FADD gene therapy using the human telomerase catalytic subunit (hTERT) gene promoter to restrict induction of apoptosis to tumors in vitro and in vivo.
Gene transfer vectors will dramatically increase the safety and effectiveness of cancer gene therapy, if they could restrict expression of the therapeutic products to the target tumors. To realize such a tumor-targeting system, telomerase is one of the most promising candidates. It is because telomerase activity is detected in the vast majority of tumors, but not in most normal cells. Activation of telomerase is tightly regulated at the transcriptional level of the telomerase catalytic subunit (hTERT). Therefore, the use of the hTERT promoter-driven vector system could restrict the expression of therapeutic products to telomerase-positive tumors. In this study, we constructed the expression vector of FADD gene with death domain afforded by the hTERT promoter (hTERT/FADD) and investigated its effect on tumors in vitro and in vivo. Transient transfection with the hTERT/FADD construct induced apoptosis in telomerase-positive tumor cells of wide range. In contrast, normal fibroblast cells without telomerase did not undergo apoptosis following the hTERT/FADD transfer. Furthermore, the growth of subcutaneous tumors in nude mice was significantly suppressed by the intratumoral injection of the hTERT/FADD construct (every day for one week) compared to the control (P<0.0005). The findings described here indicate the high potentiality of a novel telomerase-specific gene therapy of tumors with telomerase.
Koga
S
S
The Center for Surgery Research, The Cleveland Clinic Foundation, OH 44195, USA.
Hirohata
S
S
Kondo
Y
Y
Komata
T
T
Takakura
M
M
Inoue
M
M
Kyo
S
S
Kondo
S
S
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins; D053200:Fas-Associated Death Domain Protein; D005347:Fibroblasts / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D020287:In Situ Nick-End Labeling; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D008156:Luciferases; D019098:Telomerase