Enhanced DNA-directed effects of FdUMP[10] compared to 5FU.
FdUMP[N] molecules and conjugates are much more effective at inhibiting the proliferation of human tumor cells than is the widely used anticancer drug 5-fluorouracil (5FU). We have evaluated the inhibition of thymidylate synthase (TS), the extent of DNA damage, cell cycle arrest, and the induction of apoptosis by FdUMP[10] and 5FU in the human colorectal cancer cell line HT29. The magnitude and duration of TS inhibition following exposure of HT29 cells to FdUMP[10] at 1 x 10(-8) M was greater than that which occurred following exposure of these cells to 5FU at 1 x 10(-6) M. FdUMP[10] exposure also resulted in much more extensive DNA damage to HT29 cells than occurred following exposure to 100-fold higher concentrations of 5FU. Although exposure of HT29 cells to both drugs resulted in S-phase arrest, more complete accumulation of cells in S-phase was achieved following FdUMP[10] exposure at much lower drug concentrations. FdUMP[10] was also much more effective at inducing apoptosis in HT29 cells than was 5FU. The results are consistent with FdUMP[10] being much more efficient that 5FU at inducing DNA damage that results in apoptotic cell death in colon cancer cells.
Gmeiner
William H
WH
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1016, USA. bgmeiner@wfubmc.edu
Trump
Eric
E
Wei
Cui
C
D003110:Colonic Neoplasms / Q000188:drug therapy*; D004247:DNA / Q000187:drug effects*; D005468:Fluorodeoxyuridylate / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans
D005468:Fluorodeoxyuridylate; D004247:DNA; D005472:Fluorouracil