Antitumor Effect of Low-Dose of Rapamycin in a Transgenic Mouse Model of Liver Cancer

Abstract

Purpose: We investigate whether low-dose rapamycin is effective in preventing hepatocellular carcinoma (HCC) growth and treating HCC after tumor development in transgenic mice. Materials and Methods: We established transgenic mice with HCC induced by activated HrasG12V and p53 suppression. Trans genic mice were randomly assigned to five experimental groups: negative control, positive control, tacrolimus only, rapamycin only, and tacrolimus plus rapamycin. The mice were further divided into two groups according to time to commencement of im munosuppressant treatment: de novo treatment and post-tumor development. Results: In the de novo treatment group, marked suppression of tumor growth was observed in the rapamycin only group. In the post-tumor development group, the rapamycin only group displayed no significant suppression of tumor growth, compared to the positive control group. In T lymphocyte subset analysis, the numbers of CD4+effector T cells and CD4+ regulatory T cells were significantly lower in the positive control, tacrolimus only, and tacrolimus plus rapamycin groups than the negative control group. Immunohistochemical analysis revealed significantly higher expression of phosphorylated-mTOR, 4E-BP1, and S6K1 in the posi tive control group than in the rapamycin only group. Conclusion: Low-dose rapamycin might be effective to prevent HCC growth, but may be ineffective as a treatment option after HCC development.