Abstract
Gemcitabine is used in clinical chemo-radiotherapy; however, the mechanism underlying enhanced radiosensitivity by gemcitabine is not fully elucidated. We evaluated the role of gemcitabine in mammalian cell lines using a therapeutic high energy 10 MeV linac-X-ray irradiation device. Rodent cell lines CHO and xrs5 were used. A total of 5 μM gemcitabine for 24 hours was administered with or without post-X-ray irradiation. DNA double-strand breaks (DSBs) and cell enlargement were observed by using singly gemcitabine. Enhanced cell killing effects by radiotherapy were observed with gemcitabine pre-treatment in both CHO and xrs5 cells. We focused on the dynamics of phosphorylated p53-binding protein 1 (53BP1)-positive foci after irradiation. Significantly higher numbers of 53BP1 foci were observed after irradiation in gemcitabine pre-treated cells than in untreated cells. The radiosensitizing effect of gemcitabine was not suppressed in the non-homologous end joining (NHEJ) deficient xrs5 cells. We confirmed that in rodent cells the radiosensitizing effect of gemcitabine is related to suppression of a repair pathway other than NHEJ.
Highlights
Gemcitabine (4 - amino - 1 - [3, 3 - difluoro - 4 - hydroxyl - 5 - tetrahydrofuran – 2 - yl] - 1H – pyrimidin – 2 - one) is a deoxycytidine analogue that is well known for its anti-tumor activity, and used as a standard therapy for patients with advanced pancreatic cancer
Ionizing radiation induces an array of lesions in DNA, including base damage, single-strand breaks and double-strand breaks (DSBs), and damage to the phosphodiester backbone
DNA DSBs are potentially dangerous to cells because they may lead to chromosome breakage and loss of genetic information; DSBs are thought to be the most relevant lesion in radiation-induced cell death
Summary
Gemcitabine (4 - amino - 1 - [3, 3 - difluoro - 4 - hydroxyl - 5 - (hydro-xymethyl) tetrahydrofuran – 2 - yl] - 1H – pyrimidin – 2 - one) is a deoxycytidine analogue that is well known for its anti-tumor activity, and used as a standard therapy for patients with advanced pancreatic cancer. It is one of the more effective drugs for sensitization of cells to radiation, because most pancreatic cancers do not respond to gemcitabine alone [1,2,3,4]. To evaluate the involvement of gemcitabine in radiosensitization, we used two cell lines, a wild-type Chinese hamster ovary (CHO) cell line and a Ku80-deficient CHO cell line (xrs5) that is deficient in NHEJ repair
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