To investigate acquired 5-fluorouracil (5FU)-resistance in cancer cells, we established four monoclonal 5FU-resistant cell lines from human endometrial adenocarcinoma cells by long-term 5FU-exposure cultures and limiting dilution cultures. The established subclones exhibited 5-25 times greater 5FU-resistance than the parent cells, and showed suppression of 5FU-induced DNA fragmentation. All four 5FU-resistant subclones were 25-125 times more resistant to SN38, 4-hydroxy-cyclophosphamide, paclitaxel and etoposide than the parent cells while none of the four subclones showed resistance to mitomycin. Two of the four subclones showed no resistance to pirarubicin and bleomycin. Although all four 5FU-resistant subclones were 5-25 times more resistant to anti-Fas IgM than the parent cells, the resistance levels to anti-Fas IgM of the individual subclones did not coincide with the strengths of their multidrug resistance. Karyotyping analyses revealed that the parent cells and the three 5FU-resistant subclones examined had normal 46XX karyotypes. These results indicate that the cell death signals induced by mitomycin, pirarubicin and bleomycin are distinctly different from the Fas-mediated apoptotic signals, that acquisition of 5FU-resistance can occur without any large chromosomal deletions or rearrangements, and that there are several possible molecular changes during the acquisition of 5FU-resistance. The established cell lines represent useful tools for investigating the mechanisms and treatments of acquired 5FU-resistance.

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