Enhancement of chemosensitivity in human bladder cancer cells by adenoviral-mediated p53 gene transfer.
BACKGROUND
Drug resistance is a major problem in tumor chemotherapy, and recent studies have suggested that the differential sensitivity of cancer cells to chemotherapy is associated with different susceptibilities to undergoing apoptosis. The aim of this study was to evaluate the effects of introduction of wild-type p53 or p21WAF1/CIP1 (p21) on chemosensitivity of bladder cancer cells.


METHODS
The human bladder cancer cell line HT1376, which contains mutant p53 and p21 genes, was used in this study. The effects of adenoviral-mediated p53 or p21 gene transfer on sensitivity of HT1376 cells to cisplatin were analyzed both in vitro and in vivo.


RESULTS
The introduction of wild-type p53 gene into HT1376 markedly enhanced the sensitivity to cisplatin in vitro. Direct injection of the p53-adenoviral vector into subcutaneous HT1376 tumors established in nude mice, followed by intraperitoneally administration of cisplatin, induced massive apoptotic destruction of the tumors. In contrast, the sensitivity of HT1376 to cisplatin was not increased by the introduction of the p21 gene either in vitro or in vivo.


CONCLUSIONS
These findings suggest that the combined regimen of adenoviral-mediated p53 gene transfer and cisplatin may become an efficient and powerful tool for treatment of bladder cancer.
Department of Urology, Kobe University School of Medicine, Japan.
H
H
Miyake
I
I
Hara
K
K
Gohji
K
K
Yamanaka
S
S
Arakawa
S
S
Kamidono
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003131:Combined Modality Therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D018014:Gene Transfer Techniques; D016158:Genes, p53; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000628:therapy*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D002945:Cisplatin