Development of human chorionic gonadotropin subunit-beta promoter-based toxic gene therapy for testicular cancer.
OBJECTIVE
To develop a new toxic gene therapy using the tissue-specific human chorionic gonadotropin-beta (hCG-beta) promoter for testicular cancer. Although most patients presenting with disseminated testicular tumor are cured through the use of chemotherapy with or without surgery, those patients with relapse after initial therapy present a difficult clinical problem. The serum tumor marker hCG-beta is frequently elevated in patients with testicular cancer, and the pretreatment and post-treatment levels of serum hCG-beta are highly predictive of treatment outcome.


METHODS
Human testicular embryonal carcinoma cell line, NEC 8, a human prostate cancer cell line, PC-3, and a human bladder cancer cell line, WH, were used in this study. A transient expression experiment was used to analyze the activity of a 729-bp hCG-beta promoter in all three cell lines. A recombinant adenovirus carrying thymidine kinase (Ad-hCG-beta-TK) under control of the hCG-beta promoter was generated. The tissue-specific activity of Ad-hCG-beta-TK was tested in vitro and in vivo.


RESULTS
The hCG-beta promoter had significantly greater activity in the hCG-beta-producing cell line (NEC 8) than in the non-hCG-beta-producing cell lines (PC-3 and WH). In vitro, Ad-hCG-beta-TK with acyclovir significantly inhibited NEC 8 growth but not PC-3 or WH cell growth. In vivo, Ad-hCG-beta-TK with acyclovir significantly inhibited NEC 8 subcutaneous tumor growth in nude mice.


CONCLUSIONS
In this study, we explored the possibility of developing a new therapeutic agent to target and induce the killing of testicular germ cell tumor selectively by using tissue-specific hCG-beta promoters.
Shirakawa
Toshiro
T
International Center for Medical Research, Kobe University School of Medicine, Kobe, Japan.
Gotoh
Akinobu
A
Zhang
Zhujun
Z
Kao
Chinghai
C
Chung
Leland W K
LW
Gardner
Thomas A
TA
D000212:Acyclovir / Q000627:therapeutic use; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood; D002277:Carcinoma / Q000473:pathology; D018236:Carcinoma, Embryonal / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000096:biosynthesis / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D011355:Prodrugs / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D016879:Salvage Therapy; D013736:Testicular Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D018997:Chorionic Gonadotropin, beta Subunit, Human; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D013937:Thymidine Kinase; D000212:Acyclovir