Reference : The ribonucleoside diphosphate reductase inhibitor (E)-2'-Deoxy-(fluoromethylene) cy...
Scientific journals : Article
Human health sciences : Hematology
Human health sciences : Oncology
The ribonucleoside diphosphate reductase inhibitor (E)-2'-Deoxy-(fluoromethylene) cytidine, acts as a cytotoxic radiosensitizer on human cancer cell lines in vitro.
Coucke, Philippe mailto [Centre Hospitalier Universitaire Vaudois > > > >]
Decosterd, L-A [ > > ]
Li, Y-X [ > > ]
Cottin, E [ > > ]
Chen, X [ > > ]
Sun, L-Q [ > > ]
Stern, S [ > > ]
Paschoud, N [ > > ]
Denekamp, J [ > > ]
Cancer Research
American Association for Cancer Research, Inc. (AACR)
Yes (verified by ORBi)
[en] radiotherapy ; radiosensitization ; deoxynucleotide ; FMdC ; DNA Synthesis
(E)-2*-Deoxy-(fluoromethylene)cytidine (FMdC) is known as an inhibitor
of ribonucleoside diphosphate reductase, a key enzyme in the de novo
pathway of DNA synthesis. FMdC was tested as a modifier of radiation
response in vitro on a human colon carcinoma cell line (WiDr), and the
observed radiosensitization was confirmed on two human cervix cancer
cell lines (C33-A and SiHa). Using the clonogenic assay, the effect ratio
(ER) at a clinically relevant dose level of 2 Gy was 2.10 (50 nM FMdC),
1.70 (30 nM FMdC), and 1.71 (40 nM FMdC) for the three cell lines WiDr,
C33-A, and SiHa, respectively. A more detailed analysis of the importance
of timing and concentration of FMdC was done on the WiDr cell line
alone, yielding an increased ER(2Gy) with increasing concentration and
duration of exposure to the drug, ranging from 1.0 (6 h) to 1.8 (72 h) at 30
nM FMdC and from 1.2 (6 h) to 3.5 (24 h) at 300 nM. We investigated the
effect of FMdC on the cellular deoxynucleotide triphosphate pool in WiDr
cells and demonstrated a marked depletion of dATP and a significant rise
of TTP levels. Cell cycle analysis showed early S-phase accumulation
induced by FMdC alone, G2-M block induced by irradiation alone, and an
increased accumulation of cells in G2-M if both modalities are used. Our
data suggest that FMdC is a radiation response modifier in vitro on
different cancer cell lines. The observed radiosensitization may in part be
explained by alteration of the deoxynucleotide triphosphate pool, which is
consistent with the effect of FMdC on ribonucleoside diphosphate reductase.
Researchers ; Professionals

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