PMID: 9167189Jan 1, 1997Paper

Determinants of cytotoxicity with prolonged exposure to fluorouracil in human colon cancer cells

Oncology Research
Q RenJean L Grem

Abstract

To explore the determinants of cytotoxicity during prolonged exposure to pharmacologically relevant concentrations of 5-fluorouracil (FUra), we studied the effects of FUra at concentrations ranging from 0.1 to 1 microM in HCT 116 and HT 29 colon cancer cells grown in the presence of physiologic levels of leucovorin. A 5- and 7-day exposure to 1 microM FUra reduced cell growth to 46% and 20% of control in HT 29 cells and to 74% and 38% of control in HCT 116 cells. Concurrent exposure to thymidine (10 or 20 microM) or uridine (1 mM) provided partial protection against FUra toxicity in HT 29 cells, but did not protect HCT 116 cells. After a 24-h exposure to 1 microM [3H]FUra, free 5-fluoro-2'-deoxyuridine-5' -monophosphate (FdUMP) and FUDP. + FUTP levels were 0.7 and 144 pmol/10(6) cells in HT 29 cells, respectively, and 3.9 and 178 pmol/10(6) cells in HCT 116 cells. FdUMP and FUDP + FUTP pools increased by 5.7- and 2.0-fold in HT 29 cells and by 1.7- and 3.3-fold in HCT 116 cells over the next 48 h, but did not accumulate thereafter. After a 24-h exposure to 1 microM [3H]FUra, FUra-RNA levels were 158 and 280 fmol/microgram in HT 29 and HCT 116 cells, respectively; FUra-RNA levels increased over time, and reached 700 and 1156 fmo...Continue Reading

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