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In vivo studies of adenovirus-based p53 gene therapy for ovarian cancer
V E von Gruenigen1, J T Santoso, R L Coleman
1Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas 75235-9032, USA.
Objectives:
To test the safety, efficacy, and toxicity of gene therapy using wild-type p53-expressing adenovirus (Ad-CMV-p53) in a nude mouse model with intraperitoneal (i.p.) 2774 human ovarian cancer cell line that contains a p53 mutation.
Study Design:
An initial study of adenovirus tolerance was determined in nude mice by a single i.p. injection of increasing doses of Ad-CMV-p53. Nude mice were implanted with an LD100 dose of 1 x 10(7) cells. To study the efficacy and specificity of Ad-CMV-p53 treatment, the mice received treatment with different adenovirus constructs. One group received Ad-CMV-p53 and another group received a control adenovirus construct, Ad-CMV-beta gal. To study the treatment response to Ad-CMV-p53, the mice were divided into groups and received various treatment schedules of 1 x 10(8) pfu of Ad-CMV-p53.
Results:
The mice tolerated Ad-CMV-p53 without adverse effects at doses of 1 x 10(8) pfu. The response to Ad-CMV-p53 showed significant survival duration in each dose regimen, with a survival time greater than that of untreated animals (P = 0.0173). However, no statistically significant survival advantage was observed between Ad-CMV-p53- and Ad-CMV-beta gal-treated mice.
Conclusions:
These studies show that at the adenovirus dose and administration regimen used, there is effective but not specific 2774 tumor growth inhibition in vivo. Efficient introduction of biologically active genes into tumor cells would greatly facilitate cancer therapy. Thus, although promising, these results caution that much effort will be required to realize the potential for clinical application of adenovirus-based ovarian cancer gene therapy.
Insights
Gene therapy using wild-type p53-expressing adenovirus showed effective tumor growth inhibition in a mouse model. While safe and improving survival, specificity for ovarian cancer requires further research for clinical application.
Area of Science:
- Oncology
- Gene Therapy
- Viral Vectors
Background:
- Ovarian cancer often harbors p53 mutations, impacting tumor suppressor function.
- Adenovirus vectors are being explored for targeted cancer gene therapy.
Purpose of the Study:
- To evaluate the safety and efficacy of wild-type p53-expressing adenovirus (Ad-CMV-p53) in a human ovarian cancer mouse model.
- To assess the toxicity and tumor growth inhibition of Ad-CMV-p53 in vivo.
Main Methods:
- Nude mice bearing human ovarian cancer cells (2774) with p53 mutations were used.
- Adenovirus tolerance was assessed via intraperitoneal injection.
- Efficacy was studied using Ad-CMV-p53 and a control Ad-CMV-beta gal construct.
Main Results:
- Ad-CMV-p53 was well-tolerated at doses up to 1 x 10(8) plaque-forming units (pfu).
- Treatment with Ad-CMV-p53 significantly increased survival duration compared to untreated controls (P = 0.0173).
- No significant survival difference was found between Ad-CMV-p53 and Ad-CMV-beta gal treatment groups.
Conclusions:
- Ad-CMV-p53 demonstrates effective, albeit non-specific, ovarian cancer tumor growth inhibition in vivo.
- Efficient gene delivery is crucial for successful cancer gene therapy.
- Further research is needed to optimize adenovirus-based gene therapy for clinical ovarian cancer treatment.