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.
Division of Urology, Rinku General Medical Center, Izumisano Municipal Hospital, Izumisano City, Osaka, Japan. t-nishikawa@rgmc.izumisano.osaka.jp
Toru
T
Nishikawa
Yasuo
Y
Kohjimoto
Masaya
M
Nishihata
Shoichi
S
Ebisuno
Isao
I
Hara
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