Development of prostate-specific antigen promoter-based gene therapy for androgen-independent human prostate cancer

Akinobu Gotoh, Song Chu Ko, Toshiro Shirakawa, Jun Cheon, Chinghai Kao, Tadayuki Miyamoto, Thomas A. Gardner, Ling Jun Ho, Catharina B.J. Cleutjens, Jan Trapman, Frank L. Graham, Leland W.K. Chung

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)220-229
Number of pages10
JournalJournal of Urology
Volume160
Issue number1
DOIs
Publication statusPublished - 1998 Jan 1
Externally publishedYes

Fingerprint

Prostate-Specific Antigen
Genetic Therapy
Androgens
Prostatic Neoplasms
Acyclovir
Cell Line
Neoplasms
Thymidine Kinase
Poisons
Urinary Bladder Neoplasms
Adenoviridae

Keywords

  • Androgen
  • Gene therapy
  • Hormonal refractory cancer
  • Prostate cancer
  • PSA
  • Tissue specific promoter

ASJC Scopus subject areas

  • Urology

Cite this

Development of prostate-specific antigen promoter-based gene therapy for androgen-independent human prostate cancer. / Gotoh, Akinobu; Ko, Song Chu; Shirakawa, Toshiro; Cheon, Jun; Kao, Chinghai; Miyamoto, Tadayuki; Gardner, Thomas A.; Ho, Ling Jun; Cleutjens, Catharina B.J.; Trapman, Jan; Graham, Frank L.; Chung, Leland W.K.

In: Journal of Urology, Vol. 160, No. 1, 01.01.1998, p. 220-229.

Research output: Contribution to journalArticle

Gotoh, A, Ko, SC, Shirakawa, T, Cheon, J, Kao, C, Miyamoto, T, Gardner, TA, Ho, LJ, Cleutjens, CBJ, Trapman, J, Graham, FL & Chung, LWK 1998, 'Development of prostate-specific antigen promoter-based gene therapy for androgen-independent human prostate cancer', Journal of Urology, vol. 160, no. 1, pp. 220-229. https://doi.org/10.1016/S0022-5347(01)63094-5
Gotoh, Akinobu ; Ko, Song Chu ; Shirakawa, Toshiro ; Cheon, Jun ; Kao, Chinghai ; Miyamoto, Tadayuki ; Gardner, Thomas A. ; Ho, Ling Jun ; Cleutjens, Catharina B.J. ; Trapman, Jan ; Graham, Frank L. ; Chung, Leland W.K. / Development of prostate-specific antigen promoter-based gene therapy for androgen-independent human prostate cancer. In: Journal of Urology. 1998 ; Vol. 160, No. 1. pp. 220-229.
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abstract = "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.",
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AU - Kao, Chinghai

AU - Miyamoto, Tadayuki

AU - Gardner, Thomas A.

AU - Ho, Ling Jun

AU - Cleutjens, Catharina B.J.

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