RRC ID 38203
Author Takagi M, Sakata K, Someya M, Tauchi H, Iijima K, Matsumoto Y, Torigoe T, Takahashi A, Hareyama M, Fukushima M.
Title Gimeracil sensitizes cells to radiation via inhibition of homologous recombination.
Journal Radiother Oncol
Abstract BACKGROUND AND PURPOSE:5-Chloro-2,4-dihydroxypyridine (Gimeracil) is a component of an oral fluoropyrimidine derivative S-1. Gimeracil is originally added to S-1 to yield prolonged 5-FU concentrations in tumor tissues by inhibiting dihydropyrimidine dehydrogenase, which degrades 5-FU. We found that Gimeracil by itself had the radiosensitizing effect.
METHODS AND MATERIALS:We used various cell lines deficient in non-homologous end-joining (NHEJ) or homologous recombination (HR) as well as DLD-1 and HeLa in clonogenic assay. gamma-H2AX focus formation and SCneo assay was performed to examine the effects of Gimeracil on DNA double strand break (DSB) repair mechanisms.
RESULTS:Results of gamma-H2AX focus assay indicated that Gimeracil inhibited DNA DSB repair. It did not sensitize cells deficient in HR but sensitized those deficient in NHEJ. In SCneo assay, Gimeracil reduced the frequency of neo-positive clones. Additionally, it sensitized the cells in S-phase more than in G0/G1.
CONCLUSIONS:Gimeracil inhibits HR. Because HR plays key roles in the repair of DSBH caused by radiotherapy, Gimeracil may enhance the efficacy of radiotherapy through the suppression of HR-mediated DNA repair pathways.
Volume 96(2)
Pages 259-66
Published 2010-8-1
DOI 10.1016/j.radonc.2010.05.020
PII S0167-8140(10)00338-5
PMID 20584556
MeSH Antineoplastic Agents / pharmacology* Cell Line Cell Line, Tumor Flow Cytometry Humans Pyridines / pharmacology* Radiation Tolerance / drug effects* Recombination, Genetic / drug effects*
IF 4.856
Times Cited 23
Human and Animal Cells MRC-5 SV1 TG1(RCB0207)