Radiation-induced micronuclei in human fibroblasts in relation to clonogenic radiosensitivity

OʼDriscoll, Michael; Scott, David; Orton, Christopher; Kiltie, Anne E.; Davidson, Susan E; Hunter, Robin D; West, Catharine M L

doi:10.1038/bjc.1998.723

Cited by 13 publications

(4 citation statements)

References 21 publications

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“…The effects of the confluent state may be due to the effect of cell synchronization into G0/G1 phase, which occurs with fibroblasts under such conditions. The lack of correlation between in situ and in culture values was not due to damage depletion during culturing because the background MN in confluent cultures did not correlate with the time or number of passages needed to establish primary cultures (similar to the studies of O'Driscoll et al [39]), nor with the time needed to grow thawed fibroblasts for in culture studies. In addition, no decrease in background MN burden was observed when five strains of the fibroblasts were cultivated for four passages (up to 4-6.5 weeks of culture) without irradiation (data not shown).…”

Section: Discussionmentioning

confidence: 82%

Studies of the in vivo radiosensitivity of human skin fibroblasts

Hill

Kaspler

Griffin

et al. 2007

Radiotherapy and Oncology

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Section: Discussionmentioning

confidence: 82%

Studies of the in vivo radiosensitivity of human skin fibroblasts

Hill

Kaspler

Griffin

et al. 2007

Radiotherapy and Oncology

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“…These results support the suggestion that variation in cell radiosensitivity can be detected in vitro using radiosensitivity assays on lymphocytes derived from normal tissues of cancer patients prior to radiotherapy [ 18 , 28 - 30 ]. This wide variation in DNA DSB can be attributed to variation between individuals more than to variation due to technical or sampling errors [ 18 , 31 , 32 ]. Initial DNA damage followed a normal distribution (Kolmogorov-Smirnov test, P > 0.05), and data obtained from the present group of patients matched previously published results for breast cancer patients [ 17 , 18 ].…”

Section: Resultsmentioning

confidence: 99%

Combined low initial DNA damage and high radiation-induced apoptosis confers clinical resistance to long-term toxicity in breast cancer patients treated with high-dose radiotherapy

et al. 2011

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BackgroundEither higher levels of initial DNA damage or lower levels of radiation-induced apoptosis in peripheral blood lymphocytes have been associated to increased risk for develop late radiation-induced toxicity. It has been recently published that these two predictive tests are inversely related. The aim of the present study was to investigate the combined role of both tests in relation to clinical radiation-induced toxicity in a set of breast cancer patients treated with high dose hyperfractionated radical radiotherapy.MethodsPeripheral blood lymphocytes were taken from 26 consecutive patients with locally advanced breast carcinoma treated with high-dose hyperfractioned radical radiotherapy. Acute and late cutaneous and subcutaneous toxicity was evaluated using the Radiation Therapy Oncology Group morbidity scoring schema. The mean follow-up of survivors (n = 13) was 197.23 months. Radiosensitivity of lymphocytes was quantified as the initial number of DNA double-strand breaks induced per Gy and per DNA unit (200 Mbp). Radiation-induced apoptosis (RIA) at 1, 2 and 8 Gy was measured by flow cytometry using annexin V/propidium iodide.ResultsMean DSB/Gy/DNA unit obtained was 1.70 ± 0.83 (range 0.63-4.08; median, 1.46). Radiation-induced apoptosis increased with radiation dose (median 12.36, 17.79 and 24.83 for 1, 2, and 8 Gy respectively). We observed that those "expected resistant patients" (DSB values lower than 1.78 DSB/Gy per 200 Mbp and RIA values over 9.58, 14.40 or 24.83 for 1, 2 and 8 Gy respectively) were at low risk of suffer severe subcutaneous late toxicity (HR 0.223, 95%CI 0.073-0.678, P = 0.008; HR 0.206, 95%CI 0.063-0.677, P = 0.009; HR 0.239, 95%CI 0.062-0.929, P = 0.039, for RIA at 1, 2 and 8 Gy respectively) in multivariate analysis.ConclusionsA radiation-resistant profile is proposed, where those patients who presented lower levels of initial DNA damage and higher levels of radiation induced apoptosis were at low risk of suffer severe subcutaneous late toxicity after clinical treatment at high radiation doses in our series. However, due to the small sample size, other prospective studies with higher number of patients are needed to validate these results.

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“…One outcome of IR-induced DNA damage is the generation of acentric chromosomes that develop into circular chromatinbound micronuclei after cells complete one or more cycles of mitotic division (32)(33)(34). Three mutant EGFR NSCLCs, H820, H1975, and H2279, showed an IR dose-dependent increase in micronuclei, which were absent in WT EGFR-expressing cell lines Figure 3.…”

Section: Cancer Researchmentioning

confidence: 99%

Non–Small Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation

Das¹,

Sato

Story³

et al. 2006

Cancer Research

198

172

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Non-small cell lung cancers (NSCLCs) bearing mutations in the tyrosine kinase domain (TKD) of the epidermal growth factor receptor (EGFR) often exhibit dramatic sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Ionizing radiation (IR) is frequently used in the treatment of NSCLC, but little is known how lung tumor-acquired EGFR mutations affect responses to IR. Because this is of great clinical importance, we investigated and found that clonogenic survival of mutant EGFR NSCLCs in response to IR was reduced 500-to 1,000-fold compared with wild-type (WT) EGFR NSCLCs. Exogenous expression of either the L858R point mutant or the #E746-E750 deletion mutant form of EGFR in immortalized human bronchial epithelial cells, p53 WT NSCLC (A549), or p53-null NSCLC (NCI-H1299) resulted in dramatically increased sensitivity to IR. We show that the majority of mutant EGFR NSCLCs, including those that contain the secondary gefitinib resistance T790M mutation, exhibit characteristics consistent with a radiosensitive phenotype, which include delayed DNA repair kinetics, defective IR-induced arrest in DNA synthesis or mitosis, and pronounced increases in apoptosis or micronuclei. Thus, understanding how activating mutations in the TKD domain of EGFR contribute to radiosensitivity should provide new insight into effective treatment of NSCLC with radiotherapy and perhaps avoid emergence of single agent drug resistance.

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Radiation-induced micronuclei in human fibroblasts in relation to clonogenic radiosensitivity

Cited by 13 publications

References 21 publications

Studies of the in vivo radiosensitivity of human skin fibroblasts

Studies of the in vivo radiosensitivity of human skin fibroblasts

Combined low initial DNA damage and high radiation-induced apoptosis confers clinical resistance to long-term toxicity in breast cancer patients treated with high-dose radiotherapy

Non–Small Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation

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