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

Int J Clin Oncol. 2008 Dec;13(6):515-20. doi: 10.1007/s10147-008-0780-4. Epub 2008 Dec 18.


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.

Conclusion: Experimentally, alternate-day treatment with S-1 is equivalent to consecutive-day treatment in terms of RI of tumor growth, with lower toxicity.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / administration & dosage*
  • Apoptosis / drug effects
  • Bone Marrow Diseases / drug therapy
  • Bone Marrow Diseases / etiology
  • Bone Marrow Diseases / pathology
  • Cell Proliferation / drug effects*
  • Drug Administration Schedule
  • Drug Combinations
  • Female
  • Fluorouracil / pharmacology
  • Gastrointestinal Tract / drug effects
  • Gastrointestinal Tract / injuries
  • Humans
  • In Vitro Techniques
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Oxonic Acid / administration & dosage*
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / pathology
  • Survival Rate
  • Tegafur / administration & dosage*
  • Tetrazolium Salts / pharmacology
  • Tumor Cells, Cultured


  • 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H tetrazolium monosodium salt
  • Antimetabolites, Antineoplastic
  • Drug Combinations
  • Tetrazolium Salts
  • S 1 (combination)
  • Tegafur
  • Oxonic Acid
  • Fluorouracil