GENE-THERAPY FOR HEPATIC MICROMETASTASIS OF MURINE COLON-CARCINOMA

Backgrounds/Aims: Pit cells are located in the hepatic sinusoids and a re organ-associated natural killer cells that contribute to immune sur veillance in the liver, In the present study, the interleukin-2 gene w as introduced into hepatocytes using an adenovirus vector to induce in terleukin-2 production in an attempt to enhance the natural killer act ivity of pit cells, leading to inhibition of metastasis of colon carci noma. Methods: The recombinant adenovirus vector ''Adex1CAmIL2'' was c onstructed by inserting an expression unit which was composed of the C AG promotor (cytomegalovirus enhancer plus chicken beta-actin promotor ), murine interleukin-2 cDNA, and a rabbit beta-globin polyadenylation signal, After administration of Adex1CAmIL2 to mice (4x10(7) pfu per animal), the expression of murine interleukin-2 in hepatocytes was exa mined by immunostaining and in situ hybridization, and the natural kil ler activity of hepatic mononuclear cells was measured. Inhibition of hepatic metastasis of colon carcinoma was examined after infusion of c olon 38 tumor cells into the superior mesenteric vein. Results: After administration of Adex1CAmIL2, interleukin-2 mRNA expression was demon strated in hepatocytes until day 7, and the serum interleukin-2 level was increased, The natural killer activity: of hepatic mononuclear cel ls was markedly enhanced for 7-10 days. Hepatic metastasis was inhibit ed by administration of Adex1CAmIL2 until day 7 after turner cell inoc ulation, Conclusion: These results suggest that gene therapy using Ade x1CAmIL2 could be potentially useful for inhibiting hepatic micrometas tasis by enhancing the natural killer activity of pit cells.