title: Combination of radiotherapy and adenovirus-mediated p53 gene therapy for MDM2-overexpressing hepatocellular carcinoma.
abstract: 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-Hep1) 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-Hep1 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.
authors.affiliation: Department of Radiation Oncology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Woong Sub
authors.initials: WS
authors.lastname: Koom
authors.forename: Soo-Yeon
authors.initials: SY
authors.lastname: Park
authors.forename: Wonwoo
authors.initials: W
authors.lastname: Kim
authors.forename: Minjung
authors.initials: M
authors.lastname: Kim
authors.forename: Ji-Seong
authors.initials: JS
authors.lastname: Kim
authors.forename: Hyunki
authors.initials: H
authors.lastname: Kim
authors.forename: Il-Kyu
authors.initials: IK
authors.lastname: Choi
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
authors.forename: Jinsil
authors.initials: J
authors.lastname: Seong
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D018714:Radiotherapy, Adjuvant / Q000379:methods*; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000627:therapeutic use*; D015854:Up-Regulation
chemical_list: D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2