title: Mechanism of action of a new antitumor ribonucleoside, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106), differs from that of 5-fluorouracil.
abstract: 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106), is a new antitumor cytidine analogue, inhibiting RNA synthesis. In this study we investigated the cellular growth inhibition, intracellular metabolism, cell cycle phase specificity, and RNA synthesis of TAS-106 compared with those of 5-fluorouracil (5-FU), known to possess both DNA- (inhibition of thymidylate synthase activity) and RNA-synthesis-inhibiting activity (inhibition of RNA function). The IC50 values of TAS-106 and 5-FU ranged from 0.0173 to 3.11 microM, and from 6.80 to >1,000 microM, respectively, in a panel of 10 human tumor cells, indicating that TAS-106 possesses greater cytotoxicity than 5-FU. Using excess thymidine-synchronized cells, TAS-106 and 5-FU appeared to exert their cytotoxic effects independently of the cell cycle. The intracellular metabolism and the effect on pre-rRNA processing of TAS-106 differed from those of 5-FU. More than 50% of 5-FU incorporated into the cells was in the unchanged form, while 5-FU incorporated into RNA was approximately 20%. On the other hand, TAS-106 was incorporated in a time-dependent manner into the cells and rapidly converted to its mono-, di- and tri-phosphate form, however, the amount incorporated into RNA fraction was very small. 5-FU incorporated into RNA was confirmed to impair the normal processing of ribosomal RNA (formation of 34/32S RNA from 45S RNA), however, TAS-106 did not affect pre-rRNA processing and may be involved in the inhibition of the synthesis of ribosomal RNA. We concluded that intracellular accumulation and retention of the active metabolite of TAS-106, 3'-ethynylcytidine 5'-triphosphate (ECTP), may contribute to its potent cytotoxicity. The unique mechanism of antitumor activity and intensive cellular metabolism of TAS-106 could contribute to cancer chemotherapy through the pathways different from those of 5-FU or other antitumor nucleosides.
authors.affiliation: Hanno Research Center, Taiho Pharmaceutical Co., Ltd., Saitama 357-8527, Japan. h-kazuno@taiho.co.jp
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kazuno
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shimamoto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tsujimoto
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fukushima
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.forename: Takuma
authors.initials: T
authors.lastname: Sasaki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003562:Cytidine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D005472:Fluorouracil / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D012322:RNA Precursors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D012335:RNA, Ribosomal / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology*
chemical_list: C103084:1-(3-C-ethynylribopentofuranosyl)cytosine; D000970:Antineoplastic Agents; D012322:RNA Precursors; D012335:RNA, Ribosomal; D012263:Ribonucleosides; D003562:Cytidine; D005472:Fluorouracil