title: Ultrasound-targeted HSVtk and Timp3 gene delivery for synergistically enhanced antitumor effects in hepatoma.
abstract: Cancer gene therapy has great potential for decreasing tumor-induced mortality but has been clinically limited by non-targeted and insufficient gene transfer. We evaluated gene therapy targeting hepatocellular carcinoma (HCC) using the herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) suicide gene system and the tissue inhibitor of metalloproteinase 3 (Timp3) gene. Ultrasound-targeted microbubble destruction (UTMD) targeted gene delivery to the tumor tissue, and the α-fetoprotein promoter targeted HSVtk expression to the HCC cells. Human HepG2 cells transfected with the HSVtk or Timp3 gene demonstrated a reduction in cell viability by >40% compared with the vector control. Cell viability was further inhibited by over 50% with co-transfection of the genes. HepG2 cells were inoculated subcutaneously into athymic mice to induce tumors. UTMD-mediated delivery of HSVtk or Timp3 suppressed tumor growth by >45% and increased survival of tumor-bearing animals (P<0.01 vs vector control). Co-delivery of the genes resulted in a further 30% improvement in tumor suppression and significant extension of animal survival (P<0.01 vs vector control). Targeted gene delivery increased the number of apoptotic cells and decreased the vascular density of the tumors. Targeted co-delivery of the genes synergistically improved the antitumor effects and may provide an effective therapy for HCC.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, China.
authors.forename: B-F
authors.initials: BF
authors.lastname: Yu
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: H-W
authors.initials: HW
authors.lastname: Sung
authors.forename: J
authors.initials: J
authors.lastname: Xie
authors.forename: R-K
authors.initials: RK
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D015774:Ganciclovir / Q000008:administration & dosage / Q000493:pharmacokinetics; D018014:Gene Transfer Techniques; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011897:Random Allocation; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured; D014463:Ultrasonography
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; D013937:Thymidine Kinase; D015774:Ganciclovir