title: Cyclopentenyl cytidine analogue. An inhibitor of cytidine triphosphate synthesis in human colon carcinoma cells.
abstract: The mechanism of action of the cyclopentenyl analogue of cytidine, cCyd, was investigated in human colon carcinoma cell line HT-29. Upon exposure of cells to 10(-6)M cCyd, cell viability was reduced to 20% of control, whereas cytocidal activity was not present after 2 hr of drug exposure. Cell lethality was partially reversible by Urd, Cyd or dCyd at 10(-6)M cCyd, and fully reversible by these nucleosides at 2.5 X 10(-7)M cCyd. The incorporation of [14C]dThd and [3H]Urd into DNA and RNA was inhibited by 50% by exposure for 2 hr to 2.5 X 10(-7) and 1.5 X 10(-6)M cCyd respectively. Upon 24 hr of drug exposure, the IC50 for RNA synthesis was reduced 2.5-fold, whereas DNA synthesis was almost totally inhibited. cCyd produced a rapid and preferential reduction of CTP synthesis with a half-life of 1 hr at 10(-6)M drug. The IC50 of cCyd for reducing CTP concentrations after 2 hr of drug exposure was 4 X 10(-7)M. Concomitant with the reduction of CTP levels was the inhibition of transcription of rRNA and, to a lesser extent, tRNA, without changes in the processing nucleolar RNA. No changes in the size of DNA were produced following treatment with cCyd. These results indicate that cCyd is a potent and rapid inhibitor of CTP synthesis and that this effect correlates with its cytocidal activity.
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism*; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003570:Cytidine Triphosphate / Q000096:biosynthesis*; D003597:Cytosine Nucleotides / Q000096:biosynthesis*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D006801:Humans; D012334:RNA, Neoplasm / Q000096:biosynthesis; D014529:Uridine / Q000031:analogs & derivatives
chemical_list: D000970:Antineoplastic Agents; D003597:Cytosine Nucleotides; D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D003562:Cytidine; D003570:Cytidine Triphosphate; C045911:cyclopentenyl cytosine; D014529:Uridine