title: Treatment schedule-dependent effect of 5-fluorouracil and platinum derivatives in colorectal cancer cells.
abstract: OBJECTIVE
  Combination chemotherapy for treating cancer often is superior in clinical efficacy to monotherapy. The aim of this study was to investigate the schedule-dependent effect of 5-fluorouracil (5-FU) and platinum derivatives (cisplatin or oxaliplatin) in colorectal cancer (CRC) cell lines, and to explore factors affecting it.
  
  
  METHODS
  Two human CRC-derived cell lines, DLD-1 and HCT116, were used. Three treatment schedules were tested, and growth inhibitory effects were evaluated with a WST-1 assay. Combined effects were assessed with isobolograms and a combination index. Cellular accumulation and DNA-binding of platinum were measured with inductively coupled plasma mass spectrometry.
  
  
  RESULTS
  Exposure to 5-FU followed by cisplatin produced synergistic effects in DLD-1 cells, and the amount of platinum bound to DNA was substantially increased as compared with that for other schedules. 5-FU and oxaliplatin also tended to be synergistic when 5-FU was given first, but no significant change in the cellular kinetics of platinum was observed. On the other hand, in HCT116 cells, the combined effects of 5-FU and platinum derivatives were comparable among the three schedules.
  
  
  CONCLUSIONS
  Exposure to 5-FU followed by cisplatin had a synergistic effect in DLD-1 cells, suggesting that the amount of platinum bound to DNA contributes to this result. Also, the effect was dependent on the type of platinum derivative and cell.
authors.affiliation: Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Hyogo 670-8524, Japan. takara@gm.himeji-du.ac.jp
authors.forename: Kohji
authors.initials: K
authors.lastname: Takara
authors.forename: Megumi
authors.initials: M
authors.lastname: Fujita
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Minegaki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Minoru
authors.initials: M
authors.lastname: Takahashi
authors.forename: Teruyoshi
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Okumura
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage* / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D013058:Mass Spectrometry; D020411:Oligonucleotide Array Sequence Analysis; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077150:Oxaliplatin; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002945:Cisplatin; D005472:Fluorouracil