com
Yamanaka
Kazuki
K
Muramaki
Mototsugu
M
Hara
Isao
I
Gleave
Martin E
ME
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D051152:Clusterin; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D008207:Lymphatic Metastasis / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*
D000970:Antineoplastic Agents; C495242:CLU protein, human; C495243:Clu protein, mouse; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; D020319:Oligodeoxyribonucleotides, Antisense; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin