title: Intravesical interleukin-15 gene therapy in an orthotopic bladder cancer model.
abstract: Interleukin-15 (IL-15) is known to stimulate the proliferation of CD8(+) T-cells and natural killer cells, and also to help to maintain memory CD8(+) T cells, suggesting that it may be of value in cytokine treatment of bladder cancer. In this experiment, we tested the efficiency of intravesical liposomal IL-15 gene delivery and its antitumor effect in a mouse orthotopic bladder cancer model. We established an orthotopic bladder cancer model by implanting 5×10(5) MBT-2 cells into female C3H/HeN mice through the urethra. The mice received repeated intravesical gene delivery injected with liposome-mediated plasmids (5 μg) transurethrally. On day 23, the bladder weights in the group receiving medium alone, the beta-galactosidase gene delivery control group, and the IL-15 gene therapy group were 196±36 mg, 201±35 mg, and 96±29 mg, respectively (p<0.05), demonstrating the antitumor effect of intravesical IL-15 gene therapy in this model. In the bladders treated with IL-15 gene plasmid instillation, histological analysis revealed that many inflammatory cells were induced around the tumors. Immunohistochemical analysis confirmed that there was predominant infiltration of CD8(+) T cells around the tumor nest. After the intravesical IL-15 gene therapy, the growth of rechallenged subcutaneous MBT-2 cells in surviving mice was inhibited again via tumor-specific cytotoxic T lymphocytes, although newly implanted FM3A cells in the same mice were not rejected. The present findings indicate that IL-15 gene therapy may be a promising new adjuvant therapy for bladder cancer.
authors.affiliation: Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Eiji
authors.initials: E
authors.lastname: Kikuchi
authors.forename: Minoru
authors.initials: M
authors.lastname: Horinaga
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Takeda
authors.forename: Akira
authors.initials: A
authors.lastname: Miyajima
authors.forename: Ken
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Oya
mesh_terms: D000818:Animals; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D007150:Immunohistochemistry; D019409:Interleukin-15 / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D014162:Transfection; D014407:Tumor Cells, Cultured; D001743:Urinary Bladder / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*
chemical_list: D019409:Interleukin-15