title: Usefulness of alternate-day administration of S-1 and leucovorin in a xenograft mouse model of colorectal cancer: a shorter drug-free interval leads to more efficient antitumor effects.
abstract: BACKGROUND
  A clinical trial of S-1 with leucovorin (S-1/LV) in metastatic colorectal cancer (CRC) patients demonstrated promising efficacy; however, the gastrointestinal toxicities were so severe that it has not been applied in the clinical setting. On the other hand, alternate-day administration of S-1 has been proposed to attenuate the adverse events without reducing its anticancer activity. Our present study was conducted to confirm the feasibility of alternate-day administration of S-1/LV in in vivo xenograft tumor models.
  
  
  METHODS
  Mice were treated with S-1/LV in a daily group (2 weeks of administration followed by 2 weeks of withdrawal) or an alternate-day group (administration on alternate days for 4 weeks), then the mice were killed and the xenograft tumors were resected. We compared body weight changes, condition of feces, mucosal injury and myelosuppression and assessed adverse reactions, tumor volume, tumor growth inhibition (TGI) and expression of Ki67, TUNEL, cIAP2 and XIAP to evaluate the antitumor activity and tumor apoptosis.
  
  
  RESULTS
  Severe weight loss, diarrhea, mucosal injury and myelosuppression were observed only in the daily group; however, some myelosuppression was also observed in the alternate-day group. The TGI in the alternate-day group was better than in the daily group, possibly resulting from apoptosis due to the suppression of cIAP2 but not XIAP.
  
  
  CONCLUSIONS
  Our findings suggest that alternate-day administration of S-1/LV for CRC treatment can achieve high antitumor activity without severe adverse reactions, and we propose that clinical trials with this regimen should be conducted in CRC patients.
authors.affiliation: Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Komura
authors.forename: Koh
authors.initials: K
authors.lastname: Miura
authors.forename: Tetsuhiko
authors.initials: T
authors.lastname: Shirasaka
authors.forename: Shinobu
authors.initials: S
authors.lastname: Ohnuma
authors.forename: Miki
authors.initials: M
authors.lastname: Shimada
authors.forename: Taiki
authors.initials: T
authors.lastname: Kajiwara
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Fujishima
authors.forename: Alex
authors.initials: A
authors.lastname: Philchenkov
authors.forename: Kei
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Kudoh
authors.forename: Sho
authors.initials: S
authors.lastname: Haneda
authors.forename: Masahide
authors.initials: M
authors.lastname: Toshima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kohyama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Musha
authors.forename: Takeshi
authors.initials: T
authors.lastname: Naitoh
authors.forename: Chikashi
authors.initials: C
authors.lastname: Shibata
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control; D019073:HT29 Cells; D064593:Heterografts; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010094:Oxonic Acid / Q000008:administration & dosage / Q000009:adverse effects; D005641:Tegafur / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D002955:Leucovorin