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Efficacy of intraperitoneal adenovirus-mediated p53 gene therapy in ovarian cancer
V. E. Von Gruenigen1, J. D. O'Boyle, R. L. Coleman
1Division of Gynecologic Oncology, Departments of Obstetrics and Gynecology and Biochemistry, Hammon Center for Therapeutic Oncologic Research, The University of Texas Southwestern Medical Center, Dallas, Texas, and Introgen Therapeutics, Inc., Houston, Texas USA.
Abstract:
The purpose of this study was to determine the efficacy of adenovirus-based p53 gene therapy in the treatment of ovarian cancer using an intraperitoneal microscopic tumor animal model system. Adenovirus-mediated wild-type p53 gene was introduced into the NIH:OVCAR-3 human ovarian cancer cell line in vitro and in vivo. In order to study microscopic intraperitoneal tumor, athymic nude mice were inoculated intraperitoneally (i.p.) with 1 x 107 OVCAR-3 cells and observed for tumor growth. Three days after inoculation with OVCAR-3 cells, the mice were divided into 3 treatment groups. One group received three daily i.p. injections of 1 x 108 pfu Ad-CMV-p53, a second group received three daily i.p. injection of 1 x 108 pfu of the control adenovirus construct expressing beta galactosidase (Ad-CMV-betagal) and a third group received three daily i.p. injections of normal saline. Adenovirus-mediated introduction of the wild-type p53 gene in the ovarian cancer cell line resulted in transient high levels of p53 protein for 24-48 h. Cell cycle analysis revealed G1 arrest, as well as the appearance of apoptosis. In vitro cell growth assays showed growth inhibition of cancer cells infected with Ad-CMV-p53 compared to cells infected with Ad-CMV-betagal or normal saline. There was a significant increase in survival in the Ad-CMV-p53 adenovirus treated animals compared to the PBS treated animals (P = 0.004). Likewise, the survival in Ad-CMV-p53 treated mice was also significantly greater than mice treated with Ad-CMV-betagal (P < 0.0001). These results demonstrated that Ad-CMV-p53 treatment is effective in inhibiting tumor growth and prolonging survival in this microscopic cancer xenograft model. The results of this study constitute a step in translating promising in vitro and in vivo data from an adenovirus-based gene therapeutic model system into practical and scientifically based human cancer therapeutic trials.
Insights
Adenovirus-based p53 gene therapy effectively inhibited ovarian cancer growth and prolonged survival in a preclinical model. This study supports adenovirus p53 gene therapy for future human cancer trials.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Ovarian cancer remains a leading cause of cancer-related deaths in women.
- Gene therapy offers a promising avenue for novel cancer treatments.
- The p53 tumor suppressor gene plays a critical role in cell cycle regulation and apoptosis.
Purpose of the Study:
- To evaluate the efficacy of adenovirus-mediated wild-type p53 gene therapy against ovarian cancer.
- To assess the impact of Ad-CMV-p53 on tumor growth and survival in an intraperitoneal microscopic tumor model.
Main Methods:
- Adenovirus-mediated wild-type p53 gene (Ad-CMV-p53) was introduced into NIH:OVCAR-3 human ovarian cancer cells in vitro and in vivo.
- Athymic nude mice were inoculated intraperitoneally with OVCAR-3 cells and treated with Ad-CMV-p53, control adenovirus (Ad-CMV-betagal), or normal saline.
- Cell cycle analysis, apoptosis assays, in vitro cell growth assays, and survival studies were performed.
Main Results:
- Ad-CMV-p53 treatment led to transient high levels of p53 protein, G1 cell cycle arrest, and apoptosis in ovarian cancer cells.
- In vitro, Ad-CMV-p53 significantly inhibited cancer cell growth compared to controls.
- Ad-CMV-p53 treatment significantly increased survival rates in mice compared to both PBS and Ad-CMV-betagal treated groups (P < 0.0001).
Conclusions:
- Adenovirus-mediated p53 gene therapy demonstrates significant efficacy in inhibiting ovarian cancer growth and prolonging survival in a preclinical xenograft model.
- The findings support the potential of Ad-CMV-p53 as a therapeutic strategy for ovarian cancer.
- This study represents a crucial step towards translating gene therapy research into clinical applications for human cancer treatment.
