Inhibitory mechanisms of 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)uracil (EUrd) on RNA synthesis

Tatsushi Yokogawa, Tomoharu Naito, Hiroshi Kanda, Satoshi Takatori, Kiyoko Takenaka, Takuma Sasaki, Akira Matsuda, Masakazu Fukushima, Hye Sook Kim, Yusuke Wataya

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)uracil (EUrd) is an antimetabolite that strongly inhibits RNA synthesis and shows a broad antitumor activity in vitro and in vivo. In mouse mammary tumor FM3A cells, EUrd is sequentially phosphorylated to its 5′-triphosphate, EUTP, a major metabolite, and the RNA synthesis is inhibited proportionally to its intracellular accumulation. To study the inhibitory mechanisms of EUrd on RNA synthesis, we have performed the kinetic analysis of EUTP on RNA polymerization using isolated nuclei RNA synthesis was inhibited competitively by EUTP. The inhibition constant, Ki was much lower than the Km value of UTP (Ki value of EUTP, 84 nM; Km value of UTP, 13 μM), indicating that the high affinity of EUTP could contribute to the specific inhibition of RNA synthesis. As a result of RNA synthesis inhibition, EUrd, but not ara-C, induced shrinkage of nucleoli, which are the main sites for RNA synthesis in FM3A cells. Thus, the strong affinity of EUTP to RNA polymerase and specific inhibition of RNA synthesis could contribute to its antitumor effect. EUrd is expected to be a new antitumor drug, possessing a strong inhibitory effect on the synthesis of RNA.

Original languageEnglish
Pages (from-to)227-232
Number of pages6
JournalNucleosides, Nucleotides and Nucleic Acids
Volume24
Issue number3
DOIs
Publication statusPublished - 2005

Keywords

  • EUrd
  • Inhibitor of RNA Synthesis
  • Nucleolus

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Genetics

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