Combination of radiotherapy and adenovirus-mediated p53 gene therapy for MDM2-overexpressing hepatocellular carcinoma

The p53 gene plays a determinant role in radiation-induced cell death and its protein product is negatively regulated by mdm2. we investigated whether adenovirus-mediated modified p53 gene transfer,which blocks p53-mdm2 binding,is effective for radiation-induced cell death in hepatocellular carcinoma (hcc) at different mdm2 cellular levels. human hepatocellular carcinoma cell lines expressing mdm2 at low levels (huh7) and high levels (sk-hepl) were used. ad-p53 and ad-p53vp are replication-deficient adenoviral vectors containing human wild-type or modified p53,respectively. the anti-tumor effect was highest for ad-p53 + radiotherapy (rt) in the low-level mdm2 cells,whereas this effect was highest for ad-p53vp + rt in the mdm2-overexpressing cells. in huh-7 cells,ad-p53 + rt decreased cell viability (32%) in vitro and inhibited tumor growth (enhancement factor,1.86) in vivo. additionally,p21 expression and apoptosis were increased. in contrast,in sk-hepl cells,ad-p53vp + rt showed decreased cell viability (51%) in vitro and inhibition of tumor growth (enhancement factor,3.07) in vivo. caspase-3 expression and apoptosis were also increased. adenovirus-expressing modified p53,which blocks p53- mdm2 binding,was effective in killing tumor cells overexpressing mdm2. furthermore,the combination strategy for disruption of the p53-mdm2 interaction with rt demonstrated enhanced anti-tumor effects both in vitro and in vivo.