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MTA is a novel antifolate that has been shown in vitro to inhibit multiple folate-requiring enzymes including TS, DHFR and GARFT. The antithymine and antipurine characteristics of MTA were evaluated through studying the drug effects on folate and nucleotide pools. In CCRF-CEM cells, following the addition of up to 1 μM MTA, no accumulation of dihydrofolate was observed for 8 hr. Exposure of these cells to 300 nM MTA for 24 hr caused changes in nucleotide pools that were largely attributable to TS inhibition. Attempts were made to study the nucleotide pool changes under a condition that might circumvent the antithymine effects. At the high cell density used in the experiment, the presence of 5 μM thymidine only prevented up to 24 hr the perturbation of the nucleotide pools induced by 180 nM MTA. Cells cultured for 72 hr in the 180 nM supplemented with a combination of 30μM thymidine + 100 μM deoxycytidine were deficient mainly in purine nucleotides but had near normal or supranormal levels of pyrimidine nucleotides. These observations were discussed in light of other published data showing correlation to the inhibition of TS, DHFR and GARFT by MTA. It was concluded that the effect of MTA on folate and nucleotide metabolism was primarily on thymidylate biosynthesis and secondarily on purine biosynthesis.
Author(s): Chen VJ, Bewley JR, Smith PG, Andis SL, Schultz RM, Iversen PW, Tonkinson JL, Shih C
Publication type: Article
Publication status: Published
Journal: Advances in Enzyme Regulation
Year: 2000
Volume: 40
Issue: 1
Pages: 143-152
ISSN (print): 0065-2571
ISSN (electronic): 1873-2437
Publisher: Pergamon
URL: http://dx.doi.org/10.1016/S0065-2571(99)00027-8
DOI: 10.1016/S0065-2571(99)00027-8
PubMed id: 10828350
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