title: Replication-competent retrovirus vector-mediated prodrug activator gene therapy in experimental models of human malignant mesothelioma.
abstract: Replication-competent retrovirus (RCR) vectors have been shown to achieve significantly enhanced tumor transduction efficiency and therapeutic efficacy in various cancer models. In the present study, we investigated RCR vector-mediated prodrug activator gene therapy for the treatment of malignant mesothelioma, a highly aggressive tumor with poor prognosis. RCR-GFP vector expressing the green fluorescent protein marker gene successfully infected and efficiently replicated in human malignant mesothelioma cell lines, as compared with non-malignant mesothelial cells in vitro. In mice with pre-established subcutaneous tumor xenografts, RCR-GFP vector showed robust spread throughout entire tumor masses after intratumoral administration. Next, RCR-cytosine deaminase (RCR-CD), expressing the yeast CD prodrug activator gene, showed efficient transmission of the prodrug activator gene associated with replicative spread of the virus, resulting in efficient killing of malignant mesothelioma cells in a prodrug 5-fluorocytosine (5FC)-dose dependent manner in vitro. After a single intratumoral injection of RCR-CD followed by intraperitoneal administration of 5FC, RCR vector-mediated prodrug activator gene therapy achieved significant inhibition of subcutaneous tumor growth, and significantly prolonged survival in the disseminated peritoneal model of malignant mesothelioma. These data indicate the potential utility of RCR vector-mediated prodrug activator gene therapy in the treatment of malignant mesothelioma.
authors.affiliation: Laboratory of Host Defenses, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: A
authors.initials: A
authors.lastname: Tamamoto
authors.forename: M
authors.initials: M
authors.lastname: Takagi-Kimura
authors.forename: Y
authors.initials: Y
authors.lastname: Maeyama
authors.forename: N
authors.initials: N
authors.lastname: Yamaoka
authors.forename: N
authors.initials: N
authors.lastname: Terada
authors.forename: H
authors.initials: H
authors.lastname: Okamura
authors.forename: N
authors.initials: N
authors.lastname: Kasahara
authors.forename: S
authors.initials: S
authors.lastname: Kubo
mesh_terms: D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005437:Flucytosine / Q000008:administration & dosage / Q000493:pharmacokinetics; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics; D012190:Retroviridae / Q000235:genetics* / Q000502:physiology; D016019:Survival Analysis; D014161:Transduction, Genetic; D014779:Virus Replication
chemical_list: D011355:Prodrugs; D005437:Flucytosine; D043525:Cytosine Deaminase