Suicide gene therapy for chemically induced rat bladder tumor entailing instillation of adenoviral vectors.
The efficacy of an in vivo gene therapy protocol making use of an adenoviral vector in the treatment of bladder cancer was examined. Bladder tumors were induced in rats by oral administration of BBN (N-butyl-N-(4-hydroxybutyl)nitrosamine). Histologically, such tumors resemble those seen in human bladder cancer, and the cells can be selectively transduced using adenoviral vectors. The therapeutic protocol thus entailed instillation of an adenoviral vector containing the HSV-tk suicide gene into rat bladder followed by a regimen of intraperitoneal ganciclovir (GCV) injections. Histological examination after a short-term GCV regimen (3 days) revealed marked vacuolization of the tumor cells. Moreover, TUNEL assays showed that the cytotoxic reaction was mediated by apoptosis. Following a long-term GCV regimen (14 days), tumor growth was significantly inhibited and glandular metaplasia was observed. This is the first report demonstrating the efficacy of in vivo suicide gene therapy in a chemically induced transitional cell carcinoma like that seen in most human bladder cancer. Intravesical instillation is already a well established clinical technique. Our findings indicate that now there is a strong potential for its incorporation into new and useful gene therapies aimed at the treatment of human bladder cancer.
Akasaka
S
S
Department of Biochemistry and Molecular Biology, Center for Advanced Medical Technology, Nippon Medical School, Bunkyo-ku, Tokyo 113-8602, Japan.
Suzuki
S
S
Shimizu
H
H
Igarashi
T
T
Akimoto
M
M
Shimada
T
T
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage; D017209:Apoptosis; D002085:Butylhydroxybutylnitrosamine; D002273:Carcinogens; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage; D015316:Genetic Therapy; D005822:Genetic Vectors; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D051381:Rats; D011916:Rats, Inbred F344; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D014617:Vacuoles / Q000473:pathology
D000998:Antiviral Agents; D002273:Carcinogens; D002085:Butylhydroxybutylnitrosamine; D013937:Thymidine Kinase; D015774:Ganciclovir