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.