title: Cytosine deaminase/5-fluorocytosine gene therapy can induce efficient anti-tumor effects and protective immunity in immunocompetent mice but not in athymic nude mice.
abstract: Murine hepatocellular carcinoma cells were retrovirally transduced with the bacterial cytosine deaminase (CD) gene. CD-transduced cells exhibited more than 120-fold higher sensitivity to 5-fluorocytosine (5-FC) compared with parental cells. When syngeneic immunocompetent mice were inoculated s.c. with parental hepatocellular carcinoma cells containing as little as 5% CD-transduced cells, significant inhibition of tumor formation was induced by 5-FC treatment. Furthermore, established solid tumors in immunocompetent mice containing only 5% CD-transduced cells were infiltrated markedly with CD4- and CD8+ T lymphocytes and macrophages by 5-FC treatment, such that significant reduction or even complete regression of tumors was observed. These tumor-free mice resisted subsequent rechallenge with wild-type tumor. Conversely, when athymic nude mice were inoculated with a cell mixture containing CD-transduced cells and parental cells at a ratio of 40:60, all developed tumors despite 5-FC treatment. Our results indicate that gene therapy using the CD/5-FC system can induce efficient anti-tumor effects and protective immunity in immunocompetent mice but not in athymic immunodeficient mice, suggesting that the host's immunocompetence may be a critical factor for achieving successful gene therapy against cancer.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kuriyama
authors.forename: M
authors.initials: M
authors.lastname: Kikukawa
authors.forename: K
authors.initials: K
authors.lastname: Masui
authors.forename: H
authors.initials: H
authors.lastname: Okuda
authors.forename: T
authors.initials: T
authors.lastname: Nakatani
authors.forename: T
authors.initials: T
authors.lastname: Sakamoto
authors.forename: H
authors.initials: H
authors.lastname: Yoshiji
authors.forename: H
authors.initials: H
authors.lastname: Fukui
authors.forename: K
authors.initials: K
authors.lastname: Ikenaka
authors.forename: C A
authors.initials: CA
authors.lastname: Mullen
authors.forename: T
authors.initials: T
authors.lastname: Tsujii
mesh_terms: D000818:Animals; D043525:Cytosine Deaminase; D005437:Flucytosine / Q000627:therapeutic use*; D005472:Fluorouracil / Q000627:therapeutic use; D015316:Genetic Therapy; D005822:Genetic Vectors; D008114:Liver Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009700:Nucleoside Deaminases / Q000235:genetics* / Q000378:metabolism; D012190:Retroviridae; D013997:Time Factors
chemical_list: D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil