Synergistic chemosensitization and inhibition of tumor growth and metastasis by adenovirus-mediated p53 gene transfer in human bladder cancer model

Objectives. 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 IC50 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. UROLOGY 56: 332-336, 2000. (C) 2000, Elsevier Science Inc.