Adenovirus-mediated suicide-gene therapy in an orthotopic murine bladder tumor model.
BACKGROUND
Patients with high-grade transitional-cell carcinoma (TCC) of the bladder frequently experience recurrence and progress and have a low response rate to chemotherapy in metastatic TCC. In this study, we evaluated the feasibility and long-term efficacy of suicide-gene therapy using adenovirus (Ad)-mediated herpes simplex virus thymidine kinase gene (HSV-TK) and prodrug ganciclovir (GCV) as a potential therapeutic approach in murine-orthotopic models of TCC.


METHODS
A replication defective adenoviral vectors containing toxic HSV-TK gene under the transcriptional control of RSV (Rous sarcoma virus) promoter (Ad-RSV-TK) was used. Orthotopic bladder TCC was established with 1 x 106 murine (MBT-2) TCC cells in syngenic C3H/He female mice. Intratumoral injection of Ad-RSV-TK in combination with GCV (20 mg/kg body weight/day i.p. b.i.d. x 7 days) was administered in vivo for the determination of treatment efficacy and long-term host survival in separate controlled experiments.


RESULTS
In vivo experiments demonstrated greater than three-fold reductions in MBT-2 tumor growth for the animals treated with Ad-RSV-TK (5 x 108 plaque forming units (pfu)/GCV therapy (P < 0.01)). Central tumor necrosis and apoptosis were revealed by histomorphology and immunohistochemistry compared with other control animals (non-treated, GCV alone, Ad-RSV-TK alone). Direct intratumoral injection with Ad-RSV-TK/GCV also resulted in significantly improved survival over the control groups in separated experiment (log-rank test, P < 0.05).


CONCLUSIONS
Suicide-gene therapy using Ad-RSV-TK/GCV provides an effective therapy in an experimental murine orthotopic bladder cancer by significantly inhibiting tumor growth and improving long-term host survival.
Cheon
Jun
J
Department of Urology, Korea University College of Medicine, Seoul, Korea. jcheon@ns.kumc.or.kr
Moon
Du Geon
DG
Cho
Hyun Yee
HY
Park
Hong Seok
HS
Kim
Je Jong
JJ
Gardner
Thomas A
TA
Kao
Chinghai
C
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D002295:Carcinoma, Transitional Cell / Q000401:mortality / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use; D015316:Genetic Therapy; D051379:Mice; D008809:Mice, Inbred C3H; D018139:Simplexvirus; D013937:Thymidine Kinase / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000401:mortality / Q000628:therapy*
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir