Drug-resistant human bladder-cancer cells are more sensitive to adenovirus-mediated wild-type p53 gene therapy compared to drug-sensitive cells

We investigated the therapeutic potential and molecular mechanism of adenov irus-mediated wt p53 gene therapy for drug-resistant human bladder cancers. KK47, a human bladder-cancer cell line, along with the drug-resistant subl ines KK47/DDP10, KK47/DDP20 (cisplatin-resistant) and KK47/ADM (doxorubicin -resistant) were used for the experiments. All 4 KK47 cell lines had geneti cally normal p53 genes. Using an in vitro cytotoxicity assay, the drug-resi stant cell lines were more sensitive to Ad-CMV-p53 cell killing than the KK 47 parental cell line. Ad-CMV-p53 induced higher levels of p53 protein and mRNA in the drug-resistant cell lines than in the parental cell line and, c onsequently, higher levels of p21 and Box mRNA, which resulted in higher pe rcentages of G(1) cell-cycle arrest and apoptosis. The higher efficiencies of adenoviral gene transfer in the drug-resistant cell lines were confirmed by X-gal staining after infection with Ad-CMV-beta -gal. In conclusion, ad enovirus-mediated wt p53 gene therapy was more effective in the drug-resist ant bladder-cancer cell lines than in the drug-sensitive bladder-cancer cel l line. (C) 2001 Wiley-Liss, Inc.