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

Other Titles
 MDM2 과발현 간세포암에서 아데노바이러스 이용한 p53 유전자 치료와 방사선 병용치료의 항암 효과 
 Dept. of Radiation Oncology (방사선종양학교실) 
Issue Date
Dept. of Medicine/박사
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.
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1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 3. Dissertation
Yonsei Authors
Koom, Woong Sub(금웅섭) ORCID logo https://orcid.org/0000-0002-9435-7750
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