A nucleoside anticancer drug, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (TAS106), sensitizes cells to radiation by suppressing BRCA2 expression (original) (raw)
Related papers
Frontiers of Medicine in China, 2009
DNA double-strand break (DSB) is generally regarded as the most lethal of all DNA lesions after radiation. Ku80, DNA-PK catalytic subunit (DNA-PKcs) and ataxia telangiectasia mutated (ATM) proteins are major DSB repair proteins. In this study, survival fraction at 2Gy (SF2) values of eight human tumor cell lines (including four human cervical carcinoma cell lines HeLa, SiHa, C33A, Caski, three human breast carcinoma cell lines MCF-7, MDA-MB-231, MDA-MB-453, and one human lung carcinoma cell line A549) were acquired by clone formation assay, and western blot was applied to detect the expressions of Ku80, DNA-PKcs and ATM protein. The correlativity of protein expression with SF2 value was analyzed by Pearson linear correlation analysis. We found that the expression of the same protein in different cell lines and the expression of three proteins in the same cell line had a significant difference. The SF2 values were also different in eight tumor cell lines and there was a positive correlativity between the expression of DNA-PKcs and SF2 (r ＝0.723, P = 0.043), but Ku80 and ATM expression had no correlation with SF2 (P > 0.05). These findings suggest that the expression level of DNA-PKcs protein can be an indicator for predicting the radiosensitivity of tumor cells.
Radiation-induced DNA double-strand break rejoining in human tumour cells
British Journal of Cancer, 1995
Smm_ary Five established human breast cancer cell lines and one established human bladder cancer cell line of varying radiosensitivity have been used to determine whether the rejoining of DNA double-strand breaks (dsbs) shows a correlation with radiosensitivity. The kinetics of dsb rejoining was biphasic and both components proceeded exponentially with time. The half-time (t, j of rejoining ranged from 18.0 ± 1.4 to 36.4 ± 3.2 min (fast rejoining process) and from 1.5 ± 0.2 to 5.1 ± 0.2 h (slow rejoining process). We found a statistically significant relationship between the survival fraction at 2 Gy (SF2) and the t, of the fast rejoining component (r = 0.949, P = 0.0039). Our results suggest that cell lines which show rapid rejoining are more radioresistant. These results support the view that, as well as the level of damage induction that we have reported previously, the repair process is a major determinant of cellular radiosensitivity. It is possible that the differences found in DNA dsb rejoining and the differences in DNA dsb induction are related by a common mechanism, e.g. conformation of chromatin in the cell. Keywords radiosensitivity; DNA double-strand breaks; dsb rejoining; pulsed field gel electrophoresis
Frontiers in Oncology, 2013
Radiation therapy plays an important role in the management of a wide range of cancers. Besides innovations in the physical application of radiation dose, radiation therapy is likely to benefit from novel approaches exploiting differences in radiation response between normal and tumor cells. While ionizing radiation induces a variety of DNA lesions, including base damages and single-strand breaks, the DNA double-strand break (DSB) is widely considered as the lesion responsible not only for the aimed cell killing of tumor cells, but also for the general genomic instability that leads to the development of secondary cancers among normal cells. Homologous recombination repair (HRR), non-homologous end-joining (NHEJ), and alternative NHEJ, operating as a backup, are the major pathways utilized by cells for the processing of DSBs. Therefore, their function represents a major mechanism of radiation resistance in tumor cells. HRR is also required to overcome replication stress -a potent contributor to genomic instability that fuels cancer development. HRR and alternative NHEJ show strong cell-cycle dependency and are likely to benefit from radiation therapy mediated redistribution of tumor cells throughout the cell-cycle. Moreover, the synthetic lethality phenotype documented between HRR deficiency and PARP inhibition has opened new avenues for targeted therapies. These observations make HRR a particularly intriguing target for treatments aiming to improve the efficacy of radiation therapy. Here, we briefly describe the major pathways of DSB repair and review their possible contribution to cancer cell radioresistance. Finally, we discuss promising alternatives for targeting DSB repair to improve radiation therapy and cancer treatment.
Physics of Particles and Nuclei Letters, 2011
The influence that inhibitors of repair and replicative DNA synthesis, 1 β D arabinofuranosyl cytosine and hydroxyurea, have on the formation and repair kinetics of double strand breaks (DSBs) in peripheral human blood lymphocytes under the influence of radiation with a different linear energy transfer (LET) (gamma quanta and accelerated heavy ions) is studied. It is demonstrated that lithium and boron ions with LETs of 20 and 40 keV/μm, respectively, possess higher biological effectiveness with respect to the DNA DSB induction criterion. The value of the relative biological effectiveness of accelerated lithium and boron ions is 1.5 ± 0.1 and 1.6 ± 0.1, respectively. It is found that, upon cell irradiation by gamma quanta in the absence of inhibitors, efficient DNA DSB repair is observed during incubation. Under the conditions of cell incubation and in the presence of inhibitors, some growth in the number of DNA DSBs, rather than a reduc tion, is observed after 5 h incubation. In the case of the action of accelerated boron ions (as well as gamma quanta), under normal conditions, the efficient repair of induced DNA lesions takes place. Unlike the action of gamma quanta, in the case of cell incubation in the presence of radiomodifiers, the number of induced DNA DSBs falls. These results may testify to the fact that the repair of double strand DNS breaks takes place under the action of ionizing radiation with a different LET on mammalian cells in the presence of DNA syn thesis inhibitors Ara C and HU. It is concluded that, for cells subject to gamma irradiation, no DNA DSB repair is observed due to the large contribution of single strand incision DNA breaks formed in the postradi ation period in the course of excision nucleotide repair.
Strahlentherapie und Onkologie, 2007
Background and Purpose: DNA double-strand breaks (dsbs) in lymphoblastoid cell lines (LCLs), fibroblasts and white blood cells from healthy donors, cancer patients with and without late effects of grade 3-4 (RTOG) as well as donors with known radiosensitivity syndromes were examined with the aim to detect dsb repair ability as a marker for radiosensitivity. Material and Methods: LCLs from six healthy donors, seven patients with a heterozygous or homozygous genotype for ataxiatelangiectasia (ATM) and Nijmegen breakage syndrome (NBS), two patients with a late toxicity of grade 3-4 (RTOG), and one cell line with a ligase IV -/status and its parental cell line were examined. Furthermore, fibroblasts from patients with ATM, NBS, two healthy control individuals, and leukocytes from 16 healthy and 22 cancer patients including seven patients with clinical hypersensitivity grade 3 (RTOG) were examined. Cells were irradiated in vitro with 0-150 Gy. Initial damage as well as remaining damage after 8 and 24 h were measured using constant field gel electrophoresis. Results: In contrast to cells derived from patients homozygous for NBS, impaired dsb repair ability could be detected both in fibroblast and lymphoblastoid cells from ATM and ligase IV -/patients. The dsb repair ability of all 38 leukocyte cell lines (patients with grade 3-4 late effects and controls) was similar, whereas the initial damage among healthy donors was less. Conclusion: Despite showing a clinically elevated radiosensitivity after irradiation, the DNA repair of the patients with clinical hypersensitivity grade 3 (RTOG) appeared to be normal. Other mechanisms such as mutations, altered cell cycle or defective apoptosis could play a critical role toward determining radiosensitivity.
DNA repair inhibitors sensitize cells differently to high and low LET radiation
Scientific Reports
The aim of this study was to investigate effects of high LET α-radiation in combination with inhibitors of DDR (DNA-PK and ATM) and to compare the effect with the radiosensitizing effect of low LET X-ray radiation. The various cell lines were irradiated with α-radiation and with X-ray. Clonogenic survival, the formation of micronuclei and cell cycle distribution were studied after combining of radiation with DDR inhibitors. The inhibitors sensitized different cancer cell lines to radiation. DNA-PKi affected survival rates in combination with α-radiation in selected cell lines. The sensitization enhancement ratios were in the range of 1.6–1.85 in cancer cells. ATMi sensitized H460 cells and significantly increased the micronucleus frequency for both radiation qualities. ATMi in combination with α-radiation reduced survival of HEK293. A significantly elicited cell cycle arrest in G2/M phase after co-treatment of ATMi with α-radiation and X-ray. The most prominent treatment effect was ...
Radiation induced DNA damage and damage repair in three human tumour cell lines
Mutation Research/DNA Repair, 1996
Three human tumour cell lines (HX 142, RT 112 and MGH-U 1) with different radiosensitivities were tested for differences in the rate and/or extent of DNA unwinding in alkali as well as for differences in the induction of DNA double strand breaks by means of the pulsed field gel electrophoresis, after X-irradiation. Unlike that which has been found using the non-denaturing filter elution technique (NDE, McMillan et al., 1990), no differences in initial DNA damage (the extent of alkaline unwinding and the induction of double strand breaks) were found for the three cell lines. These data suggest that rather than a different number of DNA lesions per Da per Gy between these cell lines, structural differences in chromatin structure (related to radiosensitivity) might impair the detectability of lesions in some assays like the NDE. The nature of such structure differences remains unclear. However. the differences did not affect alkaline unwinding profiles, as all three cell lines showed identical rates of DNA unwinding after exposure to X-rays. Furthermore, the three cell lines did not show significant differences in the kinetics of DNA strand break rejoining nor in the amounts of damage remaining after 24 h repair. The results obtained in this study, together with other findings, suggest that the three cell lines may differ in their 'presentation' of DNA damage.
Physics of Particles and Nuclei Letters
With the use of the DNA comet assay and immunocytochemical staining, regularities have been studied in the induction and repair of DNA double-strand breaks(DSBs) in human cells after exposure to 60 Co γ-rays and accelerated heavy ions with different linear energy transfer (LET) in the presence of the DNA repair inhibitors cytosine arabinoside and hydroxyurea. It is shown that for heavy ions the agents' modifying effect decreases with increasing particles' LET. The approach involving DNA synthesis inhibitors used in this study allows an estimation of the proportion of enzymatic DNA DSBs in total DSB yield after exposure to ionizing radiations of different quality.
Effects of inhibitors of DNA strand break repair on HeLa cell radiosensitivity
Cancer Research, 1984
The effects of three drugs (hydroxyurea, 1-/3-o-arabinofuranosylcytosine, and diamide) known to inhibit DNA synthesis on the repair of ionizing radiation-induced DNA single-strand breaks measured by alkaline elution and on cellular radiosensitivity were examined. Inhibition of repair was observed at 10~2 M hydrox yurea, 10~4 M 1-/3-D-arabinofuranosylcytosine, and 5 x 10~5 M diamide, levels causing only 10% cell kill. While the mechanisms by which the drugs inhibit DNA synthesis differ, they are equally effective at inhibiting repair; without drug, cells, after a dose of 10 grays, repair 35% of DNA strand breaks in 3 min and a further 35% in 1 hr; with drug, only 10% is repaired in 3 min, and the deficiency in repair amount remains, even after 60 min. The effect of similar drug treatment on radiation-induced cell killing shows that radiosensitivity is increased; the major effect is reduction in Do from 1.3 grays to-0.8 grays with smaller effects on Dq. The data are consistent with the hypothesis that radiation produces potential double-strand breaks in DNA which, if not rapidly re paired, are converted into lethal actual double-strand breaks. 1This investigation was supported by USPHS Grant CA26279 awarded by the