Coexpression of the partial androgen receptor enhances the efficacy of prostate-specific antigen promoter-driven suicide gene therapy for prostate cancer cells at low testosterone concentrations.
The prostate specific antigen (PSA) promoter/enhancer has been clearly demonstrated to be tissue specific, and has been applied to prostate-specific gene therapy. However, the transcription of the PSA gene is strictly androgen dependent, and its promoter activity is very weak at low concentrations of testosterone, which are generally observed in prostatic cancer patients treated with androgen deprivation. In this study, we used a partial androgen receptor (ARf) containing amino acids 232-429 and 481-657 to transactivate the PSA gene without androgens. We made two expression vectors, ARfPPLUC and ARfPPTK. They contained ARf cDNA driven by cytomegalovirus promoter and cDNAs of either firefly luciferase (LUC) or herpes simplex virus thymidine kinase (TK) driven by PSA promoter/enhancer (PP). The expressed ARf enhanced the PP activity by about 110-fold in the PSA-producing prostate cancer cell line, LNCaP, under low testosterone concentrations. Moreover, in a PSA-nonproducing prostate cancer cell line, DU145, ARf also enhanced the PP activity by about 60-fold in an androgen-independent manner. In a growth inhibition assay, ARfPPTK treated with ganciclovir was found to inhibit the cell growth of LNCaP cells much more effectively than PPTK. Furthermore, in contrast to PPTK, ARfPPTK also had an inhibitory effect on DU145 cells. This system is thus considered to provide a useful therapeutic option in patients with prostate cancer who are receiving hormonal therapy.
Department of Urology, National Defence Medical College, Tokorozawa, Saitama, Japan.
S
S
Suzuki
T
T
Tadakuma
T
T
Asano
M
M
Hayakawa
D002455:Cell Division / Q000235:genetics; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D015774:Ganciclovir / Q000008:administration & dosage; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013739:Testosterone / Q000378:metabolism*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D010446:Peptide Fragments; D011944:Receptors, Androgen; D013739:Testosterone; D013937:Thymidine Kinase; D017430:Prostate-Specific Antigen; D015774:Ganciclovir