Original articles
Chemoprevention of hepatocellular carcinoma: Use of tamoxifen in an animal model of hepatocarcinogenesis

https://doi.org/10.1016/j.lab.2005.01.003Get rights and content

Hepatocellular carcinoma (HCC) is common worldwide and growing in importance in the West. HCC often occurs against a background of liver disease, tends to present at an advanced stage, and has a poor prognosis, suggesting that it is an ideal target for chemoprevention. We sought to identify in an animal model chemopreventive agents for HCC that might be tested in human subjects. To this end, we induced liver tumors by injecting ethyl-nitrosourea in 6-week-old male B6C3F1 mice. Two chemopreventive agents were administered over a period of 60 weeks: tamoxifen (420 mg/kg feed) and a retinoid, 13-cis-retinoic acid (200 mg/kg feed). Animals were killed at 60 weeks and their livers examined for HCC and premalignant lesions. All liver lesions (altered foci, adenomata, HCC) occurred significantly less frequently in the tamoxifen-treated group than the group given only ethylnitrosourea (HCC developed in 2 of 47 [4%] vs 11 of 44 [25%]; P<.001). On the other hand, retinoic acid appeared to increase the number of liver tumors, and in 2 animals angiosarcoma developed. Tamoxifen significantly decreased the incidence of chemical hepatocarcinogenesis in this model, suggesting an important role for estrogens in the pathogenesis of HCC and suggesting that it should be tested in human beings as a chemopreventive agent against HCC.

Section snippets

Methods

Male B6C3F1 mice, purchased from Harlan Teklad (Madison, Wis) were divided into 1 of 4 groups at 6 weeks of age: Group 1 received only a single intraperitoneal dose of saline solution, and groups 2 through 4 each received ENU in a single intraperitoneal dose of 120 μg/kg ENU. ENU was purchased from Sigma-Aldrich (St Louis, Mo) in multidose vials and reconstituted with the use of phosphate-buffered saline solution. Mice in group 2 were also administered 13-cis-retinoic acid (isotretinoin; 200

Results

We found that significantly greater number of liver tumors developed in animals treated with ENU than in those given only saline solution. Tamoxifen treatment was associated with a significant reduction in the incidence of altered foci, adenomata, and HCC. Retinoic acid appeared to increase the risk of liver lesions of all types. Among control animals treated only with saline solution, liver lesions developed in 12 of 47 (25%), including 1 (2%) with HCC, whereas, when ENU was administered, 41%

Discussion

Chemopreventive approaches are sorely needed to prevent HCC in patients at risk, including those with chronic viral hepatitis and cirrhosis, because current treatment is judged in terms of 1- to 5-year survival, not cure. Guyton and Krensler recently reviewed the subject of liver-cancer prevention and noted that vaccination against hepatitis B has proved effective in decreasing the risk of HCC in some parts of the world. Human studies of α-interferon, oltipraz, and chlorophyllin in this role

References (35)

  • H.B. El-Serag et al.

    Rising incidence of hepatocellular carcinoma in the United States

    N Engl J Med

    (1999)
  • M. Geissler et al.

    Molecular mechanisms of hepatocarcinogenesis

  • P. Bannasch et al.

    Experimental hepatocarcinogenesis. Molecular mechanisms of hepatocarcinogenesis

  • S.D. Vesselinovich

    Perinatal mouse liver carcinogenesis as a sensitive carcinogenesis model and the role of the sex hormonal environment in tumor development

  • S.D. Vesselinovich et al.

    Modifying role of partial hepatectomy and gonadectomy in ethylnitrosourea-induced hepatocarcinogenesis

    Cancer Res

    (1980)
  • S.D. Vesselinovich et al.

    Development of broad spectrum of tumors by ethylnitrosourea in mice and the modifying role of age, sex and strain

    Cancer Res

    (1974)
  • S.D. Vesselinovich et al.

    Kinetics of diethylnitroamine hepatocarcinogenesis in the infant mouse

    Cancer Res

    (1983)
    • View full text
    Copyright © 2005 Elsevier Inc. All rights reserved.