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 grow th, DNA synthesis, morphological changes, DNA fragmentation and Fas an tigen expression of cultured human uterine cervical carcinoma cells (O MC-1 squamous-cell carcinoma and OMC-4 adenocarcinoma). Apoptotic cell death in cervical carcinoma tissues from the patients after an intrav enous administration of 5-FU was also examined, Treatment of OMC-1 and OMC-4 cells with 0.1-10 mu g/ml of 5-FU (1 mu g/ml = 7.7 mu M) result ed in concentration-dependent inhibition of the number of cumulative v iable cells and 6-H-3-deoxyuridine uptake into the DNA. These effects of 5-FU were well correlated with apoptotic indices of the cells deter mined in situ by terminal deoxynucleotidyl transferase-mediated digoxi genin-dUTP nick end-labeling (TUNEL), A TU NEL signal was detectable i n nuclei of normal-looking cells and in a lobulated nucleus with dense chromatin. DNA fragmentation was observed in the cells exposed to 10 mu g/ml of 5-FU according to the nucleosomal ladder detected by electr ophoresis. Flaw cytometric analysis showed that Fas antigen expression of the cells increased upon incubation with 10 mu g/ml of 5-FU, Moreo ver, TUNEL of tissue sections of resected uterus revealed that apoptos is occurred more frequently in patients treated pre-operatively with 5 00 mg/m(2)/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 i nhibit cell growth and DNA synthesis and induce apoptotic cell death i n uterine cervical carcinoma cells, However, the relationship between 5-FU-mediated apoptosis and the Fas ligand/Fas system remains to be ex plored. (C) 1997 Wiley-Liss, Inc.