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Development of prostate-specific antigen promoter-based gene therapy for androgen-independent human prostate cancer
1Department of Urology, Molecular Urology and Therapeutics Program, University of Virginia, Charlottesville 22908, USA.
Purpose:
The goal of this study is to develop a tissue-specific toxic gene therapy utilizing the prostate specific antigen (PSA) promoter for both androgen-dependent (AD) and androgen-independent (AI) PSA-secreting prostate cancer cells. Ideally this gene therapy would be effective without the necessity of exposing the target cells to circulating androgens.
Materials And Methods:
An AI subline of LNCaP, an AD PSA-secreting human prostate cancer cell line, C4-2, was used in this study. Castrated mice bearing C4-2 tumors secrete PSA. A transient expression experiment was used to analyze the activity of two PSA promoters, a 5837 bp long PSA promoter and a 642 bp short PSA promoter, in C4-2 cells. A recombinant adenovirus (Ad-PSA-TK) carrying thymidine kinase under control of the long PSA promoter was generated. The tissue-specific activity of Ad-PSA-TK was tested in vitro and in vivo.
Results:
The long PSA promoter had superior activity over short PSA promoter, and higher activity in C4-2 cells than in LNCaP cells. High activity of Ad-PSA-TK was observed in C4-2 cells in an androgen deprived condition. In vitro, Ad-PSA-TK was further demonstrated to induce marked C4-2 cell-kill by acyclovir in medium containing 5% FBS. No cell-kill was observed in control WH cells (a human bladder cancer cell line). In vivo, Ad-PSA-P-TK with acyclovir significantly inhibited subcutaneous C4-2 tumor growth and PSA production in castrated animals.
Conclusion:
The 5837 bp long PSA promoter was active in the androgen free environment and could be used to target both androgen-dependent and independent PSA-producing prostate cancer cells in vitro, and prostate tumors in castrated hosts.
Insights
A novel gene therapy uses the prostate specific antigen (PSA) promoter to target prostate cancer cells. This PSA promoter-driven therapy effectively kills cancer cells, even without androgens.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Prostate cancer treatment often relies on androgen deprivation.
- Developing therapies targeting both androgen-dependent and independent prostate cancer is crucial.
- Prostate-specific antigen (PSA) is a biomarker for prostate cancer, making it a potential target for tissue-specific therapies.
Purpose of the Study:
- To develop a tissue-specific toxic gene therapy for prostate cancer using the PSA promoter.
- To target both androgen-dependent and androgen-independent PSA-secreting prostate cancer cells.
- To achieve efficacy without requiring circulating androgens for the therapy.
Main Methods:
- Utilized C4-2 cells, an androgen-independent subline of LNCaP cells, in castrated mice models.
- Compared the activity of a long (5837 bp) and a short (642 bp) PSA promoter.
- Generated a recombinant adenovirus (Ad-PSA-TK) carrying thymidine kinase under the long PSA promoter for in vitro and in vivo testing.
Main Results:
- The long PSA promoter exhibited superior activity in C4-2 cells, especially under androgen-deprived conditions.
- Ad-PSA-TK demonstrated significant C4-2 cell killing in vitro when combined with acyclovir.
- In vivo studies showed Ad-PSA-TK with acyclovir significantly inhibited tumor growth and PSA production in castrated mice.
Conclusions:
- The long PSA promoter is effective in an androgen-free environment.
- This PSA promoter-based gene therapy can target both androgen-dependent and independent PSA-producing prostate cancer cells.
- The developed therapy shows promise for treating prostate tumors in castrated hosts.