Intratumoral delivery of interleukin 12 expression plasmids with in vivo electroporation is effective for colon and renal cancer.
We report on an antitumor treatment involving electrogene therapy (EGT), a newly developed in vivo gene transfer method using electroporation. We carried out in vivo EGT in a subcutaneous model of CT26 colon carcinoma cells, using plasmid DNAs encoding interleukin 12 (IL-12) subunits. For this purpose, we developed two IL-12 expression systems: a cotransfer system using a plasmid encoding the IL-12 p40 subunit and a plasmid encoding the IL-12 p35 subunit, and a single-vector system using a plasmid expressing a p40-p35 fusion protein. Both transfer systems significantly inhibited the growth of CT26 tumor. Immunohistochemical analysis of IL-12 EGT-treated tumors revealed enhanced infiltration of CD8(+) cells into the tumor tissue, while reverse transcriptase-polymerase chain reaction confirmed the increased expression of interferon gamma within treated tumors. The same IL-12 EGT applied to the nude mouse model was not effective, suggesting the critical role of T cell infiltration in this treatment. The inhibitory effects revealed in experiments in which previously treated mice were rechallenged with a second inoculation of CT26 tumor cells suggested that IL-12 EGT may also establish partial systemic antitumor immunity. The growth of IL-12 EGT-treated Renca tumors, a renal cell carcinoma, was also significantly inhibited. These findings suggest that EGT of the IL-12 gene has the potential to be an effective anticancer gene therapy.
Tamura
T
T
Shionogi Institute for Medical Science, 2-5-1, Mishima, Settsu-shi, Osaka 566-0022, Japan.
Nishi
T
T
Goto
T
T
Takeshima
H
H
Dev
S B
SB
Ushio
Y
Y
Sakata
T
T
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003110:Colonic Neoplasms / Q000628:therapy*; D018076:DNA, Complementary / Q000378:metabolism; D018274:Electroporation / Q000379:methods*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D007680:Kidney Neoplasms / Q000628:therapy*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D018664:Interleukin-12; D007371:Interferon-gamma; D008156:Luciferases