Gimeracil sensitizes cells to radiation via inhibition of homologous recombination.
OBJECTIVE
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
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.
Takagi
Masaru
M
Department of Radiology, Sapporo Medical University, Hokkaido, Japan.
Sakata
Koh-ichi
K
Someya
Masanori
M
Tauchi
Hiroshi
H
Iijima
Kenta
K
Matsumoto
Yoshihisa
Y
Torigoe
Toshihiko
T
Takahashi
Akari
A
Hareyama
Masato
M
Fukushima
Masakazu
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D011725:Pyridines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D011995:Recombination, Genetic / Q000187:drug effects*
D000970:Antineoplastic Agents; D011725:Pyridines; C104201:gimeracil