Synergistic chemosensitization and inhibition of tumor growth and metastasis by adenovirus-mediated P53 gene transfer in human bladder cancer model.
OBJECTIVE
To determine whether an adenovirus-mediated p53 gene (Ad5CMV-p53) transfer enhances cisplatin cytotoxicity in vitro and whether Ad5CMV-p53 and cisplatin synergistically inhibit growth and metastasis in vivo using human bladder cancer KoTCC-1 cells.


METHODS
MTT assays and DNA fragmentation assays were used to examine the effects of treatment with Ad5CMV-p53 and/or cisplatin on growth inhibition and induction of apoptosis, respectively, in KoTCC-1 cells. The efficacies of combined Ad5CMV-p53 and/or cisplatin therapy against growth and metastasis of KoTCC-1 tumors were assessed using subcutaneous and orthotopic tumor cell injection models.


RESULTS
Ad5CMV-p53 substantially enhanced cisplatin chemosensitivity in a dose-dependent manner, reducing the median IC(50) by more than 50%. Characteristic apoptotic DNA laddering was induced by the combination of sublethal doses of Ad5CMV-p53 and cisplatin, but not by either agent alone. Furthermore, combined Ad5CMV-p53 and cisplatin therapy synergistically inhibited growth of subcutaneous KoTCC-1 tumors and the incidence of metastasis after orthotopic injection.


CONCLUSIONS
These findings illustrate that combined treatment with Ad5CMV-p53 and cisplatin could be an attractive strategy for inhibiting progression of bladder cancer through effective induction of apoptosis.
Miyake
H
H
Department of Urology, Kobe University School of Medicine, Kobe, Japan.
Hara
I
I
Hara
S
S
Arakawa
S
S
Kamidono
S
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D005260:Female; D018014:Gene Transfer Techniques; D016158:Genes, p53; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*
D000970:Antineoplastic Agents; D002945:Cisplatin