Synergistic antitumor effects of fleroxacin with 5-fluorouracil in vitro and in vivo for bladder cancer cell lines.
OBJECTIVE
To study the antitumor effects of fleroxacin against bladder tumor cell lines and the synergistic effect with 5-fluorouracil (5-FU) both in vitro and in vivo.


METHODS
In vitro, the MBT-2 and T-24 urothelial carcinoma cell lines were exposed to fleroxacin in concentrations of 0-800 microg/mL for 12, 24, and 48 hours. Cytotoxicity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay. Synergism of fleroxacin with 5-FU was evaluated using the normalized isobologram and combination index by CalcuSyn for Windows computer program. In vivo, 4-week-old female C57BL/6 mice were orally administered fleroxacin and/or 5-FU 1 week before starting administration of a carcinogenic agent (0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine) for 12 weeks. The mice were killed 8 weeks after the end of administration for histologic evaluation of the urinary bladder.


RESULTS
Fleroxacin significantly inhibited cell proliferation in a dose- and time-dependent manner at concentrations of 50-800 microg/mL for 12, 24, and 48 hours. The inhibitory effects of fleroxacin combined with 5-FU appeared synergistic using normalized isobologram and combination index analysis. In vivo, no significant changes in bladder tumor frequency were noted between the control and fleroxacin and 5-FU groups. Significant inhibition of tumor frequency was observed only when fleroxacin was administered with 5-FU.


CONCLUSIONS
Fleroxacin combined with 5-FU inhibited the proliferation of bladder tumor cell lines both in vitro and in vivo. This combination therapy might be applicable in clinical settings.
Nishikawa
Toru
T
Division of Urology, Rinku General Medical Center, Izumisano Municipal Hospital, Izumisano City, Osaka, Japan. t-nishikawa@rgmc.izumisano.osaka.jp
Kohjimoto
Yasuo
Y
Nishihata
Masaya
M
Ebisuno
Shoichi
S
Hara
Isao
I
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D016576:Fleroxacin / Q000627:therapeutic use*; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D019384:Nucleic Acid Synthesis Inhibitors / Q000627:therapeutic use*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
D000964:Antimetabolites, Antineoplastic; D019384:Nucleic Acid Synthesis Inhibitors; D016576:Fleroxacin; D005472:Fluorouracil