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

摘要: 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 vivo. In mouse mammary tumor FM3A cells, EUrd sequentially phosphorylated to its 5′-triphosphate, EUTP, major metabolite, the inhibited proportionally intracellular accumulation. To study inhibitory mechanisms of on synthesis, we have performed kinetic analysis EUTP polymerization using isolated nuclei. was competitively by EUTP. The inhibition constant, K i much lower than m value UTP (K 84 nM; UTP, 13 µM), indicating high affinity could contribute specific synthesis. As result inhibition, EUrd, but not ara-C, induced shrinkage nucleoli, which are main sites for cells. Thus, strong polymerase specif...