Interleukin-10 plasmid DNA inhibits liver and lung metastasis of Colon26 adenocarcinoma in mice

Abstract

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We demonstrated that Interluekin-10 (IL-10) gene therapy markedly inhibited liver and lung metastasis of Colon26 adenocarcinoma. The transcription factor NF-kB is constitutively activated in many human cancers, and induces the expression of multiple genes including adhesion molecules, COX-2, and VEGF. Therefore, the blocking of NF-kB activity may be associated with the suppression of angiogenesis, invasion, and metastasis. Recent papers indicate that NF-kB activation is inhibited by IL-10. Accordingly, we hypothesized that systemic IL-10 treatment could induce the blocking of NF-kB activation, resulting in the inhibition of the expression of genes that mediate metastasis. To induce a high level of IL-10 in plasma, we transferred the naked EBV-derived plasmid vectors encoding the human IL-10 gene (pGEG.IL-10) into the liver via the intravenous route. A single injection of pGEG.IL-10 elevated IL-10 in the plasma of mice with the peak levels (115 pg/mL) observed on the second day. An injection of additional pGEG.IL-10 five days later significantly increased the plasma level of IL-10 again. This high level of IL-10 was maintained by readministering pGEG.IL-10. The inoculation of Colon26 carcinoma cells into mice caused the activation of NF-kB, resulting in a marked increase in the gene expression of TNFα, COX-2, and VEGF in the liver. In contrast, pGEG.IL-10 inhibited the activation of NF-kB in the liver. pGEG.IL-10 also inhibited liver and lung metastasis of Colon26, possibly via a decrease in the transactivation of important NF-kB-driven genes necessary for the processes of cancer metastasis and growth. Our gene-transfer technique induced the IL-10 gene transfection primarily in hepatocytes, and concentrations of IL-10 in the liver were consequently high. The protocol induces the desired inhibition of liver metastasis, but an IL-10 concentration 115 pg/mL, the plasma level induced by the IL-10 gene transfection, is also sufficient to inhibit the lung metastases of colon cancer. These results demonstrate that the activation of NF-kB in response to an inoculation of carcinoma cells is an important mechanism of metastasis, and that systemic IL-10 gene therapy could be a new therapeutic strategy for cancer metastasis.