title: An armed oncolytic measles vaccine virus eliminates human hepatoma cells independently of apoptosis.
abstract: Due to late diagnosis and a pronounced chemoresistance, most patients with hepatocellular carcinoma (HCC) have an overall poor prognosis. Measles vaccine viruses (MeV) have been shown to possess anti-tumor properties and their efficacy has been enhanced by arming with suicide genes. To test armed MeV for the treatment of HCC, we equipped it with the suicide gene Super-cytosine deaminase (SCD) and tested the efficacy in cell culture and in a mouse xenograft model of human HCC. Prodrug conversion was investigated in cell culture and quantified by high-performance liquid chromatography. We observed a strong oncolytic activity of MeV-SCD against human HCC in vitro and in vivo. The prodrug was efficiently converted in infected cells leading to a significant enhancement of the cytotoxic effect. Treatment of HCC xenografts with MeV caused long-term virus replication in tumor tissue. We show that the suicide gene therapy induces an apoptosis-like cell death but is not dependent on intact apoptosis pathways. These results demonstrate that MeV-based suicide gene therapy is a promising novel therapy regimen for HCC overcoming resistance towards conventional therapy. The independence from apoptosis raises hopes for the treatment of patients whose tumor cells exert defects in this cell death mechanism.
authors.affiliation: Department of Internal Medicine, Division of Hepatology, Gastroenterology and Infectiology, Medical University Hospital, Tübingen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Lampe
authors.forename: S
authors.initials: S
authors.lastname: Bossow
authors.forename: T
authors.initials: T
authors.lastname: Weiland
authors.forename: I
authors.initials: I
authors.lastname: Smirnow
authors.forename: R
authors.initials: R
authors.lastname: Lehmann
authors.forename: W
authors.initials: W
authors.lastname: Neubert
authors.forename: M
authors.initials: M
authors.lastname: Bitzer
authors.forename: U M
authors.initials: UM
authors.lastname: Lauer
mesh_terms: D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002853:Chromatography, Liquid; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D056945:Hep G2 Cells; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000628:therapy; D008458:Measles Vaccine; D008459:Measles virus / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics; D014407:Tumor Cells, Cultured; D014709:Vero Cells; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D008458:Measles Vaccine; D043525:Cytosine Deaminase