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HER-2/neu-targeting cancer therapy via adenovirus-mediated E1A delivery in an animal model
1Department of Tumor Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Abstract:
Overexpression of HER-2/neu has been demonstrated in human ovarian cancer and correlated with poor prognosis. We previously found that the adenovirus type 5 early region 1A (E1A) gene product can repress overexpression and suppress the tumorigenic potential of the HER-2/neu-overexpressing cancer cells. To develop an efficient HER-2/neu-targeting gene therapy with E1A, a replication-deficient adenovirus containing the E1A gene, Ad.E1A(+), was used to transduce the HER-2/neu-overexpressing human ovarian cancer cell line SK-OV3.ip1. Tumor cell growth in vitro and colony formation in soft agarose were greatly inhibited by Ad.E1A(+) transduction. To test therapeutic efficacy in vivo, tumor-bearing mice were established by i.p. injection with ovarian cancer cells and treated by i.p. injection of 10(8) PFU viral solution containing either replication-deficient Ad.E1A(+); control virus Ad.E1A(-) which is the same adenovirus as Ad.E1A(+) except for E1A deletion, or just PBS. Ad.E1A(+) significantly prolonged survival in treated mice for 1 year (80%) whereas in control groups, all mice died of cancer within 4.5 months. Immunohistochemistry analysis indicated that Ad.E1A protein was expressed in tumor tissue and expression of HER-2/neu p185 protein was suppressed in vivo. As a control, another ovarian cancer cell line 2774, in which HER-2/neu is expressed at a basal level, was also inoculated i.p. following the same therapeutic procedure. Ad.E1A(+) could not prolong survival of 2774 cells, indicating that Ad.E1A(+) specifically targeted HER-2/neu-overexpressing tumor cells and functioned as an antitumor agent.
Insights
Gene therapy using adenovirus type 5 early region 1A (E1A) gene, Ad.E1A(+), effectively suppressed HER-2/neu-overexpressing ovarian cancer. This targeted approach significantly improved survival rates in mice, demonstrating its potential as an antitumor agent.
Area of Science:
- Oncology
- Gene Therapy
- Virology
Background:
- HER-2/neu overexpression is linked to poor prognosis in human ovarian cancer.
- The adenovirus type 5 early region 1A (E1A) gene product can repress HER-2/neu overexpression and suppress tumor potential.
- Developing efficient HER-2/neu-targeting gene therapy is crucial for ovarian cancer treatment.
Purpose of the Study:
- To evaluate the therapeutic efficacy of Ad.E1A(+) in targeting HER-2/neu-overexpressing ovarian cancer cells.
- To assess the in vitro and in vivo antitumor activity of Ad.E1A(+) gene therapy.
- To determine the specificity of Ad.E1A(+) in targeting HER-2/neu-overexpressing tumors.
Main Methods:
- Replication-deficient adenovirus containing the E1A gene (Ad.E1A(+)) was used to transduce HER-2/neu-overexpressing human ovarian cancer cell line SK-OV3.ip1.
- In vitro studies assessed tumor cell growth and soft agarose colony formation.
- In vivo studies involved i.p. injection of tumor-bearing mice with Ad.E1A(+), control virus Ad.E1A(-), or PBS, followed by survival analysis and immunohistochemistry.
Main Results:
- Ad.E1A(+) transduction significantly inhibited in vitro tumor cell growth and colony formation.
- Ad.E1A(+) treatment significantly prolonged survival in tumor-bearing mice (80% survival at 1 year) compared to control groups (all mice died within 4.5 months).
- Immunohistochemistry confirmed Ad.E1A protein expression and suppressed HER-2/neu p185 protein in tumors. Ad.E1A(+) did not prolong survival in mice with basal HER-2/neu expressing cells (2774).
Conclusions:
- Ad.E1A(+) demonstrates potent in vitro and in vivo antitumor activity against HER-2/neu-overexpressing ovarian cancer.
- Ad.E1A(+) gene therapy specifically targets and suppresses HER-2/neu-overexpressing tumor cells, offering a promising therapeutic strategy.
- This study validates Ad.E1A(+) as a potential targeted gene therapy agent for HER-2/neu-driven ovarian cancers.