Anti-tumor mechanisms of 3'-ethynyluridine and 3'-ethynylcytidine as RNA synthesis inhibitors: development and characterization of 3'-ethynyluridine-resistant cells.

To discover the mechanisms of anti-tumor action of 3'-ethynyluridine (EUrd) and 3'-ethynylcytidine (ECyd), we established an EUrd-resistant variant from human fibrosarcoma HT-1080 cells. The cells were cross-resistant to ECyd. Uridine/cytidine kinase activity diminished in the resistant cells. The incorporation of EUrd and ECyd into the RNA fraction in the resistant cells was less than that of the parental cells. EUrd-triphosphate inhibited RNA synthesis by human RNA polymerase II. The results led us to conclude that EUrd and ECyd are phosphorylated by uridine/cytidine kinase to 5'-triphosphates, and that their triphosphates might inhibit RNA polymerase.