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

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.

journal_name

Anticancer Drugs

journal_title

Anti-cancer drugs

authors

Avallone A,Di Gennaro E,Bruzzese F,Laus G,Delrio P,Caraglia M,Pepe S,Comella P,Budillon A

doi

10.1097/CAD.0b013e32809ef9b7

subject

Has Abstract

pub_date

2007-08-01 00:00:00

pages

781-91

issue

7

eissn

0959-4973

issn

1473-5741

pii

00001813-200708000-00005

journal_volume

18

pub_type

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