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

• Published in: European journal of pharmaceutical sciences 2012-02, Vol.45 (3), p.272-281
• Main Authors: Takara, Kohji, Fujita, Megumi, Minegaki, Tetsuya, Yamamoto, Kazuhiro, Takahashi, Minoru, Yokoyama, Teruyoshi, Okumura, Katsuhiko
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Cisplatin; Cisplatin - administration & dosage; Cisplatin - pharmacokinetics; Cisplatin - therapeutic use; Colorectal cancer; Colorectal Neoplasms - drug therapy; Drug Synergism; Fluorouracil - administration & dosage; Fluorouracil - therapeutic use; Gene Expression - drug effects; General pharmacology; HCT116 Cells; Humans; Mass Spectrometry; Medical sciences; Oligonucleotide Array Sequence Analysis; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - pharmacokinetics; Organoplatinum Compounds - therapeutic use; Oxaliplatin; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Treatment schedule; Tumor Cells, Cultured
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2011.11.023

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. 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. 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. 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.