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Adenovirus‐mediated suicide‐gene therapy in an orthotopic murine bladder tumor model
Author(s) -
Cheon Jun,
Moon Du Geon,
Cho Hyun Yee,
Park Hong Seok,
Kim Je Jong,
Gardner Thomas A.,
Kao Chinghai
Publication year - 2002
Publication title -
international journal of urology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.172
H-Index - 67
eISSN - 1442-2042
pISSN - 0919-8172
DOI - 10.1046/j.1442-2042.2002.00464.x
Subject(s) - suicide gene , ganciclovir , medicine , genetic enhancement , thymidine kinase , in vivo , cancer research , syngenic , herpes simplex virus , apoptosis , rous sarcoma virus , immunology , virus , gene , biology , human cytomegalovirus , biochemistry , microbiology and biotechnology , immune system
AbstractBackground: 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 × 10 6 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. × 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 × 10 8 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.