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Molecular therapy with recombinant p53 adenovirus in an androgen-independent, metastatic human prostate cancer model
S C Ko1, A Gotoh, G N Thalmann
1Urology Research Laboratory, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Abstract:
The lethal phenotypes of advanced prostate cancer are androgen independent (AI) and metastatic to the axial skeleton. Our laboratory has developed an AI mouse model of metastatic human prostate cancer. In this communication, we report the development of tumor suppressor gene therapy in this AI and metastatic (C4-2) cancer model. By using recombinant adenovirus as a delivery vehicle, we introduced a wild-type p53 tumor suppressor gene into prostate cancer cell lines. Despite a silent mutation at codon 152 of the p53 gene, C4-2 cells express functional, but low, levels of p53 protein. However, the other prostatic cell lines, PC-3 and DU145, have a deletion mutation and two point mutations of the p53 gene, respectively. In vitro studies showed that cell growth, as measured by the thymidine incorporation assay, was inhibited in the C4-2, PC-3, and DU145 cells infected with wild-type p53 adenovirus in comparison to control viruses. Recombinant wild-type p53 adenovirus inhibited prostate tumor growth and its production of prostate-specific antigen (PSA) when injected into C4-2 tumors in nude mice. All p53-treated mice were tumor free as long as 12 weeks after cessation of the 8-week treatment regimen. Two of 8 p53-treated mice developed small tumors growing at distant sites after a prolonged period of follow-up observation. Moreover, other AI prostate cancer cells, PC-3 and DU145, treated with Ad5-CMV-p53 failed to develop into tumors in vivo. This gene therapy strategy may be used against AI prostatic cancer regardless of p53 gene mutation status.
Insights
Gene therapy using wild-type p53 adenovirus effectively inhibited androgen-independent prostate cancer growth and PSA production in mouse models. This approach shows promise for treating advanced prostate cancer, even with existing p53 mutations.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Advanced prostate cancer is often androgen-independent (AI) and metastasizes to the skeleton.
- A novel AI mouse model of metastatic human prostate cancer (C4-2) was developed.
- Prostate cancer cell lines PC-3 and DU145 harbor p53 gene mutations, while C4-2 cells express low levels of functional p53.
Purpose of the Study:
- To develop and evaluate tumor suppressor gene therapy for AI and metastatic prostate cancer.
- To investigate the efficacy of wild-type p53 gene delivery using recombinant adenovirus in prostate cancer models.
- To determine if this gene therapy is effective irrespective of the p53 gene mutation status.
Main Methods:
- Recombinant adenovirus carrying the wild-type p53 gene (Ad5-CMV-p53) was used for gene delivery.
- In vitro studies assessed the effect of p53 gene therapy on prostate cancer cell growth (C4-2, PC-3, DU145) using thymidine incorporation assays.
- In vivo studies involved injecting Ad5-CMV-p53 into C4-2 tumors in nude mice and monitoring tumor growth and prostate-specific antigen (PSA) levels.
Main Results:
- In vitro, Ad5-CMV-p53 significantly inhibited the growth of C4-2, PC-3, and DU145 prostate cancer cells.
- In vivo, Ad5-CMV-p53 treatment led to complete tumor eradication in C4-2 xenografts, with mice remaining tumor-free for up to 12 weeks post-treatment.
- PC-3 and DU145 cells treated with Ad5-CMV-p53 also failed to develop tumors in vivo.
- A small percentage of treated mice developed distant tumors after a prolonged observation period.
Conclusions:
- Wild-type p53 gene therapy delivered via adenovirus is a potent strategy against androgen-independent prostate cancer.
- This gene therapy approach demonstrates efficacy in eradicating established tumors and preventing tumor formation in vivo.
- The treatment's success across different p53 mutation statuses suggests broad applicability for advanced prostate cancer.