Synergistic antitumour effect of raltitrexed and 5-fluorouracil plus folinic acid combination in human cancer cells

Antonio Avallone, Elena Di Gennaro, Francesca Bruzzese, Gianluca Laus, Paolo Delrio, Michele Caraglia, Stefano Pepe, Pasquale Comella, Alfredo Budillon

Research output: Contribution to journalArticlepeer-review

Abstract

5-Fluorouracil, usually in combination with folinic acid, is widely used in the treatment of both colorectal and head and neck squamous cell cancer patients. Since 5-fluorouracil plus folinic acid and the antifolate thymidylate synthase inhibitor; raltitrexed have distinct mechanisms of action and toxicity profiles, we have evaluated the potential synergistic antitumor interaction between these two agents combined with a sequential schedule of administration in KB (wt-p53) and Cal27 (mut-p53) head and neck squamous cell carcinomas, and LoVo (wt-p53) and HT29 (mut-p53) colorectal cell lines. The combination between a 24-h exposure to raltitrexed followed by a 4-h exposure to 5-fluorouracil plus folinic acid was globally synergistic, as assessed by the median effect principle and combination index. A specific contribution of folinic acid to the cytotoxic effect of the raltitrexed/5-fluorouracil combination was clearly demonstrated by the evaluation of the potentiation factor. In all cell lines, a 1.5- up to 17-fold reduction in the IC50 of both raltitrexed and 5-fluorouracil plus folinic acid was observed in the combination setting compared with the concentrations of the each drug used alone. Moreover, we demonstrated that raltitrexed/5-fluorouracil plus folinic acid induced a distinct S-phase block of the cell cycle, as well as a potentiation of the apoptotic cell death, compared with 5-fluorouracil plus folinic acid or raltitrexed/5-fluorouracil combination. This preclinical work represents, at least to our knowledge, the first demonstration of a synergistic interaction between raltitrexed and 5-fluorouracil modulated by folinic acid, and could represent a rationale for further clinical investigation of raltitrexed/5-fluorouracil plus folinic acid combination.

Original languageEnglish
Pages (from-to)781-791
Number of pages11
JournalAnti-Cancer Drugs
Volume18
Issue number7
DOIs
Publication statusPublished - Aug 2007

Keywords

  • 5-fluorouracil
  • Colorectal cancer
  • Folinic acid
  • Head and neck cancer
  • Raltitrexed
  • Thymidylate synthase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology

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