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High-Dose and Long-Term Therapy With Interferon-Alfa Inhibits Tumor Growth and Recurrence in Nude Mice Bearing Human Hepatocellular Carcinoma Xenografts With High Metastatic Potential
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Postoperative recurrence of human hepatocellular carcinoma (HCC) is the major issue that must be addressed to further improve prognosis. This study was undertaken to investigate the effects of interferon-alfa-1b (IFN-a-1b) on recurrent tumor and metastasis after curative resection in nude mice bearing an HCC xenograft with high metastatic potential. Tumor tissues from LCI-D20, a metastatic model of HCC in nude mice, were orthotopically implanted in 105 nude mice. Eleven days later, 64 mice underwent curative resection of liver tumors. IFN-a at different doses was administered subcutaneously to mice with or without resection. In mice without resection, when comparison was made among control, IFN 7.5 3 106 U/kg/day, 1.5 3 107 U/kg/day for treated groups, and 3 3 107 U/kg/day; tumor volume was 8,475 mm3 6 2,636 mm3, 7,963 mm3 6 3,214 mm3, 769 mm3 6 287 mm3, and 13 mm3 6 9 mm3; incidence of lung metastasis being 100%, 80%, 40%, and 0%; life span was 45 6 4 days, 53 6 8 days, 81 6 6 days, and 105 6 24 days, respectively. In mice with curative resection, when comparison was made among control, IFN 5 3 105 U/kg/day, 1 3 106 U/kg/day, 4 3 106 U/kg/day, 7.5 3 106 U/kg/day, 1.5 3 107 U/kg/day, and 3 3 107 U/kg/day for treated groups; incidence of recurrent tumor was 100%, 100%, 87.5%, 100%, 87.5%, 62.5%, and 12.5%; lung metastasis being 100%, 75%, 87.5%, 50%, 62.5%, 0%, and 0%, respectively. IFN-a inhibited neovascularization induced by LCI-D20 tumor specimens implanted into the micropocket of nude mice corneas. In conclusion, high-dose and longterm therapy with IFN-a dose-dependently inhibits tumor growth and recurrence after resection of HCC. The effect of IFN-a may be attributed to antiangiogenesis in this experiment. These results provide potential clinical implication, particularly for the prevention of recurrence after curative resection of HCC.
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