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Gene therapy of epithelial ovarian cancer using adenoviral vectors
1Department of Obstetrics and Gynecology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
Abstract:
Ovarian cancer is the fourth most common cause of death in women. Gene therapy using the herpes simplex virus thymidine kinase (HSV-tk) gene followed by ganciclovir (GCV) treatment has been successfully applied in the treatment of different cancers in experimental animals and in humans. In a recent report, we have demonstrated that the HSV-tk/GCV system can be used efficiently to kill human epithelial ovarian cancer cells (Gynecol Obstet Invest 1997;43:268-75). In this work, we wanted to test the ability of the HSV-tk/GCV to treat ovarian cancer in an animal model.The immune-deficient nude mice model was employed, and mice were injected intraperitoneally with the human epithelial ovarian cancer cell line OVCAR3, 10(8) cell/mouse. The mice were divided into three different groups, groups 1 and 2 were treated by intraperitoneal injection of adenovirus carrying the HSV-tk gene (ad-tk) on day 3 after cell implantation. Group 1 received 2 x 10(8) pfu/mouse; group 2 received 20 x 10(8) pfu/mouse. Group 3 did not receive any viral injection and served as our negative control. All mice received GCV 10 mg/kg IP bid for 6 days. All mice were hosted in the same facilities and had access to food and water ad libitum. Mice in group 3 started to show clinical manifestations of disease by day 10, and all mice were dead by day 21 (16 +/- 1.5). At this point mice in groups 1 and 2 appeared perfectly healthy. Autopsy done on group 3 mice demonstrated multiple cancer implants in the abdominal cavity plus hemorrhagic ascitis. In contrast, autopsy on sample mice from groups 1 and 2 at the same time point failed to demonstrate any macroscopic or microscopic cancer.On further follow-up, mice in groups 1 and 2 started to show cancer-related signs, eg, weight loss, movement difficulty, poor reflex response, and finally death. Survival varied between 50 and 101 days with a mean of 66 +/- 17 days for group 1 and 74 +/- 13 days for group 2. Autopsy done on treated mice demonstrated multiple cancer implants and ascitis. In conclusion, a single injection of ad-tk/GCV was able to improve survival in an ovarian cancer mouse model from an average of 16 days to 74 days. Trials with multiple injection in a novel immune-competent mouse model of ovarian cancer are underway in our laboratory.
Insights
Gene therapy using the herpes simplex virus thymidine kinase (HSV-tk) gene and ganciclovir (GCV) effectively treated ovarian cancer in a mouse model. This approach significantly improved survival rates, offering a promising avenue for future ovarian cancer therapies.
Area of Science:
- Oncology
- Gene Therapy
- Virology
Background:
- Ovarian cancer is a leading cause of cancer death in women.
- Gene therapy with the herpes simplex virus thymidine kinase (HSV-tk) gene followed by ganciclovir (GCV) has shown promise in cancer treatment.
- Previous studies demonstrated the HSV-tk/GCV system's efficacy against human ovarian cancer cells.
Purpose of the Study:
- To evaluate the therapeutic potential of the HSV-tk/GCV gene therapy system in an animal model of ovarian cancer.
- To assess the impact of adenovirus-mediated HSV-tk gene transfer and GCV treatment on ovarian cancer progression and survival in mice.
Main Methods:
- An immune-deficient nude mice model was established by intraperitoneal injection of human epithelial ovarian cancer cells (OVCAR3).
- Mice were divided into groups receiving different doses of adenovirus carrying the HSV-tk gene (ad-tk) or serving as a control group.
- All groups received ganciclovir (GCV) treatment, and tumor progression and survival were monitored.
Main Results:
- The control group (no ad-tk) showed rapid tumor progression and died within 21 days.
- Mice treated with ad-tk and GCV exhibited significantly improved survival, with mean survival times of 66 and 74 days for different dosage groups.
- Autopsies confirmed the absence of macroscopic or microscopic cancer in treated mice initially, though tumors reappeared later in the study.
Conclusions:
- A single administration of ad-tk/GCV gene therapy significantly improved survival in an ovarian cancer mouse model.
- The HSV-tk/GCV system demonstrates potent anti-cancer effects against ovarian cancer in vivo.
- Further research involving multiple injections and immune-competent models is warranted to optimize this therapeutic strategy.