Abstract:
:The growth inhibitory effects of 5-fluorouracil (FUra) or 5-fluoro-2'-deoxyuridine (FdUrd) combined with 5-methyltetrahydrofolate (5-CH3-H4PteGlu) were determined, as a function of time, dose, and sequence of exposure, on human T-lymphoblast leukemia cells, CCRF-CEM. Synergistic inhibitory effects on cell growth were obtained when exponentially growing CCRF-CEM cells were exposed to 5-CH3-H4PteGlu (1-100 microM) for 4 hr and to FUra (250 microM) or FdUrd (0.5 microM) during the last 2 hr. Synergism was dependent on 5-CH3-H4PteGlu dose (100 greater than 10 greater than 1 microM) and did not occur at 0.1 microM. No clear dependence of synergism on sequence was observed with FUra and 5-CH3-H4PteGlu combinations (5-CH3-H4PteGlu----FUra,5-CH3-H4PteGlu + FUra, or FUra----5-CH3-H4PteGlu). With 5-CH3-H4PteGlu and FdUrd combinations, synergism was dependent on sequence of exposure (5-CH3-H4PteGlu + FdUrd, 5-CH3-H4PteGlu----FdUrd were synergistic, but FdUrd----5-CH3-H4PteGlu was not). Thymidine (0.1 microM), added after drug treatment, substantially rescued CCRF-CEM cells from 5-CH3-H4PteGlu----FUra cytotoxicity. L-methionine (1500 mg/l) completely protected CCRF-CEM cells from enhanced cytotoxicity of the combination, 5-CH3-H4PteGlu-FdUrd. The results are consistent with the hypothesis that the mechanism by which 5-CH3-H4PteGlu potentiates fluoropyrimidine cytotoxicity is the enhancement of complex formation between thymidylate synthase and 5-fluorodeoxyuridylate, as a consequence of an increase of intracellular levels of 5,10-methylenetetrahydrofolate generated from 5-CH3-H4PteGlu. Also, enhanced stability of the complex in the presence of high levels of this folate coenzyme may contribute to the synergism observed. These data provide a rationale basis for further trials of folate coenzymes and fluoropyrimidine combinations in the clinic.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Mini E,Mazzei T,Coronnello M,Criscuoli L,Gualtieri M,Periti P,Bertino JRdoi
10.1016/0006-2952(87)90201-2subject
Has Abstractpub_date
1987-09-15 00:00:00pages
2905-11issue
18eissn
0006-2952issn
1873-2968pii
0006-2952(87)90201-2journal_volume
36pub_type
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