Mechanisms of action of FdUMP[10]: Metabolite activation and thymidylate synthase inhibition

  • Authors:
    • I. V. Bijnsdorp
    • E. M. Comijn
    • J. M. Padron
    • W. H. Gmeiner
    • G. J. Peters
  • View Affiliations

  • Published online on: July 1, 2007     https://doi.org/10.3892/or.18.1.287
  • Pages:287-291
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Abstract

FdUMP[10] is a multimer of FdUMP, a suicide inhibitor of thymidylate synthase (TS), and was designed to bypass resistance to 5-fluorouracil (5FU). The aim of the study was to compare the effect of FdUMP[10] with 5FU and 5-fluoro-2-deoxyuridine (FUdR) in their efficacy to inhibit their target TS in resistant cells. Therefore cell lines FM3A/0, FM3A/TK− (deficient in thymidine kinase) and FM3A/TS− (deficient in thymidylate synthase) were used to determine TK dependency and specificity for TS inhibition. FdUMP[10] inhibited cell growth with greater potency than 5FU and FdUMP. Direct folate-based inhibitors Raltitrexed, GW1843U89 and Pemetrexed were also evaluated using these cell lines. In TK-deficient cells these folate-based inhibitors had greater potency than the fluoropyrimidines (FPs). Surprisingly, Pemetrexed even inhibited cell growth in TS-deficient cells. Incubation with nucleotidase and phosphatase inhibitors resulted in a reduction of cytotoxicity of FdUMP[10], indicating that the drug can be degraded outside the cells. In the TS in situ inhibition assay (TSIA) 24 h exposure of FM3A cells to 0.5 µM FdUMP and 0.05 µM FdUMP[10] decreased TSIA to 7 and 1% of control. Inhibition of nucleotidase and phosphatase activities reduced the effect of FdUMP[10], while the inhibitory effect was lower in cells lacking TK. FdUMP[10] can enter the cells intact, but also to some extent after dephosphorylation. In conclusion, FdUMP[10] can bypass resistance to FUdR by direct inhibition of TS.

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July 2007
Volume 18 Issue 1

Print ISSN: 1021-335X
Online ISSN:1791-2431

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APA
Bijnsdorp, I.V., Comijn, E.M., Padron, J.M., Gmeiner, W.H., & Peters, G.J. (2007). Mechanisms of action of FdUMP[10]: Metabolite activation and thymidylate synthase inhibition. Oncology Reports, 18, 287-291. https://doi.org/10.3892/or.18.1.287
MLA
Bijnsdorp, I. V., Comijn, E. M., Padron, J. M., Gmeiner, W. H., Peters, G. J."Mechanisms of action of FdUMP[10]: Metabolite activation and thymidylate synthase inhibition". Oncology Reports 18.1 (2007): 287-291.
Chicago
Bijnsdorp, I. V., Comijn, E. M., Padron, J. M., Gmeiner, W. H., Peters, G. J."Mechanisms of action of FdUMP[10]: Metabolite activation and thymidylate synthase inhibition". Oncology Reports 18, no. 1 (2007): 287-291. https://doi.org/10.3892/or.18.1.287