Adenovirus mediated gelsolin gene therapy for orthotopic human bladder cancer in nude mice.
OBJECTIVE
Gelsolin is an actin regulatory protein that is undetectable or reduced in human bladder tumors compared with normal epithelial cells. Whether the over expression of gelsolin could inhibit tumor growth was investigated in an orthotopic bladder cancer nude mouse model using recombinant adenovirus encoding wild-type gelsolin (Ad-GSN).


METHODS
The 2 human bladder cancer cell lines KU-7 and UMUC-2 were transduced with Ad-GSN in vitro. Flow cytometric analysis was done to examine the cell cycle after transducing the adenovirus. Cell growth was compared with control groups of these cells transduced with adenovirus containing the Escherichia coli beta-galactosidase gene Ad-betagal. In vivo KU-7 cells were introduced into the bladder of nude mice (day 0), followed by 3 injections into the urethra (days 2 to 4) with Ad-GSN or Ad-betagal (1 x 10 pfu). At 8 days after initial adenovirus exposure (day 10) each bladder was sectioned and stained, and the mass of the tumor was digitally determined.


RESULTS
Bladder cancer cell growth (KU-7 and UMUC-2) was inhibited after these cells were transduced with Ad-GSN in vitro. Based on flow cytometric analysis over expression of gelsolin may cause these cells to arrest or delay at the G2/M phase of the cell cycle. In the orthotopic bladder cancer model the mass of the tumor was approximately 90% less in Ad-GSN treated animals than in controls.


CONCLUSIONS
Ad-GSN provides a significant tumor suppressive effect on human bladder cancer cells in this orthotopic nude mouse model. Adenovirus mediated over expression of gelsolin may be useful therapy for human bladder cancer.
Sazawa
Ataru
A
Division of Cancer Gene Regulation, Institute for Genetic Medicine, Department of Urologic Surgery, Graduate School of Medicine, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan.
Watanabe
Takafumi
T
Tanaka
Motoyoshi
M
Haga
Kazunori
K
Fujita
Hisakazu
H
Harabayashi
Touru
T
Shinohara
Nobuo
N
Koyanagi
Tomohiko
T
Kuzumaki
Noboru
N
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D004926:Escherichia coli / Q000235:genetics; D018260:Gelsolin / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D001616:beta-Galactosidase / Q000235:genetics
D018260:Gelsolin; D001616:beta-Galactosidase