title: Molecular mechanisms of sequence-dependent antitumor effects of SN-38 and 5-fluorouracil combination therapy against colon cancer cells.
abstract: BACKGROUND
  The aim of this study was to clarify the molecular mechanisms of the sequence-dependent antitumor activity of SN-38 and 5-fluorouracil (5-FU) against colon cancer cells.
  
  
  METHODS
  KM12SM and HCT116 colon cancer cells were exposed to 5-FU and/or SN-38 in various conditions. The nature of interactions was determined by median-effect analysis. Cell cycle, apoptosis, and expression of thymidylate synthase (TS) were analyzed.
  
  
  RESULTS
  A strong synergism was observed after initial sequential exposure of SN-38, and the activity was enhanced by a 24 h-interval to the drug-exposure. Antagonism was observed after low-dosage initial sequential exposure of 5-FU. Low-dosage 5-FU caused G(2) arrest and high-dosage 5-FU caused G(1) arrest. TS protein level significantly decreased after exposure to SN-38.
  
  
  CONCLUSIONS
  The sequence dependency between SN-38 and 5-FU against colon cancer cells may be related to the dual action on cell cycle regulation by 5-FU and to the down-regulation of TS level by SN-38.
authors.affiliation: Department of Surgery, Kurume University Medical Center, Kurume, Fukuoka 839-0863, Japan.
authors.forename: Shoujiro
authors.initials: S
authors.lastname: Torigoe
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ogata
authors.forename: Keiko
authors.initials: K
authors.lastname: Matono
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shirouzu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005472:Fluorouracil / Q000008:administration & dosage; D016193:G1 Phase / Q000187:drug effects*; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D000077146:Irinotecan; D013940:Thymidylate Synthase / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000077146:Irinotecan; D013940:Thymidylate Synthase; D005472:Fluorouracil; D002166:Camptothecin