ライフサイエンスコーパス: FdUMP

1 FdUMP inhibits thymidylate synthase and causes the accum

2 FdUMP shows a similar profile, while dGMP does not alter

3 FdUMP[10] exhibits more potent antiproliferative activit

4 FdUMP[10] induces DNA single-strand breaks and cellular

5 FdUMP[10] inhibited thymidylate synthase (TS) and trappe

6 FdUMP[10] remained effective against cells expressing th

7 FdUMP[10] was better tolerated than 5-FU or cytarabine p

8 FdUMP[10], a 10mer of 5-fluoro-2'-deoxyuridine 5'-monoph

9 +)[BMP](2-)) and antitumor agents ([ZrO](2+)[FdUMP](2-)) with an up to 80% load of active drug is pos

10 s and by ternary complex formation with [32P]FdUMP and 5,10-methylenetetrahydrofolate.

11 In order to create 5-FdUMP resistant enzymes to protect chemosensitive normal

12 is metabolized to 5-fluorodeoxyuridylate (5-FdUMP), a tight binding covalent inhibitor of thymidylat

13 cells and further understand mechanisms of 5-FdUMP resistance, we have randomized four residues withi

14 This 5-FdUMP-resistant mutant, or others similarly selected, is

15 based inhibitor, 5-fluoro-2'-deoxyuridylate (FdUMP), into a ternary complex.

16 the mechanism-based inhibitor 5-fluoro-dUMP (FdUMP) and methylenetetrahydrofolate (CH2THF) have been

17 esent, in addition to the nucleotides (dUMP, FdUMP, or dGMP), a Td of 72 degrees C is achieved and th

18 The stabilization of dUMP, FdUMP, and dGMP binding to Escherichia coli thymidylate

19 The folic acid conjugate FA-FdUMP[10] showed improved cytotoxicity toward human colo

20 Enhanced cytotoxicity was observed for FA-FdUMP[10] relative to nonconjugated FdUMP[10] for cells

21 Thus, FA-FdUMP[N] may prove useful for the treatment of 5-FU-resi

22 y complex of TS with 5-fluorodeoxyuridylate (FdUMP) and 5, 10-methylenetetrahydrofolylpolyglutamate w

23 The novel fluoropyrimidine, FdUMP[10], was highly active against both human AML cell

24 eveloped a novel class of fluoropyrimidines, FdUMP[N], that are oligodeoxynucleotides (ODNs) composed

25 rate that the dissociation constant (Kd) for FdUMP binding into the ternary complex was 20-fold highe

26 exposed to IFN-alpha + gamma and FUra, free FdUMP levels became detectable, whereas [3H]FUra-RNA inc

27 ilibrium binding studies with the inhibitor, FdUMP, demonstrate that the dissociation constant (Kd) f

28 y respects: (i) the methylene bridge linking FdUMP and CH2THF is rotated about 60 degrees to a differ

29 d between TS protein and the FdU metabolite, FdUMP.

30 de 5-fluoro-2'-deoxyuridine-5'monophosphate (FdUMP).

31 f 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) is added to growing DM-transformed cells, the com

32 f 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), the thymidylate synthase inhibitory metabolite o

33 erted to 5-fluorodeoxyuridine monophosphate (FdUMP) and 5-fluorodeoxyuridine triphosphate (FdUTP).

34 5-fluoro-2'-deoxyuridine-5'-O-monphosphate (FdUMP) nucleotides.

35 d for FA-FdUMP[10] relative to nonconjugated FdUMP[10] for cells grown under folate-restricted condit

36 In all cases, the IC(50) of FdUMP[10] was lower than for cytarabine and approximatel

37 tion and (ii) the electron density for C6 of FdUMP, which is covalently linked to Cys 146, is more di

38 it conjugation of folic acid to the 5'-OH of FdUMP[10] via a phosphodiester linkage using automated s

39 ction involving the intracellular release of FdUMP.

40 g is possible (BMP = betamethason phosphate, FdUMP = 5'-fluoro-2'-deoxyuridine 5'-monophosphate).

41 ovel haloethyl and piperidyl phosphoramidate FdUMP prodrug analogues has been synthesized, and the gr

42 In summary, FdUMP[10] was highly efficacious and better tolerated th

43 more potent antiproliferative activity than FdUMP or 5-fluoro-2'-deoxyuridine (FdU) and is markedly

44 We propose that FdUMP[10] damages DNA by trapping Top1 at uracil and FdU

45 The FdUMP[10]-induced Top1-DNA complexes are not inhibited b

46 e cross-resistant to FdUMP[10] as well as to FdUMP, FdU, and the thymidylate synthase inhibitor ralti

47 sts that <50% of the prodrug is converted to FdUMP intracellularly by this pathway.

48 45 cells lacking Top1 are cross-resistant to FdUMP[10] as well as to FdUMP, FdU, and the thymidylate

49 h complexes are also observed in response to FdUMP, FdU, raltitrexed, and FU.

50 In the crystal structure of a V3F.FdUMP binary complex, the nucleotide is bound in an alte

51 In vivo, FdUMP[10] was active against a syngeneic AML model with

52 Escherichia coli TS in ternary complex with FdUMP and the inhibitor 10-propargyl-5,8-dideazafolic ac

53 , TS protein was altered upon treatment with FdUMP, but 5-FU toxicity seemed to be largely RNA-based,