Growth inhibition and apoptotic cell death in uterine cervical carcinoma cells induced by 5-fluorouracil.

We have investigated the effects of 5-fluorouracil (5-FU) on cell growth, DNA synthesis, morphological changes, DNA fragmentation and Fas antigen expression of cultured human uterine cervical carcinoma cells (OMC-1 squamous-cell carcinoma and OMC-4 adenocarcinoma). Apoptotic cell death in cervical carcinoma tissues from the patients after an intravenous administration of 5-FU was also examined. Treatment of OMC-1 and OMC-4 cells with 0.1-10 microg/ml of 5-FU (1 microg/ml = 7.7 microM) resulted in concentration-dependent inhibition of the number of cumulative viable cells and 6-3H-deoxyuridine uptake into the DNA. These effects of 5-FU were well correlated with apoptotic indices of the cells determined in situ by terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick end-labeling (TUNEL). A TUNEL signal was detectable in nuclei of normal-looking cells and in a lobulated nucleus with dense chromatin. DNA fragmentation was observed in the cells exposed to 10 microg/ml of 5-FU according to the nucleosomal ladder detected by electrophoresis. Flow cytometric analysis showed that Fas antigen expression of the cells increased upon incubation with 10 microg/ml of 5-FU. Moreover, TUNEL of tissue sections of resected uterus revealed that apoptosis occurred more frequently in patients treated pre-operatively with 500 mg/m2/day of 5-FU for 8 days than in those who did not receive 5-FU. These results suggest that achievable therapeutic levels of 5-FU inhibit cell growth and DNA synthesis and induce apoptotic cell death in uterine cervical carcinoma cells. However, the relationship between 5-FU-mediated apoptosis and the Fas ligand/Fas system remains to be explored.