Intravesical liposome-mediated interleukin-2 gene therapy in orthotopic murine bladder cancer model.
Using a novel orthotopic MBT-2 murine bladder tumor model, we evaluated the feasibility of intravesical gene therapy utilizing a cationic liposome, DMRIE/DOPE. Superficial bladder tumors were consistently established by intravesical instillation of 5x10(5) MBT-2 cells in syngeneic C3H female mice. In situ gene transfer to bladder tumors was accomplished via intravesical instillation of plasmid DNA/DMRIE/DOPE lipoplex. Beta-Galactosidase (beta-gal) gene expression was preferentially evident in bladder tumors and was present for at least 7 days after a single 30 min in situ transfection. Murine interleukin-2 (IL-2) gene was used for treatment of 3-day-old pre-established bladder tumors. Forty percent of animals treated with IL-2 gene were completely free of tumors by 60 days following the initial tumor implantation, while all control groups treated with beta-gal gene died. Those animals initially cured of pre-established tumors were completely resistant to a subsequent tumor re-challenge and their splenocyte-derived cytotoxic T lymphocytes were shown to be specific to MBT-2 cells, indicating that immunological memory against MBT-2 tumors was elicited by the treatment. These results demonstrate the possibility of an effective clinical application of this in situ intravesical IL-2 gene delivery system to high-risk superficial bladder tumors, obviating a need for tumor procurement and ex vivo gene transfer.
Horiguchi
Y
Y
Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Larchian
W A
WA
Kaplinsky
R
R
Fair
W R
WR
Heston
W D
WD
D000283:Administration, Intravesical; D000818:Animals; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005260:Female; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000235:genetics*; D008081:Liposomes; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D014162:Transfection; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*
D007376:Interleukin-2; D008081:Liposomes