title: Bystander effect caused by cytosine deaminase gene and 5-fluorocytosine in vitro is substantially mediated by generated 5-fluorouracil.
abstract: Because it appears impossible to transfer toxic genes to all the cells of a cancer, the bystander effect is critical to induce effective antitumor effects. In the present study, possible in vitro mechanisms of the bystander effect by the cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) were investigated. CD-transduced cancer cells exhibited much higher sensitivity to 5-FC compared to parental cells. CD-transduced cells caused killing of neighboring parental cells in the presence of 5-FC, irrespective of direct cell-to-cell contact. Media conditioned by CD-transduced cells and 5-FC contained considerable amounts of 5-fluorouracil (5-FU) and exhibited profound cytotoxicity on parental cells. Furthermore, this killing ability of conditioned media correlated well with 5-FU levels converted from 5-FC by CD-transduced cells. CD was shown not to be secreted into media from cells. These results indicate that diffusible 5-FU plays the substantially causative role in the in vitro bystander effect caused by the CD/5-FC system.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kuriyama
authors.forename: K
authors.initials: K
authors.lastname: Masui
authors.forename: T
authors.initials: T
authors.lastname: Sakamoto
authors.forename: T
authors.initials: T
authors.lastname: Nakatani
authors.forename: M
authors.initials: M
authors.lastname: Kikukawa
authors.forename: H
authors.initials: H
authors.lastname: Tsujinoue
authors.forename: A
authors.initials: A
authors.lastname: Mitoro
authors.forename: M
authors.initials: M
authors.lastname: Yamazaki
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; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D043525:Cytosine Deaminase; D005437:Flucytosine / Q000378:metabolism / Q000494:pharmacology*; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009700:Nucleoside Deaminases / Q000235:genetics* / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D017077:Culture Media, Conditioned; D011355:Prodrugs; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil