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.
Ueda
M
M
Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki-shi, Japan.
Kumagai
K
K
Ueki
K
K
Inoki
C
C
Orino
I
I
Ueki
M
M
D000230:Adenocarcinoma / Q000473:pathology*; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D053938:DNA Fragmentation; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D014407:Tumor Cells, Cultured / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000473:pathology*; D019014:fas Receptor / Q000096:biosynthesis
D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D019014:fas Receptor; D005472:Fluorouracil