TY - JOUR
T1 - Cytotoxicity of 5 fluoro 2' deoxyuridine
T2 - Requirement for reduced folate cofactors and antagonism by methotrexate
AU - Ullman, B.
AU - Lee, M.
AU - Martin, D. W.
AU - Santi, D. V.
PY - 1978
Y1 - 1978
N2 - Potent in vitro inhibition of thymidylate synthetase (5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45) by 5-fluoro-2'-deoxyuridylate requires 5,10-methylenetetrahydrofolate. The cytotoxicity of 5-fluoro-2'-deoxyuridine towards cultured L1210 mouse leukemia cells is reduced when intracellular reduced folates are depleted, either by limiting the source in media or by inhibition of dihydrofolate reductase with methotrexate. Likewise, the intracellular amount of 5-fluoro-2'-deoxyuridylate covalently bound to thymidylate synthase in L1210 cells treated with 5-fluoro-2'-deoxyuridine is greatly diminished when cells are depleted of folate cofactors. The folate requirements for optimal growth of L1210 cells is lower than that required for maximal cytotoxicity of 5-fluoro-2'-deoxyuridine. These findings provide a biochemical rationale that may be useful in designing clinical protocols that use 5-fluorinated uracil analogs.
AB - Potent in vitro inhibition of thymidylate synthetase (5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45) by 5-fluoro-2'-deoxyuridylate requires 5,10-methylenetetrahydrofolate. The cytotoxicity of 5-fluoro-2'-deoxyuridine towards cultured L1210 mouse leukemia cells is reduced when intracellular reduced folates are depleted, either by limiting the source in media or by inhibition of dihydrofolate reductase with methotrexate. Likewise, the intracellular amount of 5-fluoro-2'-deoxyuridylate covalently bound to thymidylate synthase in L1210 cells treated with 5-fluoro-2'-deoxyuridine is greatly diminished when cells are depleted of folate cofactors. The folate requirements for optimal growth of L1210 cells is lower than that required for maximal cytotoxicity of 5-fluoro-2'-deoxyuridine. These findings provide a biochemical rationale that may be useful in designing clinical protocols that use 5-fluorinated uracil analogs.
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U2 - 10.1073/pnas.75.2.980
DO - 10.1073/pnas.75.2.980
M3 - Article
C2 - 147465
AN - SCOPUS:0005086073
SN - 0027-8424
VL - 75
SP - 980
EP - 983
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 2
ER -