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Title: Radiosensitization effect of zidovudine on human malignant glioma cells

Abstract

Telomeres are shortened with each cell division and play an important role in maintaining chromosomal integrity and function. Telomerase, responsible for telomere synthesis, is activated in 90% of human tumor cells but seldom in normal somatic cells. Zidovudine (AZT) is a reverse transcriptase inhibitor. In this study, we have investigated the effects of {gamma}-radiation in combination with AZT on telomerase activity (TA), telomere length, DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs), and the changes in radiosensitivity of human malignant glioma cell line U251. The results showed that the TA was suppressed by AZT but enhanced by irradiation, resulting in a deceleration of restored rate of shortened telomere, decreased repair rate of DNA strand breaks, and increased radiosensitivity of U251 cells. Our results suggested that telomerase activity and telomere length may serve as markers for estimating the efficacy of cancer radiotherapy and reverse transcriptase inhibitors, such as AZT, may be used clinically as a new radiosensitizer in cancer radiotherapy.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2]
  1. Department of Chemo-Radiotherapy Oncology, Zhongnan Hospital, Wuhan University, Cancer Center of Wuhan University, Wuhan, Hubei 430071 (China)
  2. Department of Chemo-Radiotherapy Oncology, Zhongnan Hospital, Wuhan University, Cancer Center of Wuhan University, Wuhan, Hubei 430071 (China). E-mail: yfzhouwhu@163.com
Publication Date:
OSTI Identifier:
20979822
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 354; Journal Issue: 2; Other Information: DOI: 10.1016/j.bbrc.2006.12.180; PII: S0006-291X(06)02818-X; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; BIOLOGICAL REPAIR; CELL DIVISION; DNA; GAMMA RADIATION; GLIOMAS; IRRADIATION; RADIOSENSITIVITY; RADIOTHERAPY; SOMATIC CELLS; STRAND BREAKS; TELOMERES; TUMOR CELLS

Citation Formats

Zhou Fuxiang, Liao Zhengkai, Dai Jing, Xiong Jie, Xie CongHua, Luo Zhiguo, Liu Shiquan, and Zhou Yunfeng. Radiosensitization effect of zidovudine on human malignant glioma cells. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2006.12.180.
Zhou Fuxiang, Liao Zhengkai, Dai Jing, Xiong Jie, Xie CongHua, Luo Zhiguo, Liu Shiquan, & Zhou Yunfeng. Radiosensitization effect of zidovudine on human malignant glioma cells. United States. doi:10.1016/j.bbrc.2006.12.180.
Zhou Fuxiang, Liao Zhengkai, Dai Jing, Xiong Jie, Xie CongHua, Luo Zhiguo, Liu Shiquan, and Zhou Yunfeng. Fri . "Radiosensitization effect of zidovudine on human malignant glioma cells". United States. doi:10.1016/j.bbrc.2006.12.180.
@article{osti_20979822,
title = {Radiosensitization effect of zidovudine on human malignant glioma cells},
author = {Zhou Fuxiang and Liao Zhengkai and Dai Jing and Xiong Jie and Xie CongHua and Luo Zhiguo and Liu Shiquan and Zhou Yunfeng},
abstractNote = {Telomeres are shortened with each cell division and play an important role in maintaining chromosomal integrity and function. Telomerase, responsible for telomere synthesis, is activated in 90% of human tumor cells but seldom in normal somatic cells. Zidovudine (AZT) is a reverse transcriptase inhibitor. In this study, we have investigated the effects of {gamma}-radiation in combination with AZT on telomerase activity (TA), telomere length, DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs), and the changes in radiosensitivity of human malignant glioma cell line U251. The results showed that the TA was suppressed by AZT but enhanced by irradiation, resulting in a deceleration of restored rate of shortened telomere, decreased repair rate of DNA strand breaks, and increased radiosensitivity of U251 cells. Our results suggested that telomerase activity and telomere length may serve as markers for estimating the efficacy of cancer radiotherapy and reverse transcriptase inhibitors, such as AZT, may be used clinically as a new radiosensitizer in cancer radiotherapy.},
doi = {10.1016/j.bbrc.2006.12.180},
journal = {Biochemical and Biophysical Research Communications},
number = 2,
volume = 354,
place = {United States},
year = {Fri Mar 09 00:00:00 EST 2007},
month = {Fri Mar 09 00:00:00 EST 2007}
}
  • DNA polymerase inactivation is compared to thermal radiosensitization and inhibition of damage recovery in human glioma cells. Two human glioma cell lines (U87MG and U373MG) were exposed to hyperthermia and irradiation. Hyperthermia was given at 43[degrees]C and 45[degrees]C and DNA polymerase [alpha] + [delta] + [epsilon] and [beta] activities were measured. Hyperthermia was given at various times before irradiation and the degree of radiosensitization and polymerase activity was assessed at various times after heating. In addition the ability of cells to undergo repair of potentially lethal radiation damage was assessed for cells irradiated at various times after heating. Polymerase [alpha]more » + [delta] + [epsilon] and polymerase [beta] both recovered after heating but polymerase [beta] was faster and was complete in U373MG but not in the U87MG cell lines after 48 h incubation after heating (45[degrees]C, 60 min). Incubation, between hyperthermia and irradiation resulted in a loss of radiosensitization and a loss of inhibition of repair of potentially lethal damage. These changes correlated well with recovery of polymerase [beta] but not with polymerase [alpha] + [delta] + [epsilon]. The correlation of polymerase [beta] activity and thermoradiosensitization and its recovery indicate that polymerase [beta] may be one of the mechanisms involved in thermoradiosensitization. 35 refs., 7 figs.« less
  • Purpose: Current treatments for glioblastoma multiforme are inadequate and limited by the radiation sensitivity of normal brain. Because glioblastoma multiforme are rapidly proliferating tumors within nondividing normal tissue, the therapeutic ratio might be enhanced by combining radiotherapy with a replication-specific radiosensitizer. KU-0059436 (AZD2281) is a potent and nontoxic inhibitor of poly(ADP-ribose) polymerase-1 (PARP-1) undergoing a Phase II clinical trial as a single agent. Methods and Materials: Based on previous observations that the radiosensitizing effects of PARP inhibition are more pronounced in dividing cells, we investigated the mechanisms underlying radiosensitization of human glioma cells by KU-0059436, evaluating the replication dependence ofmore » this effect and its therapeutic potential. Results: KU-0059436 increased the radiosensitivity of four human glioma cell lines (T98G, U373-MG, UVW, and U87-MG). Radiosensitization was enhanced in populations synchronized in S phase and abrogated by concomitant exposure to aphidicolin. Sensitization was further enhanced when the inhibitor was combined with a fractionated radiation schedule. KU-0059436 delayed repair of radiation-induced DNA breaks and was associated with a replication-dependent increase in {gamma}H2AX and Rad51 foci. Conclusion: The results of our study have shown that KU-0059436 increases radiosensitivity in a replication-dependent manner that is enhanced by fractionation. A mechanism is proposed whereby PARP inhibition increases the incidence of collapsed replication forks after ionizing radiation, generating persistent DNA double-strand breaks. These observations indicate that KU-0059436 is likely to enhance the therapeutic ratio achieved by radiotherapy in the treatment of glioblastoma multiforme. A Phase I clinical trial is in development.« less
  • The induction and repair of DNA double-strand breaks were studied in cells of two isogenic human malignant glioma cell lines which vary in their SF2 values by a factor of {approximately}30.M059J cells are radiosensitive (SF2 = 0.02) and lack the p350 component of DNA-dependent protein kinase (DNA-PK); M059K cells are radioresistant (SF2 = 0.64) and express normal levels of DNA-PK. Zero integrated field gel electrophoresis and alkaline sucrose gradient experiments indicated that equivalent numbers of DNA lesions were produced by ionizing radiation in M059J and M059K cells. To compare the capacity of both lines to repair sublethal damage, the split-dosemore » recovery experiment after exposure to equitoxic doses of radiation was carried out. Significant sublethal damage repair was shown for M059K cells, with a 5.8-fold increase in relative survival peaking at 4 h, whereas M059J cells showed little repair activity. Electrophoresis studies indicated that more double-strand breaks were repaired by 30 min in M059K cells than in M059J cells. These results suggest that deficient DNA repair processes may be a major determinant of radiosensitivity in M059J cells. 24 refs., 5 figs., 2 tabs.« less
  • Purpose: We investigated whether miR-203 could modulate the radiation sensitivity of glioblastoma (GBM) cells and which target gene(s) could be involved. Methods and Materials: Three human malignant glioma (MG) cell lines and normal human astrocytes were transfected with control microRNA, pre-miR-203, or antisense miR-203. Real-time PCR (RT-PCR), clonogenic assays, immunofluorescence, and invasion/migration assays were performed. To predict the target(s), bioinformatics analyses using microRNA target databases were performed. Results: Overexpression of miR-203 increased the radiation sensitivity of all 3 human MG cell lines and prolonged radiation-induced γ-H2AX foci formation. Bioinformatics analyses suggested that miR-203 could be involved in post-transcriptional control of DNAmore » repair, PI3K/AKT, SRC, and JAK/STAT3 and the vascular signaling pathway. Western blot analysis validated the fact that miR-203 downregulated ATM, RAD51, SRC, PLD2, PI3K-AKT, JAK-STAT3, VEGF, HIF-1α, and MMP2. Overexpression of miR-203 inhibited invasion and migration potentials, downregulated SLUG and Vimentin, and upregulated Claudin-1 and ZO1. Conclusions: These data demonstrate that miR-203 potentially controls DNA damage repair via the PI3K/AKT and JAK/STAT3 pathways and may collectively contribute to the modulation of radiation sensitivity in MG cells by inhibiting DNA damage repair, prosurvival signaling, and epithelium-mesenchyme transition. Taken together, these findings demonstrate that miR-203 could be a target for overcoming the radiation resistance of GBM.« less
  • The effects of thymidine and uridine on the phosphorylation of 3'-azido-3'-deoxythymidine (AZT) were studied in various human mononuclear cell preparations. Thymidine suppressed ({sup 3}H)AZT phosphorylation in the same concentration range (20 to 100 microM) in which it antagonizes the anti-human immunodeficiency virus activity of AZT. Uridine, in turn, had no influence on AZT phosphorylation, just as it has no effect on the anti-human immunodeficiency virus activity of AZT. These findings are consistent with a close relationship between the inhibition of AZT phosphorylation and the influence of physiological nucleosides on the antiviral activity of AZT.