Comparative study between daily and 5-days-a-week administration of oral 5-fluorouracil chemotherapy in mice: determining the superior regimen.
BACKGROUND
Oral administration of derivatives of 5-fluorouracil (5-FU) is currently used to treat colorectal cancer in the United States. Oral chemotherapy possesses certain advantages: it is simple, easy to administer, and has few side effects. We compared conventional daily oral administration of 5-FU (daily schedule) with administration on 5 consecutive days followed by 2 drug-free days (5-days-a-week schedule) in a mouse tumor model.


METHODS
The maximal tolerated dose (MTD) in the 5-days-a-week schedule and in the daily schedule were determined in 6-week-old non-tumor-bearing CDF1 male mice. In antitumor experiments, CDF1 mice were inoculated subcutaneously with Colon26 cells (1x10(6) per mouse). Antitumor efficacy was evaluated in terms of the ratio of tumor size in treated to control mice (T/C ratio).


RESULTS
The MTD of 5-FU in the 5-days-a-week schedule was 42 mg/kg, and in the daily schedule was 29 mg/kg. In the 5-days-a-week schedule dose escalation nearly 1.4 times that in the daily schedule was possible, although the total dose over 7 days was similar between the two schedules (203 mg/kg and 210 mg/kg, respectively). When the doses of 5-FU were compared under the condition of no body weight loss, the 5-days-a-week schedule produced a comparative dose escalation of 2.1 times per day (from 20 to 42 mg/kg), and 1.5 times per total weekly amount (from 140 to 210 mg/kg) compared to the daily schedule. With regard to the antitumor effect as indicated by the T/C ratio, the 5-days-a-week schedule produced over 70% tumor suppression, whereas the daily schedule produced only 50% suppression at the MTD. Therapeutic efficacy was calculated in terms of the ratio of body weight change to antitumor effect (T/C ratio), and revealed that the MTD of 42 mg/kg 5-FU in the 5-days-a-week schedule produced a therapeutic efficacy almost three times that of the MTD of 29 mg/kg 5-FU in the daily schedule (P<0.001).


CONCLUSIONS
Using oral administration of 5-FU, we confirmed that the 5-days-a-week schedule allowed dose intensity escalation and was superior to the daily schedule in both enhancement of antitumor effect and protection against adverse effects.
Makino
M
M
First Department of Surgery, Tottori University, Faculty of Medicine, Yonago, Japan. drmakino@grape.med.tottori-u.ac.jp
Shoji
H
H
Takemoto
D
D
Honboh
T
T
Nakamura
S
S
Kurayoshi
K
K
Kaibara
N
N
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D001835:Body Weight / Q000187:drug effects; D004334:Drug Administration Schedule; D005472:Fluorouracil / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil