Comparison of alternate-day versus consecutive-day treatment with S-1: assessment of tumor growth inhibition and toxicity reduction in gastric cancer cell lines in vitro and in vivo.
BACKGROUND
The toxic effects of S-1 can lead to discontinuation of treatment. Strategies for reducing toxicity without compromising therapeutic effectiveness are required.


METHODS
We used the human gastric cancer cell lines MKN28 and MKN45 to examine such strategies in vitro. The cell lines were treated with three different regimens, given on alternate days (alternate-day) or on consecutive days (consecutive-day). On consecutive days, treatment A provided the same total dose as the alternate-day treatment, and treatment B was given for the same number of days as the alternate-day treatment. A fourth group served as control. In vitro, the relative inhibition (RI) of tumor growth by 5-fluorouracil was calculated using the 2-(2-methyl-4-nitrophenyl)-3-(4-nitrophyl)-5-2, 4-disulfophenyl)-2H-tetrazolium (WST-8) method. We also carried out an in vivo experiment in which tumor-bearing nude mice (BALBc/nu-nu) were used to examine the antitumor activity of S-1. Leukocyte counts and gastrointestinal mucosal injury were compared in mice that received alternate-day and consecutive-day treatments.


RESULTS
In vitro, for MKN28, the RI was 22.9% for alternate-day, 34.1% for consecutive-day A, and 37.7% for consecutive-day B treatments. For MKN45, the RI was 51.1% for alternate-day, 52.2% for consecutive-day A, and 50.5% for consecutive-day B treatments. In vivo, for MKN28, the treated groups showed higher inhibition than the control, and inhibition of tumor growth was higher with alternate-day than with consecutive-day treatment. The RI was significantly higher with alternate-day (49.3%) than with consecutive-day treatment (16.2%; P < 0.05). For MKN45, the RI was greater than 50% in both treated groups. With consecutive-day treatment, 5 of the 14 mice used died during treatment. Leukocyte counts were lower in the mice with consecutive-day than with alternate-day treatment, or control. Atrophic changes and inflammatory cell infiltration of the small intestinal mucosa were severe after consecutive-day, but minimal after alternate-day treatment.


CONCLUSIONS
Experimentally, alternate-day treatment with S-1 is equivalent to consecutive-day treatment in terms of RI of tumor growth, with lower toxicity.
Arai
Wataru
W
Department of Surgery, Jichi Medical University, 3311-1 Shimotsuke, Tochigi, 329-0498, Japan. waraitu@v005.vaio.ne.jp
Hosoya
Yoshinori
Y
Haruta
Hidenori
H
Kurashina
Kentaro
K
Saito
Shin
S
Hirashima
Yuuki
Y
Yokoyama
Taku
T
Zuiki
Toru
T
Sakuma
Kazuya
K
Hyodo
Masanobu
M
Yasuda
Yoshikazu
Y
Nagai
Hideo
H
Shirasaka
Tetsuhiko
T
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001855:Bone Marrow Diseases / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000293:injuries; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010094:Oxonic Acid / Q000008:administration & dosage*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D005641:Tegafur / Q000008:administration & dosage*; D013778:Tetrazolium Salts / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C476329:2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H tetrazolium monosodium salt; D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D013778:Tetrazolium Salts; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D005472:Fluorouracil