title: Antitumor effects of systemically delivered adenovirus harboring trans-splicing ribozyme in intrahepatic colon cancer mouse model.
abstract: OBJECTIVE
  Our previous studies suggested that human telomerase reverse transcriptase (hTERT) RNA-targeting trans-splicing ribozyme could be a useful tool for cancer gene therapy. Here, we investigated whether adenoviruses harboring this ribozyme can be systemically delivered to mice, and whether they selectively mark tumors expressing hTERT and sensitize them to ganciclovir treatments.
  
  
  METHODS
  We constructed adenoviral vectors containing modified hTERT-targeting trans-splicing ribozyme with downstream reporter gene (Ad-Ribo-LacZ) or suicide gene (Ad-Ribo-HSVtk) driven by a cytomegalovirus promoter. The tumor-specific trans-splicing reaction and the tumor-killing effect of adenoviruses harboring ribozyme were investigated both in vitro and in vivo using mice with intrahepatic colon cancer metastasis via systemic administration. The safety of systemic administration of the viruses was also evaluated.
  
  
  RESULTS
  We showed that Ad-Ribo-LacZ, when injected i.v., performs a highly specific trans-splicing reaction on hTERT mRNA and that it selectively marks tumors expressing hTERT in mice. More importantly, i.v. injection of Ad-Ribo-HSVtk plus ganciclovir significantly reduced tumor burden, with minimal liver toxicity, in mice with metastatic liver cancer, compared with the untreated group (P = 0.0009). Moreover, animals receiving Ad-Ribo-HSVtk showed improved survival compared with controls (P < 0.0001).
  
  
  CONCLUSIONS
  This study shows that systemically delivered adenovirus harboring trans-splicing ribozyme can recognize cancer-specific transcripts and reprogram them to combat the cancer cells. Use of trans-splicing ribozymes seems to be a potentially useful gene therapy for cancer.
authors.affiliation: Department of Pathology and Medical Research Center for Cancer Molecular Therapy, Dong-A University College of Medicine, Busan, Korea.
authors.forename: Jin-Sook
authors.initials: JS
authors.lastname: Jeong
authors.forename: Seong-Wook
authors.initials: SW
authors.lastname: Lee
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Hong
authors.forename: Yoon-Jong
authors.initials: YJ
authors.lastname: Lee
authors.forename: Haeng-Im
authors.initials: HI
authors.lastname: Jung
authors.forename: Kyung-Sook
authors.initials: KS
authors.lastname: Cho
authors.forename: Hye-Hyun
authors.initials: HH
authors.lastname: Seo
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sohee
authors.initials: S
authors.lastname: Park
authors.forename: Min-Sun
authors.initials: MS
authors.lastname: Song
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Kim
authors.forename: In-Hoo
authors.initials: IH
authors.lastname: Kim
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D003110:Colonic Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D016337:RNA, Catalytic / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D020040:Trans-Splicing
chemical_list: D016337:RNA, Catalytic; D012333:RNA, Messenger; D019098:Telomerase