title: Cancer-specific killing by the CD suicide gene using the human telomerase reverse transcriptase promoter.
abstract: Human telomerase reverse transcriptase (hTERT), the catalytic subunit of the telomerase, is transcriptionally upregulated in more than 90% of tumor cells. It may be used as a tool for driving a gene to kill tumors specifically. To test this idea, luciferase reporter gene was used and the results showed that hTERT promoter could restrict the gene expression in the telomerase-positive tumor cells. A tumor-specific expression plasmid phTERT-CD was constructed, in which the E. coli cytosine deaminase (CD) gene was controlled by the hTERT promoter. A colorectal cancer cell line (LoVo) and a normal amnion cell line (WISH) were transfected by this plasmid. It was shown that the expression of the CD gene increased the sensitivity of LoVo cells to the prodrug, 5-fluorocytosine (5FC), over 800-fold, while the sensitivity of WISH cells to 5FC was increased only 6-fold. Mixed cell experiments showed a strong "bystander effect" on CD-negative cells. Furthermore, a significant anti-tumor effect of the phTERT-CD/5FC system was observed in nude mice bearing mammalian carcinoma induced by s.c. inoculation of LoVo cells when the mice were given 250 mg/kg 5FC twice a day for 10 consecutive days. These results indicated that hTERT promoter could target the suicidal effect of CD gene to tumor cells, and therefore, may be a novel and promising targeting approach to the treatment of cancer.
authors.affiliation: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zou
authors.forename: Ming-Fei
authors.initials: MF
authors.lastname: Lang
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.forename: Lan-Ying
authors.initials: LY
authors.lastname: Sun
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Wang
authors.forename: Qi-Jun
authors.initials: QJ
authors.lastname: Qian
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Liu
mesh_terms: D000818:Animals; D002460:Cell Line; D043525:Cytosine Deaminase; D004268:DNA-Binding Proteins; D005437:Flucytosine / Q000493:pharmacokinetics / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009700:Nucleoside Deaminases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D005437:Flucytosine; D019098:Telomerase; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase