Gene therapy for hepatic micrometastasis of murine colon carcinoma.
OBJECTIVE
Pit cells are located in the hepatic sinusoids and are organ-associated natural killer cells that contribute to immune surveillance in the liver. In the present study, the interleukin-2 gene was introduced into hepatocytes using an adenovirus vector to induce interleukin-2 production in an attempt to enhance the natural killer activity of pit cells, leading to inhibition of metastasis of colon carcinoma.


METHODS
The recombinant adenovirus vector "Adex1CAmIL2" was constructed by inserting an expression unit which was composed of the CAG 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 examined by immunostaining and in situ hybridization, and the natural killer activity of hepatic mononuclear cells was measured. Inhibition of hepatic metastasis of colon carcinoma was examined after infusion of colon 38 tumor cells into the superior mesenteric vein.


RESULTS
After administration of Adex1CAmIL2, interleukin-2 mRNA expression was demonstrated in hepatocytes until day 7, and the serum interleukin-2 level was increased. The natural killer activity of hepatic mononuclear cells was markedly enhanced for 7-10 days. Hepatic metastasis was inhibited by administration of Adex1CAmIL2 until day 7 after tumor cell inoculation.


CONCLUSIONS
These results suggest that gene therapy using Adex1CAmIL2 could be potentially useful for inhibiting hepatic micrometastasis by enhancing the natural killer activity of pit cells.
Shiratori
Y
Y
Department of Internal Medicine (II), Faculty of Medicine, University of Tokyo, Japan.
Kanai
F
F
Hikiba
Y
Y
Moriyama
H
H
Hamada
H
H
Matsumura
M
M
Tanaka
T
T
Lan
K H
KH
Ohashi
M
M
Okano
K
K
Naito
M
M
Omata
M
M
D000199:Actins / Q000235:genetics; D000256:Adenoviridae; D000818:Animals; D017690:Cell Transplantation; D002478:Cells, Cultured; D002645:Chickens; D003110:Colonic Neoplasms / Q000628:therapy*; D015316:Genetic Therapy; D005914:Globins / Q000235:genetics; D007249:Inflammation; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000166:cytology* / Q000276:immunology / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015345:Oligonucleotide Probes; D011817:Rabbits; D014162:Transfection; D001616:beta-Galactosidase / Q000096:biosynthesis
D000199:Actins; D007376:Interleukin-2; D015345:Oligonucleotide Probes; D005914:Globins; D001616:beta-Galactosidase