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

被引:99
作者
Gotoh, A
Ko, SC
Shirakawa, T
Cheon, J
Kao, CH
Miyamoto, T
Gardner, TA
Ho, LJ
Cleutjens, CBJ
Trapman, J
Graham, FL
Chung, LWK
机构
[1] Univ Virginia, Hlth Sci Ctr, Dept Urol, Mol Urol & Therapeut Program, Charlottesville, VA 22908 USA
[2] Erasmus Univ, Dept Pathol, NL-3000 DR Rotterdam, Netherlands
[3] McMaster Univ, Dept Biol, Hamilton, ON, Canada
[4] McMaster Univ, Dept Pathol, Hamilton, ON, Canada
关键词
gene therapy; PSA; prostate cancer; tissue specific promoter; androgen; hormonal refractory cancer;
D O I
10.1016/S0022-5347(01)63094-5
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:220 / 229
页数:10
相关论文
共 44 条
[41]   DERIVATION OF ANDROGEN-INDEPENDENT HUMAN LNCAP PROSTATIC-CANCER CELL SUBLINES - ROLE OF BONE STROMAL CELLS [J].
WU, HC ;
HSIEH, JT ;
GLEAVE, ME ;
BROWN, NM ;
PATHAK, S ;
CHUNG, LWK .
INTERNATIONAL JOURNAL OF CANCER, 1994, 57 (03) :406-412
[42]  
YANG CL, 1995, CANCER RES, V55, P4210
[43]  
ZHANG WW, 1994, CANCER GENE THER, V1, P5
[44]   A FETAL-RAT UROGENITAL SINUS MESENCHYMAL CELL-LINE (RUGM) - ACCELERATED-GROWTH AND CONFERRAL OF ANDROGEN-INDUCED GROWTH RESPONSIVENESS UPON A HUMAN BLADDER-CANCER EPITHELIAL-CELL LINE IN-VIVO [J].
ZHAU, HE ;
HONG, SJ ;
CHUNG, LWK .
INTERNATIONAL JOURNAL OF CANCER, 1994, 56 (05) :706-714