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 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 (US)
Pages (from-to)220-229
Number of pages10
JournalJournal of Urology
Volume160
Issue number1
DOIs
StatePublished - Jul 1998
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; Ho, Ling Jun; Cleutjens, Catharina B J; Trapman, Jan; Graham, Frank L.; Chung, Leland W K.

In: Journal of Urology, Vol. 160, No. 1, 07.1998, p. 220-229.

Research output: Contribution to journalArticle

Gotoh, A, Ko, SC, Shirakawa, T, Cheon, J, Kao, C, Miyamoto, T, Gardner, T, 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 ; 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

AU - Ho, Ling Jun

AU - Cleutjens, Catharina B J

AU - Trapman, Jan

AU - Graham, Frank L.

AU - Chung, Leland W K

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