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In vivo gene therapy with p53 or p21 adenovirus for prostate cancer
J A Eastham1, S J Hall, I Sehgal
1Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA.
Abstract:
We introduced the gene for wild-type human p53 or p21, a critical downstream mediator of p53-induced growth suppression, into a p53-deficient mouse prostate cancer cell line using a recombinant adenoviral vector (Ad5CMV-p53 or Ad5CMV-p21). Elevated levels of endogenous mouse p21 mRNA provided evidence for the functional activity of virally transduced p53. Functional activity of viral-transduced p21 was demonstrated through immunoprecipitation of cellular protein extracts, which showed that the viral-transduced p21 associates with cyclin-dependent kinase 2 and was sufficient to down-regulate the activity of the cyclin-dependent kinase by approximately 65%. In vitro growth assays revealed significantly higher growth suppression after Ad5CMV-p21 infection compared to Ad5CMV-p53. In vivo studies in syngeneic male mice with established s.c. prostate tumors demonstrated that the rate of growth and final tumor volume were reduced to a much greater extent in mice that received intratumor injection of Ad5CMV-p21 compared to Ad5CMV-p53. In addition, the survival of host animals bearing tumors that were infected with Ad5CMV-p21, but not Ad5CMV-p53, was significantly extended. These data suggest that Ad5CMV-p21 may be effective as a therapeutic agent for prostate cancer.
Insights
Gene therapy using Ad5CMV-p21 effectively suppressed prostate cancer growth in mice. Introducing the p21 gene significantly reduced tumor volume and extended survival, suggesting its therapeutic potential.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Prostate cancer is a leading cause of mortality.
- The p53 tumor suppressor pathway is frequently inactivated in cancer.
- p21 is a key mediator of p53-induced growth suppression.
Purpose of the Study:
- To investigate the therapeutic potential of introducing human p53 or p21 genes into a p53-deficient mouse prostate cancer cell line.
- To evaluate the efficacy of Ad5CMV-p21 gene therapy in preclinical models of prostate cancer.
Main Methods:
- Recombinant adenoviral vectors (Ad5CMV-p53 and Ad5CMV-p21) were used to introduce genes into a p53-deficient mouse prostate cancer cell line.
- In vitro growth assays and in vivo studies in mice with established prostate tumors were performed.
- Functional activity of transduced p53 and p21 was confirmed via mRNA analysis, immunoprecipitation, and kinase activity assays.
Main Results:
- Transduced p21 associated with cyclin-dependent kinase 2 and reduced its activity by approximately 65%.
- Ad5CMV-p21 infection led to significantly greater in vitro growth suppression compared to Ad5CMV-p53.
- In vivo, Ad5CMV-p21 significantly reduced tumor growth rate and volume, and extended host survival.
Conclusions:
- Ad5CMV-p21 demonstrates potent anti-tumor activity in preclinical prostate cancer models.
- p21 gene therapy holds promise as a potential therapeutic strategy for prostate cancer.
- Further investigation into Ad5CMV-p21 as a prostate cancer therapeutic agent is warranted.