Bystander effect caused by cytosine deaminase gene and 5-fluorocytosine in vitro is substantially mediated by generated 5-fluorouracil.
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.
Kuriyama
S
S
Third Department of Internal Medicine, Nara Medical University, Japan.
Masui
K
K
Sakamoto
T
T
Nakatani
T
T
Kikukawa
M
M
Tsujinoue
H
H
Mitoro
A
A
Yamazaki
M
M
Yoshiji
H
H
Fukui
H
H
Ikenaka
K
K
Mullen
C A
CA
Tsujii
T
T
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
D000964:Antimetabolites, Antineoplastic; D017077:Culture Media, Conditioned; D011355:Prodrugs; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil