title: Targeted therapy of DNA tumor virus-associated cancers using virus-activated transcription factors.
abstract: DNA tumor virus-mediated tumorigenic processes typically involve functional inactivation of cellular tumor suppressors pRB and p53 by viral oncoproteins, with concomitant activation of oncogenic transcription factors such as E2Fs. This feature could be exploited to design a treatment for corresponding malignancies. Here, we report a gene therapy strategy for DNA tumor virus-associated cancers using a synthetic, E2F-regulated gene expression system named pESM6. This system contains multimerized E2F-responsive elements in combination with the binding sites for ubiquitous transcription factors Sp1 and CTF/NF1. pESM6 could drive a high-level transgene expression comparable to that of the CMV IE promoter and exert constitutive activity in cells expressing DNA tumor viral oncogenes. In contrast, it was effectively repressed by pRB and thus only minimally active in nontransformed cells. Expression of cytosine deaminase from pESM6 resulted in a highly efficient and specific killing of HPV-transformed fibroblasts (C3) after treatment with the prodrug 5-fluorocytosine. Also, an effective tumor mass reduction was observed when the vector was injected directly into C3 tumors implanted in C57BL/6 mice. pESM6 showed a superior performance throughout these experiments compared to the previously known E2F-regulated gene vector. These results clearly demonstrate the potential usability of pESM6 for the gene therapy of DNA tumor virus-associated cancers.
authors.affiliation: Laboratory of Human Genomics, Korea Research Institute of Bioscience and Biotechnology, 52 Eoeun-dong, Yusong-gu, Taejon 305-333, Korea.
authors.forename: Mi Jung
authors.initials: MJ
authors.lastname: Lim
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Min
authors.forename: Jae-Jung
authors.initials: JJ
authors.lastname: Lee
authors.forename: Il Chul
authors.initials: IC
authors.lastname: Kim
authors.forename: Ji Tae
authors.initials: JT
authors.lastname: Kim
authors.forename: Dong Chul
authors.initials: DC
authors.lastname: Lee
authors.forename: Nam-Soon
authors.initials: NS
authors.lastname: Kim
authors.forename: Sangkyun
authors.initials: S
authors.lastname: Jeong
authors.forename: Mi Na
authors.initials: MN
authors.lastname: Kim
authors.forename: Kwang Dong
authors.initials: KD
authors.lastname: Kim
authors.forename: Jong-Seok
authors.initials: JS
authors.lastname: Lim
authors.forename: Sang Bae
authors.initials: SB
authors.lastname: Han
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Dae Seog
authors.initials: DS
authors.lastname: Heo
authors.forename: Young Il
authors.initials: YI
authors.lastname: Yeom
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D002522:Chlorocebus aethiops; D004263:DNA Tumor Viruses / Q000235:genetics*; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051839:NFI Transcription Factors / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C077305:CTF-1 transcription factor; D050684:E2F Transcription Factors; D051839:NFI Transcription Factors; D016329:Sp1 Transcription Factor; D014157:Transcription Factors