Biochemical rationale for the synergism of 5-fluorouracil and folinic acid.
The fluoropyrimidines, FUra and 5-fluoro-2'-deoxyuridine (FUdR), have been found to be more growth inhibitory and cytotoxic to both mouse and human tumor cells when grown in cell culture medium containing folinic acid. The increment in the activity of these drugs observed in folinate-containing medium was similar for a mouse leukemia cell line and for 4 human leukemia cell lines. This suggests that the mechanism of action of the fluoropyrimidines against these mouse and human cell lines is similar. The most probable mechanism of the interaction between folinic acid and the fluoropyrimidines is stabilization of thymidylate synthase (TS) in inactive complexes with 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) and folate cofactor. Such trapping of enzyme in inactive form would negate the effects of the accumulation of the reaction substrate 2'-deoxyuridine-5'-monophosphate. It is suggested that the combination of FUra with folinic acid and, in addition, an inhibitor of ribonucleotide reductase such as hydroxyurea may be more effective than FUra and folinic acid alone.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003856:Deoxyuracil Nucleotides / Q000378:metabolism; D004357:Drug Synergism; D005467:Floxuridine / Q000008:administration & dosage; D005472:Fluorouracil / Q000008:administration & dosage* / Q000627:therapeutic use; D006918:Hydroxyurea / Q000627:therapeutic use; D002955:Leucovorin / Q000008:administration & dosage*; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D003856:Deoxyuracil Nucleotides; D005467:Floxuridine; D002955:Leucovorin; D005472:Fluorouracil; D006918:Hydroxyurea