The inhibitory effects of combined 5-methyltetrahydrofolate (5-CH3-THF), the physiological circulating folate species, and fluoropyrimidines, 5-fluorouracil (FUra) and 5-fluoro-2'-deoxyuridine (FdUrd), on growth of human leukemia cells, CCRF-CEM, were determined as a function of time, dose, and sequence of exposure. Exposure of CCRF-CEM cells in exponential growth to 5-CH3-THF (1-100 microM) for 4 h and to FUra (250 microM) or FdUrd (0.5 microM) during the last 2 h resulted in having synergistic inhibitory effects on cell growth. Synergy was dependent on 5-CH3-THF dose (100 greater than 10 greater than 1 microM) and did not occur at 0.1 microM. No clear dependency of synergy on sequence was observed with FUra and 5-CH3-THF combinations (4 h exposure, 5-CH3-THF----FUra, 5-CH3-THF + FUra, or FUra----5-CH3-THF). With 5-CH3-THF and FdUrd combinations, synergy was dependent on sequence of exposure (5-CH3-THF----FdUrd and 5-CH3-THF + FdUrd were synergistic, but FdUrd----5-CH3-THF was not). Thymidine (0.1 microM), added after drug treatment, substantially rescued CCRF-CEM cells from 5-CH3-THF-FUra cytotoxicity. L-Methionine (1500 mg/l) completely protected CCRF-CEM cells from the toxicity of the combination 5-CH3-THF-FdUrd. The results are consistent with the hypothesis that the mechanism by which 5-CH3-THF potentiated fluoropyrimidine cytotoxicity is the enhancement of ternary complex formation between thymidylate synthase and 5-fluorodeoxyuridylate, the active metabolite of fluoropyrimidines, as a consequence of an increase of intracellular levels of 5-10-methylenetetrahydrofolate generated from 5-CH3-THF.

Enhancement of fluoropyrimidine cytotoxicity by 5-methyltetrahydrofolate in a human leukemia cell line, CCRF-CEM / Mini, E; Mazzei, T; Coronnello, M; Criscuoli, L; Gualtieri, M; Periti, P. - In: CHEMIOTERAPIA. - ISSN 0392-906X. - STAMPA. - 4:(1985), pp. 454-459.

Enhancement of fluoropyrimidine cytotoxicity by 5-methyltetrahydrofolate in a human leukemia cell line, CCRF-CEM

Mini, E;Mazzei, T;Coronnello, M;Criscuoli, L;Periti, P
1985

Abstract

The inhibitory effects of combined 5-methyltetrahydrofolate (5-CH3-THF), the physiological circulating folate species, and fluoropyrimidines, 5-fluorouracil (FUra) and 5-fluoro-2'-deoxyuridine (FdUrd), on growth of human leukemia cells, CCRF-CEM, were determined as a function of time, dose, and sequence of exposure. Exposure of CCRF-CEM cells in exponential growth to 5-CH3-THF (1-100 microM) for 4 h and to FUra (250 microM) or FdUrd (0.5 microM) during the last 2 h resulted in having synergistic inhibitory effects on cell growth. Synergy was dependent on 5-CH3-THF dose (100 greater than 10 greater than 1 microM) and did not occur at 0.1 microM. No clear dependency of synergy on sequence was observed with FUra and 5-CH3-THF combinations (4 h exposure, 5-CH3-THF----FUra, 5-CH3-THF + FUra, or FUra----5-CH3-THF). With 5-CH3-THF and FdUrd combinations, synergy was dependent on sequence of exposure (5-CH3-THF----FdUrd and 5-CH3-THF + FdUrd were synergistic, but FdUrd----5-CH3-THF was not). Thymidine (0.1 microM), added after drug treatment, substantially rescued CCRF-CEM cells from 5-CH3-THF-FUra cytotoxicity. L-Methionine (1500 mg/l) completely protected CCRF-CEM cells from the toxicity of the combination 5-CH3-THF-FdUrd. The results are consistent with the hypothesis that the mechanism by which 5-CH3-THF potentiated fluoropyrimidine cytotoxicity is the enhancement of ternary complex formation between thymidylate synthase and 5-fluorodeoxyuridylate, the active metabolite of fluoropyrimidines, as a consequence of an increase of intracellular levels of 5-10-methylenetetrahydrofolate generated from 5-CH3-THF.
4
454
459
Mini, E; Mazzei, T; Coronnello, M; Criscuoli, L; Gualtieri, M; Periti, P
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1285688
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