Differential growth inhibition by 5-fluorouracil in human colorectal carcinoma cell lines

The effects of 5-fluorouracil (5-FU) on cell growth were investigated using a primary culture of human fibroblasts, MRC-5, and three established human colon cancer cell lines, DLD-1, LoVo and SW620. Detailed flow cytometric a nalyses revealed differential growth inhibition among these cell lines incl uding three modes of cell growth modulation: (a) loss or accumulation of S phase cells, (b) G2/M block; and (c) G1-S arrest. From analyses on the amou nt of 5-FU incorporated into cellular RNA and the activity of thymidylate s ynthase (TS), suppression of TS and depletion of dTTP, a possible consequen ce of the former, was considered to be the major action of 5-FU in these ce lls. Differences in the cellular responses to the nucleotide pool imbalance appeared to make the cell growth modulation diverse. Loss of S phase cells and G1-S phase arrest were evident in p53 wild-type cells, MRC-5 and LoVo. Cells proficient in DNA mismatch repair, SW620 and MRC-5, showed marked mo dulations in S-G2/M progression. These findings suggest that multiple facto rs, including p53 and DNA mismatch repair, participate in diverse cell grow th modulations in cells treated with 5-FU. Cellular resistance to 5-FU corr elated well with a loss of modulations in S-G2/M progression, rather than w ith a defect of GI-S arrest, which suggests the significance of DNA mismatc h repair as a factor affecting the sensitivity of cells to 5-FU. (C) 2000 E lsevier Science Ltd. All rights reserved.