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p53 selective and nonselective replication of an E1B-deleted adenovirus in hepatocellular carcinoma
C M Vollmer1, A Ribas, L H Butterfield
1Division of Surgical Oncology, University of California Los Angeles, 90095-1782, USA.
Abstract:
An E1B gene-attenuated adenovirus (dl1520) has been proposed to have a selective cytolytic activity in cancer cells with a mutation or deletion in the p53 tumor suppressor gene (p53-null), a defect present in almost half of human hepatocellular carcinomas (HCCs). In this study, the in vitro and in vivo antitumor activity of dl1520 was investigated focusing on two human HCC cell lines, a p53-wild type (p53-wt) cell line and a p53-null cell line. dl1520 was tested for in vitro cytopathic effects and viral replication in the human HCC cell lines Hep3B (p53-null) and HepG2 (p53-wt). The in vivo antitumor effects of dl1520 were investigated in tumors grown s.c. in a severe combined immunodeficient mouse model. In addition, the combination of dl1520 infection with systemic chemotherapy was assessed in these tumor xenografts. At low multiplicities of infection, dl1520 had an apparent p53-dependent in vitro viral growth in HCC cell lines. At higher multiplicities of infection, dl1520 viral replication was independent of the p53 status of the target cells. In vivo, dl1520 significantly retarded the growth of the p53-null Hep3B xenografts, an effect augmented by the addition of cisplatin. However, complete tumor regressions were rare, and most tumors eventually grew progressively. dl1520 had no effect on the in vivo growth of the p53-wt HepG2 cells, with or without cisplatin treatment. The E1B-deleted adenoviral vector dl1520 has an apparent p53-dependent effect in HCC cell lines. However, this effect is lost at higher viral doses and only induces partial tumor regressions without tumor cures in a human HCC xenograft model.
Insights
An E1B gene-attenuated adenovirus (dl1520) shows p53-dependent effects against hepatocellular carcinoma (HCC) cells in vitro. In vivo, dl1520 partially reduced tumor growth, especially when combined with chemotherapy, but did not cure tumors.
Area of Science:
- Oncolytic virotherapy
- Hepatocellular carcinoma (HCC) research
- Tumor suppressor gene function
Background:
- Hepatocellular carcinoma (HCC) frequently harbors p53 tumor suppressor gene mutations (p53-null).
- Adenovirus dl1520, with an E1B gene deletion, targets cancer cells with p53 defects.
- Selective oncolytic activity of dl1520 in p53-null cancer cells is proposed.
Purpose of the Study:
- To investigate the in vitro and in vivo antitumor activity of dl1520 in HCC.
- To evaluate dl1520's efficacy in p53-wild type (p53-wt) and p53-null HCC cell lines.
- To assess combination therapy of dl1520 with chemotherapy in HCC xenografts.
Main Methods:
- In vitro cytopathic effects and viral replication assays using Hep3B (p53-null) and HepG2 (p53-wt) HCC cell lines.
- In vivo antitumor efficacy assessment in severe combined immunodeficient mouse models with HCC xenografts.
- Combination therapy studies involving dl1520 infection and systemic cisplatin chemotherapy.
Main Results:
- dl1520 exhibited p53-dependent in vitro viral growth at low multiplicities of infection (MOI).
- At higher MOI, dl1520 replication was independent of p53 status in HCC cell lines.
- In vivo, dl1520 significantly retarded p53-null Hep3B xenograft growth, enhanced by cisplatin, but complete regressions were rare.
- dl1520 showed no effect on p53-wt HepG2 xenografts, with or without cisplatin.
Conclusions:
- The E1B-deleted adenovirus dl1520 demonstrates an apparent p53-dependent effect in HCC cell lines.
- This p53-dependent effect is lost at higher viral doses.
- dl1520 induces partial tumor regressions in vivo but does not achieve tumor cures in the studied HCC xenograft model.