Treatment schedule-dependent effect of 5-fluorouracil and platinum derivatives in colorectal cancer cells

Eur J Pharm Sci. 2012 Feb 14;45(3):272-81. doi: 10.1016/j.ejps.2011.11.023. Epub 2011 Dec 3.


Aim: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cisplatin / administration & dosage*
  • Cisplatin / pharmacokinetics
  • Cisplatin / therapeutic use
  • Colorectal Neoplasms / drug therapy*
  • Drug Synergism
  • Fluorouracil / administration & dosage*
  • Fluorouracil / therapeutic use
  • Gene Expression / drug effects
  • HCT116 Cells
  • Humans
  • Mass Spectrometry
  • Oligonucleotide Array Sequence Analysis
  • Organoplatinum Compounds / administration & dosage*
  • Organoplatinum Compounds / pharmacokinetics
  • Organoplatinum Compounds / therapeutic use
  • Oxaliplatin
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Organoplatinum Compounds
  • Oxaliplatin
  • Cisplatin
  • Fluorouracil