Synergistic antitumour effect of raltitrexed and 5-fluorouracil plus folinic acid combination in human cancer cells.
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.
Avallone
Antonio
A
National Tumour Institute, Federico II University Medical School, Via M. Semmola, 80131 Naples, Italy.
Di Gennaro
Elena
E
Bruzzese
Francesca
F
Laus
Gianluca
G
Delrio
Paolo
P
Caraglia
Michele
M
Pepe
Stefano
S
Comella
Pasquale
P
Budillon
Alfredo
A
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D020128:Inhibitory Concentration 50; D002955:Leucovorin / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D013876:Thiophenes / Q000008:administration & dosage
D011799:Quinazolines; D013876:Thiophenes; C068874:raltitrexed; D002955:Leucovorin; D005472:Fluorouracil