Combination therapy with PEG-IFN-alpha and 5-FU inhibits HepG2 tumour cell growth in nude mice by apoptosis of p53.
Combination therapy with PEG-IFN-alpha and 5-FU inhibits HepG2 tumour cell growth in nude mice by apoptosis of p53.
复制标题
DOI：
10.1038/sj.bjc.6604058
复制
发表时间：
2007-12-03
影响因子：
8.8
通讯作者：
Munakata, H
中科院分区：
文献类型：
--
作者：
Hagiwara, S;Kudo, M;Nakatani, T;Sakaguchi, Y;Nagashima, M;Fukuta, N;Kimura, M;Hayakawa, S;Munakata, H
当肿瘤抑制因子p53被DNA损伤激活时，它会刺激其靶基因的转录，从而诱导细胞周期阻滞或细胞凋亡。在这里，我们研究了p53在聚乙二醇化干扰素(PEG-IFN)-α和5-氟尿嘧啶（5-FU）联合治疗的抗肿瘤作用中所起的作用，聚乙二醇化干扰素(PEG-IFN)-α和5-氟尿嘧啶（5-FU）联合治疗已被证明能有效治疗晚期肝细胞癌（HCC）。裸鼠皮下注射培养的HepG2细胞，其中p53具有功能。一周后用PEG-IFN和/或5-FU治疗7周，之后我们测量和检查他们的肿瘤。联合治疗组肿瘤体积明显小于其他治疗组，肿瘤细胞凋亡明显高于其他治疗组。联合治疗和PEG-IFN单药治疗也显著升高了肿瘤中p53蛋白和mRNA的水平，但只有联合治疗增加了p53丝氨酸46磷酸化的程度，并诱导p53调节的凋亡诱导蛋白1 （p53AIP1）的表达。联合治疗的抗肿瘤作用部分是由于PEG-IFN升高p53蛋白和mRNA的表达，部分是由于5-FU产生的DNA损伤，其诱导p53丝氨酸46磷酸化，进而上调p53AIP1的表达。
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)-α 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.