Combination of IL-12 and IL-18 of electro-gene therapy synergistically inhibits tumor growth.
BACKGROUND
We previously showed that IL-12 electro-gene therapy (EGT) induces significant antitumor immunity. However, because interleukin (IL)-18 acts synergistically with IL-12 to augment Th1 responses and interferon (IFN)-gamma, we designed an EGT protocol using IL-12 + IL-18 with the aim of enhancing the antitumor effects obtained with IL-12 alone.


METHODS
Expression plasmids harboring the gene for IL-12 or IL-18 were cotransferred to subcutaneous murine CT26 tumors. Subsequent expression of IFN-gamma and the presence of CD8+ T cells within treated tumors were analyzed by semiquantitative RT-PCR.


RESULTS
IL-12 + IL-18 EGT inhibited tumor growth significantly better than IL-12 EGT, which was consistent with significantly higher intratumoral levels of IFN-gamma. Enhanced infiltration of tumor tissues by CD8+ T cells was confirmed with both IL-12 and IL-12 + IL-18 EGT. Finally, IL-12 + IL-18 EGT, but not IL-12 EGT, significantly suppressed untreated contralateral tumors.


CONCLUSIONS
EGT with IL-12 and IL-18 is potentially an effective antitumor gene therapy.
Tamura
Takahiko
T
Osaka University Graduate School of Medicine, Division of Molecular Regenerative Medicine, Osaka 565-0871, Japan. tamura@onbich.med.osaka-u.ac.jp
Nishi
Toru
T
Goto
Tomoaki
T
Takeshima
Hideo
H
Ushio
Yukitaka
Y
Sakata
Tsuneaki
T
D000230:Adenocarcinoma / Q000139:chemically induced / Q000628:therapy*; D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000628:therapy*; D004274:DNA, Recombinant / Q000008:administration & dosage / Q000627:therapeutic use*; D004357:Drug Synergism; D018274:Electroporation; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000235:genetics*; D020382:Interleukin-18 / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009605:Nitrosomethylurethane; D010957:Plasmids / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology*; D014162:Transfection / Q000379:methods
D004274:DNA, Recombinant; D020382:Interleukin-18; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12; D009605:Nitrosomethylurethane; D007371:Interferon-gamma