Enhanced DNA‐Directed Effects of FdUMP[10] Compared to 5FU
- 1 January 2004
- journal article
- research article
- Published by Informa UK Limited in Nucleosides, Nucleotides and Nucleic Acids
- Vol. 23 (1), 401-410
- https://doi.org/10.1081/ncn-120028336
Abstract
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 × 10− 8 M was greater than that which occurred following exposure of these cells to 5FU at 1 × 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.Keywords
This publication has 19 references indexed in Scilit:
- 5-Fluorouracil: mechanisms of action and clinical strategiesNature Reviews Cancer, 2003
- Oral Fluoropyrimidine Treatment of Colorectal CancerClinical Colorectal Cancer, 2001
- 5-Fluorouracil: Forty-Plus and Still Ticking. A Review of its Preclinical and Clinical DevelopmentInvestigational New Drugs, 2000
- α-Fluoro-β-alanine: Effects on the antitumor activity and toxicity of 5-fluorouracilBiochemical Pharmacology, 2000
- Increased Cytotoxicity and Decreased In Vivo Toxicity of FdUMP[10] Relative to 5-FUNucleosides and Nucleotides, 1999
- Comparison of 5-fluoro-2′-deoxyuridine with 5-fluorouracil and their role in the treatment of colorectal cancerEuropean Journal Of Cancer, 1998
- Thymineless death in colon carcinoma cells is mediated via Fas signalingProceedings of the National Academy of Sciences of the United States of America, 1997
- Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: Evidence for the involvement of RNA perturbationProceedings of the National Academy of Sciences of the United States of America, 1997
- Preparation of Oligomeric 2′-Deoxy-5-Fluorouridylate of Defined Length and Backbone Composition: A Novel Pro-Drug form of the Potent Anti-Cancer Drug 2′-Deoxy-5-FluorouridylateNucleosides and Nucleotides, 1995
- Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylateBiochemistry, 1974