Synergistic antitumor effects of interleukin-12 gene transfer and systemic administration of interleukin-18 in a mouse bladder cancer model.
We introduced the interleukin-12 (IL-12) gene into the mouse bladder cancer cell line (MBT2) to establish sublines that secrete bioactive IL-12. IL-12-secreting MBT2 (MBT2/IL-12) sublines were completely rejected when subcutaneously implanted into immunocompetent syngeneic C3H mice. Although this antitumor effect did not change when IL-12-secreting cells were injected into immunodeficient mice whose CD8(+) T or CD4(+) T cells had been depleted by the corresponding antibody, it was abrogated when natural killer cells were depleted by anti-asialoGM1 antibody. In addition, when parental MBT2 cells mixed with MBT2/IL-12 cells were subcutaneously injected into mice, admixed MBT2/IL-12 inhibited the growth of the parental tumor. Furthermore, this antitumor effect was enhanced by systemic IL-18 administration. This synergism was abrogated when the mice were treated with interferon-gamma-neutralizing antibody in vivo. In conclusion, local secretion of IL-12 led to effective antitumor activity that was enhanced by systemic administration of IL-18. Interferon-gamma plays an important role in the synergism of IL-12 gene transduction and systemic administration of IL-18.
Yamanaka
K
K
Department of Urology and Department of Dermatology, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0010, Japan.
Hara
I
I
Nagai
H
H
Miyake
H
H
Gohji
K
K
Micallef
M J
MJ
Kurimoto
M
M
Arakawa
S
S
Kamidono
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000961:Antilymphocyte Serum; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002277:Carcinoma / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D015316:Genetic Therapy; D006084:Graft Rejection; D007111:Immunity, Cellular; D007155:Immunologic Factors / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D020382:Interleukin-18 / Q000627:therapeutic use*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*
D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D007155:Immunologic Factors; D020382:Interleukin-18; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12; D007371:Interferon-gamma