1. ¹Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Japan
2. ²Department of Pathology, Kinki University School of Medicine, Osaka-Sayama, Japan
3. ³Department of Biochemistry, Kinki University School of Medicine, Osaka-Sayama, Japan

Correspondence: Professor M Kudo, Department of Gastroenterology and Hepatology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511, Japan. E-mail: m-kudo@med.kindai.ac.jp

Revised 24 August 2007; Accepted 1 October 2007; Published online 30 October 2007.

Abstract

When the tumour suppressor p53 is activated by DNA damage, it stimulates the transcription of its target genes, which then induce cell cycle arrest or apoptosis. Here, we examined the role p53 plays in the antitumour effect of combination treatment with pegylated interferon (PEG-IFN)- and 5-fluorouracil (5-FU), which has been shown to effectively treat advanced hepatocellular carcinoma (HCC). Nude mice were injected subcutaneously with cultured HepG2 cells, in which p53 is functional. They were treated a week later with PEG-IFN and/or 5-FU for 7 weeks, after which we measured and examined their tumours. Combination groups showed significantly lower tumour volumes and higher tumour cell apoptosis than the other groups. Combination treatment and PEG-IFN monotherapy also significantly elevated the p53 protein and mRNA levels in the tumour but only combination treatment increased the degree of p53 phosphorylation at serine46 and induced p53-regulated apoptosis-inducing protein 1 (p53AIP1) expression. The antitumour effects of combination treatment is due in part to the elevation by PEG-IFN of p53 protein and mRNA expression and in part to the DNA damage that is generated by 5-FU, which induces p53 serine46 phosphorylation, which in turn upregulates p53AIP1 expression.