Intravesical interleukin-12 gene therapy in an orthotopic bladder cancer model.
OBJECTIVE
To evaluate the antitumor effect of intravesical cationic liposome-mediated interleukin-12 (IL-12) gene delivery in an orthotopic murine bladder cancer model, and to investigate the immunologic memory against tumors between IL-12 gene therapy and bacille Calmette-Guérin (BCG) therapy.


METHODS
Orthotopic murine bladder tumors were established by implanting 5 x 10(5) MBT-2 cells into the bladder of syngeneic female C3H mice. Intravesical IL-12 gene therapy was evaluated at varying doses: 0 microg (control) and 3, 5, and 10 microg (n = 8 for each group). Intravesical treatments were performed every 3 days and repeated six times beginning 5 days after tumor implantation. To compare the long-term, tumor-specific immunity between IL-12-treated mice (n = 18) and BCG-treated mice (n = 20), the animals surviving at day 60 and 10 new control mice were rechallenged with MBT-2 cells and received no additional treatment. On day 120, all surviving mice were killed and underwent necropsy.


RESULTS
In the IL-12 groups at doses of 0, 3, 5, and 10 microg, 0, 2, 3, and 3 mice survived, respectively. Mice in the 5-microg and 10-microg IL-12 groups survived significantly longer than did the control group. All mice cured by IL-12 treatment successfully rejected the rechallenge with MBT-2 cells; however, mice cured by BCG and the new control mice died of the rechallenged bladder tumors.


CONCLUSIONS
Intravesical IL-12 gene therapy, which induced long-lasting tumor-specific immunologic memory compared with BCG therapy, improved survival in an orthotopic bladder cancer model.
Horinaga
Minoru
M
Department of Cancer Biology, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. m5508985@ra2.so-net.ne.jp
Harsch
Kelley M
KM
Fukuyama
Ryuichi
R
Heston
Warren
W
Larchian
William
W
D000818:Animals; D001500:BCG Vaccine / Q000627:therapeutic use*; D005260:Female; D015316:Genetic Therapy; D018664:Interleukin-12 / Q000235:genetics* / Q000627:therapeutic use*; D008081:Liposomes; D051379:Mice; D009368:Neoplasm Transplantation; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
D001500:BCG Vaccine; D008081:Liposomes; D018664:Interleukin-12