[Modulation of the biochemical effect of 5-fluorouracil (5-FU) by leucovorin measured by thymidylate synthase activity and nucleoside incorporation into DNA].
Experimental data show that Leucovorin (LCV) can remarkably modify the cytotoxicity of 5-fluorouracil (5-FU). The combined use of both substances results in a more prolonged and pronounced inhibition of DNA-metabolism by inhibiting thymidylate-synthase (TS) activity. This effect is caused by stabilisation of the ternary complex of 5-fluoro-deoxyuridine monophosphate (5-FdUMP), TS and N5,N10-methylenetetrahydrofolate (CH2FH4). The influence of the combined treatment with 5-FU and LCV has been studied on permanently growing human lymphoblastoid cells. Two different methods were used: a) Tritium-release-assay for measurement of TS activity; b) incorporation of 3H-deoxyuridine (3H-dUR) and 3H-thymidine (3H-dTR) into the DNA for determination of the intrinsic nucleoside pools. The results with both methods were similar. Neither with sequential nor with simultaneous application of both substances was it possible to demonstrate a significantly increased substances was it possible to demonstrate a significantly increased inhibition of TS as compared with 5-FU alone. The methods demonstrated are easy to perform and permit the biochemical characterisation of cell populations in which the combination of LCV + 5-FU is not more effective than 5-FU alone. It is suggested that lymphoid cells and normal bone marrow are such populations.
Kau
B
B
Medizinische Klinik III, Klinikum Grosshadern, Ludwig-Maximilians-Universität München.
Rieger
M
M
Sauer
H
H
D000971:Antineoplastic Combined Chemotherapy Protocols; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects*; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology*; D009705:Nucleosides / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D009705:Nucleosides; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil
Modulation der biochemischen Wirkung von 5-Fluorouracil (5-FU) durch Leucovorin (LCV) gemessen anhand der Thymidylat-Synthase-Aktivität und des Nucleosid-Einbaus in die DNS.