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 language | English |
|---|---|
| Pages (from-to) | 227-232 |
| Number of pages | 6 |
| Journal | Nucleosides, Nucleotides and Nucleic Acids |
| Volume | 24 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2005 |
Fingerprint
Keywords
- EUrd
- Inhibitor of RNA Synthesis
- Nucleolus
ASJC Scopus subject areas
- Genetics
- Biochemistry
Cite this
Inhibitory mechanisms of 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)uracil (EUrd) on RNA synthesis. / Yokogawa, Tatsushi; Naito, Tomoharu; Kanda, Hiroshi; Takatori, Satoshi; Takenaka, Kiyoko; Sasaki, Takuma; Matsuda, Akira; Fukushima, Masakazu; Kim, Hye-Sook; Wataya, Yusuke.
In: Nucleosides, Nucleotides and Nucleic Acids, Vol. 24, No. 3, 2005, p. 227-232.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inhibitory mechanisms of 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)uracil (EUrd) on RNA synthesis
AU - Yokogawa, Tatsushi
AU - Naito, Tomoharu
AU - Kanda, Hiroshi
AU - Takatori, Satoshi
AU - Takenaka, Kiyoko
AU - Sasaki, Takuma
AU - Matsuda, Akira
AU - Fukushima, Masakazu
AU - Kim, Hye-Sook
AU - Wataya, Yusuke
PY - 2005
Y1 - 2005
N2 - 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.
AB - 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.
KW - EUrd
KW - Inhibitor of RNA Synthesis
KW - Nucleolus
UR - http://www.scopus.com/inward/record.url?scp=20944437995&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20944437995&partnerID=8YFLogxK
U2 - 10.1081/NCN-200055727
DO - 10.1081/NCN-200055727
M3 - Article
C2 - 15892261
AN - SCOPUS:20944437995
VL - 24
SP - 227
EP - 232
JO - Nucleosides and Nucleotides
JF - Nucleosides and Nucleotides
SN - 0732-8311
IS - 3
ER -