Sequence-dependent cytotoxic effects of the combination of a new nitrosourea, fotemustine, with 5-fluorouracil plus folinic acid.
The present study was designed to analyse the cytotoxic effects of the combination of fotemustine with 5-fluorouracil (5-FU) plus 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 using the MTT (tetrazolium bromide) 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 prior to treatment with 5-FU, the final cytotoxic effects on 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 that modified the effects of the drug combination from antagonism (at low 5-FU concentrations) to synergism (high 5-FU concentrations; P less than 0.001). The addition of FA (10(-5) M) resulted in a significant shift towards synergistic associations in both cell lines. Administration of 5-FU prior to treatment with fotemustine caused marked antagonism, which 10(-5) M FA could not 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
D000970:Antineoplastic Agents / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000633:toxicity; D006801:Humans; D002955:Leucovorin / Q000633:toxicity; D008175:Lung Neoplasms / Q000188:drug therapy; D009607:Nitrosourea Compounds / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; C054368:fotemustine; D002955:Leucovorin; D005472:Fluorouracil