High-lose and long-term therapy with interferon-alfa inhibits tumor growth and recurrence in nude mice bearing human hepatocellular carcinoma xenografts with high metastatic potential

Abstract

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-␣-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-␣ 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 ؋ 10 6 U/kg/day, 1.5 ؋ 10 7 U/kg/day for treated groups, and 3 ؋ 10 7 U/kg/day; tumor volume was 8,475 mm 3 ؎ 2,636 mm 3 , 7,963 mm 3 ؎ 3,214 mm 3 , 769 mm 3 ؎ 287 mm 3 , and 13 mm 3 ؎ 9 mm 3 ; incidence of lung metastasis being 100%, 80%, 40%, and 0%; life span was 45 ؎ 4 days, 53 ؎ 8 days, 81 ؎ 6 days, and 105 ؎ 24 days, respectively. In mice with curative resection, when comparison was made among control, IFN 5 ؋ 10 5 U/kg/day, 1 ؋ 10 6 U/kg/day, 4 ؋ 10 6 U/kg/day, 7.5 ؋ 10 6 U/kg/day, 1.5 ؋ 10 7 U/kg/day, and 3 ؋ 10 7 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-␣ inhibited neovascularization induced by LCI-D20 tumor specimens implanted into the micropocket of nude mice corneas. Hepatocellular carcinoma (HCC) is one of the most frequent fatal malignancies occurring in Asia and Africa. 1 In China, it is the second major cause of cancer death in males and the third in females. 2,3 Surgical resection is the most important treatment. Unfortunately, the postoperative recurrence rate remains high. 4,5 HCC is generally not sensitive to chemotherapy. HCC is a typical hypervascular tumor. Intrahepatic and lung metastases suggest its hematogenous dissemination. Recently, angiogenesis was proved to be an important factor influencing HCC metastases and recurrence. 6 Therefore, agents that inhibit angiogenesis maybe provide a new approach to suppress the tumor growth and recurrence of HCC. In addition to the well-documented, antiproliferative, and immunomodulatory effects of interferon (IFN), the antiangiogenic properties of IFN have been proven. [7][8][9][10][11] The systemic administration of IFN-␣ decreased the expression of angiogenic factors, such as bFGF, 12 inhibited the angiogenesis, and resulted in regression of human tumors. 13,14 This study evaluates whether IFN-␣-1b can suppress tumor growth, prolong animal life-span, and inhibit recurrence after resection by inhibition of angiogenesis.

Replication efficiency and sequence analysis of full‐length hepatitis B virus isolates from hepatocellular carcinoma tissues

“…It was reported recently that when high dosage and long term interferon-alpha was given to nude mice bearing human HCC xenografts, tumor growth and recurrence was inhibited. 21 If there was replicating form of HBV in the xenografts, the inhibitory effect could also be associated with the antiviral effect of interferon-alpha. Therefore, antiviral therapy at an early stage of HBV infection, would not only contribute to the prevention of HCC by suppressing infection, but could also help to block HCC development in patients with active virus replication by inhibiting the above mechanism.…”

The prognostic significance of clinical and pathological features in hepatocellular carcinoma

“…The result of RCT carried in authors' institute also showed that IFN-alpha therapy could decrease the postoperative recurrence rate of HCC and prolong the DFS after HCC resection. This might be attributed to antiangiogenesis effect of IFN-alpha [94] . Recently, one RCT indicated that a single 1850 MBq dose of intra-arterial 131 I-lipiodol given after curative resection significantly decreased the rate of recurrence and increased the 3-year overall survival rate from 46.3% to 86.4% [95] .…”

Effects of interferon alpha treatment on recurrence and survival after complete resection or ablation of hepatocellular carcinoma: A meta‐analysis of randomized controlled trials

“…20 Among these, IFN therapy may be one of the most promising approaches because IFNs not only possess antitumor properties including antiproliferative, 21,22 antiangiogenic, [23][24][25] and immunomodulatory effects 26 on tumors, but also have antiviral activities with clearance or suppression of hepatitis B virus (HBV) and hepatitis C virus (HCV) (HBV and HCV infections are the most common etiologies of HCC) in a variable proportion of patients. [27][28][29] In recent years, several clinical trials have suggested that adjuvant IFN-a treatment could obviously influence recurrence and survival of HCC patients after resection or ablation, while results in these trials were inconsistent.…”