IL-12 cDNA direct injection: Antimetastatic effect from a single injection in a murine hepatic metastases model

Sharon M. Weber, Chen Qi, Zane Neal, Paul Sondel, David M. Mahvi

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Interleukin 12 (IL-12) gene therapy is an effective antitumor agent in local and metastatic murine tumor models. We sought to evaluate the antimetastatic effect of IL-12 cDNA in a liver metastases model. A liver metastases model was induced by creating a "primary" splenic tumor through inoculation of 1 × 10 5 TS/A adenocarcinoma cells directly into the inferior pole of the spleen in female BALB/c mice. On day 4, 50 μg of IL-12 cDNA or control plasmid DNA was injected into splenic tumor, followed by splenectomy on day 8. Mice were sacrificed on day 25 to assess liver tumor burden. IL-12 mRNA and mIL-12 and IFN-γ protein levels were assessed after IL-12 injection. Peripheral blood CD4+, CD8+, and NK cells were quantified on day 14 using FACS. To determine the significance of site of cytokine DNA injection, IL-12 cDNA was injected on day 4 into splenic tumor or into the non-involved spleen after isolation of the inferior and superior portions of the spleen, respectively, with surgical clips. Splenectomy was performed on day 8 and sacrifice was performed on day 25. IL-12 mRNA was detected in the liver 8 h after injection, with a peak at 24 h. After splenic injection, protein levels of IL-12 and IFN-γ were detectable in the liver and spleen 24 h after treatment. IL-12 and IFN-γ were not detectable in control animals. In the peripheral blood, there was a marked increase in NK cells (13% of total lymphocytes versus 4%, control) and in the CD4+/CD8+ ratio (5.5 versus 1.9). At day 25, there was a marked antimetastatic effect after IL-12 injection into either splenic tumor [liver:body weight, 6.2 versus 10.9 (control), P = 0.007] or non-involved spleen (6.8 g versus 10.7 g, P = 0.005). There was no difference in the antimetastatic effect between animals injected into splenic tumor or non-involved spleen (P = 0.3). Injection with a single dose of IL-12 cDNA into splenic tumor or non-involved spleen resulted in a profound antimetastatic effect. Splenic IL-12 injection results in mRNA expression in the liver, protein expression in the liver and spleen, and a marked increase in NK cells and the CD4+/CD8+ ratio in peripheral blood.

Original languageEnglish (US)
Pages (from-to)210-217
Number of pages8
JournalJournal of Surgical Research
Volume122
Issue number2
DOIs
StatePublished - Dec 2004

Keywords

  • IL-12
  • immunotherapy

ASJC Scopus subject areas

  • Surgery

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