[Cytotoxic effects of the combination of a new nitrosourea, fotemustine, combined with 5-fluorouracil and folinic acid depend on the sequence of their administration].
The present study was designed to analyse the cytotoxic effects of the combination of fotemustine plus 5-fluorouracil (5-FU) and folinic acid (FA). Two human tumor cell lines were used; one line was derived from colon cancer (WIDR) and the other from a non-small cell lung cancer (CAL 12). Cytotoxic effects were assessed by the MTT semi-automated test in 96-well incubation plates. The effects of various drug combinations were evaluated by the isobologram method. The drug combinations tested included fotemustine concentrations of 20, 30, 40, 50 and 70 micrograms/ml, 5-FU concentrations of 5, 15 and 30 micrograms/ml, and a constant FA concentration of 10(-5) M. A total of 180 different experimental conditions were tested. When cells were exposed to fotemustine before 5-FU the final cytotoxic effects for both cell lines were additive or synergistic in the majority of cases (P less than 0.001). The 5-FU concentration was a determinant factor affecting modification of the effects of the drug combination from antagonism (with low 5-FU concentrations) to synergism (high 5-FU concentrations) (P less than 0.001). Addition of FA (10(-5) M) resulted in a significant shift towards synergistic associations for both cell lines. Administration of 5-FU before fotemustine caused a marked antagonism which 10(-5) M FA was unable to significantly shift towards simple additivity.
Fischel
J L
JL
Centre Antoine-Lacassagne, Nice, France.
Formento
P
P
Berlion
M
M
Berille
J
J
Gioanni
J
J
Bizzari
J P
JP
Milano
G
G
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology* / Q000633:toxicity; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D009607:Nitrosourea Compounds / Q000494:pharmacology* / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; C054368:fotemustine; D002955:Leucovorin; D005472:Fluorouracil
Les effets cytotoxiques de la combinaison d'une nouvelle nitrosourée, la fotémustine, avec l'association 5-fluorouracile et acide folinique dépendent de la séquence de leur administration.