title: Adeno-associated virus mediated endostatin gene therapy in combination with topoisomerase inhibitor effectively controls liver tumor in mouse model.
abstract: OBJECTIVE
  rAAV mediated endostatin gene therapy has been examined as a new method for treating cancer. However, a sustained and high protein delivery is required to achieve the desired therapeutic effects. We evaluated the impact of topoisomerase inhibitors in rAAV delivered endostatin gene therapy in a liver tumor model.
  
  
  METHODS
  rAAV containing endostatin expression cassettes were transduced into hepatoma cell lines. To test whether the topoisomerase inhibitor pretreatment increased the expression of endostatin, Western blotting and ELISA were performed. The biologic activity of endostatin was confirmed by endothelial cell proliferation and tube formation assays. The anti-tumor effects of the rAAV-endostatin vector combined with a topoisomerase inhibitor, etoposide, were evaluated in a mouse liver tumor model.
  
  
  RESULTS
  Topoisomerase inhibitors, including camptothecin and etoposide, were found to increase the endostatin expression level in vitro. The over-expressed endostatin, as a result of pretreatment with a topoisomerase inhibitor, was also biologically active. In animal experiments, the combined therapy of topoisomerase inhibitor, etoposide with the rAAV-endostatin vector had the best tumor-suppressive effect and tumor foci were barely observed in livers of the treated mice. Pretreatment with an etoposide increased the level of endostatin in the liver and serum of rAAV-endostatin treated mice. Finally, the mice treated with rAAV-endostatin in combination with etoposide showed the longest survival among the experimental models.
  
  
  CONCLUSIONS
  rAAV delivered endostatin gene therapy in combination with a topoisomerase inhibitor pretreatment is an effective modality for anticancer gene therapy.
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, Youngdong PO Box 1217, Seoul, Korea.
authors.forename: Sung-Yi
authors.initials: SY
authors.lastname: Hong
authors.forename: Myun-Hee
authors.initials: MH
authors.lastname: Lee
authors.forename: Kyung-Sup
authors.initials: KS
authors.lastname: Kim
authors.forename: Hyun-Cheol
authors.initials: HC
authors.lastname: Jung
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Roh
authors.forename: Woo-Jin
authors.initials: WJ
authors.lastname: Hyung
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Noh
authors.forename: Seung-Ho
authors.initials: SH
authors.lastname: Choi
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004357:Drug Synergism; D043169:Endostatins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality; D051379:Mice; D012509:Sarcoma / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate; D059003:Topoisomerase Inhibitors; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D043169:Endostatins; D004791:Enzyme Inhibitors; D059003:Topoisomerase Inhibitors; D005047:Etoposide; D002166:Camptothecin