The ribonucleoside diphosphate reductase inhibitor (E)-2'-deoxy-(fluoromethylene)cytidine as a cytotoxic radiosensitizer in vitro
Détails
ID Serval
serval:BIB_96FE26517659
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
The ribonucleoside diphosphate reductase inhibitor (E)-2'-deoxy-(fluoromethylene)cytidine as a cytotoxic radiosensitizer in vitro
Périodique
Cancer Research
ISSN
0008-5472 (Print)
Statut éditorial
Publié
Date de publication
10/1999
Volume
59
Numéro
20
Pages
5219-26
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Oct 15
Research Support, Non-U.S. Gov't --- Old month value: Oct 15
Résumé
(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.
Mots-clé
Antineoplastic Agents/*pharmacology
Cell Cycle/drug effects
Cell Division/drug effects
Chromatography, High Pressure Liquid
Deoxyadenine Nucleotides/analysis
Deoxycytidine/*analogs & derivatives/pharmacology
Deoxyguanine Nucleotides/analysis
Humans
Radiation-Sensitizing Agents/*pharmacology
Ribonucleoside Diphosphate Reductase/*antagonists & inhibitors
Tumor Cells, Cultured
Pubmed
Web of science
Création de la notice
25/01/2008 11:51
Dernière modification de la notice
20/08/2019 15:58