High-LET radiations induce a large proportion of non-rejoining DNA breaks

Ritter, Mark A.; Cleaver, James E.; Tobias, Cornelius A.

doi:10.1038/266653a0

Cited by 342 publications

(106 citation statements)

References 18 publications

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“…We now provide additional evidence to support a role of BRCA1 in DNA damage repair by directly demonstrating that a loss-of-function mutation of BRCA1 results in chromosomal abnormalities, including numerical and structural changes. It was shown that the most common damage caused by ionizing irradiation is double-strand breaks (DSB) of DNA (Ritter et al, 1977). Thus, the hypersensitivity of Brca1 117/7 blastocysts to g-irradiation may suggest a role of BRCA1 in the DSB repair.…”

Section: Discussionmentioning

confidence: 99%

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A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability

et al. 1998

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Germline mutations of the Brca1 gene are responsible for most cases of familial breast and ovarian cancers, but somatic mutations are rarely detected in sporadic events. Moreover, mouse embryos de®cient for Brca1 have been shown to die during early embryogenesis due to a proliferation defect. These ®ndings seem incompatible with the tumor suppress function assigned to this gene and raise questions about the mechanism by which Brca1 mutations cause tumorigenesis. We now directly demonstrate that BRCA1 is responsible for the integrity of the genome. Murine embryos carrying a Brca1 null mutation are developmentally retarded and hypersensitive to girradiation, suggesting a failure in DNA damage repair. This notion is supported by spectral karyotyping (SKY) of metaphase chromosomes, which display numerical and structural aberrations. However, massive chromosomal abnormalities are only observed when a p53 7/7 background is introduced. Thus, a p53 dependent cell cycle checkpoint arrests the mutant embryos and prevents the accumulation of damaged DNA. Brca1 7/7 ®broblasts are not viable, nor are Brca1 7/7 : p53 7/7 ®broblasts. However, proliferative foci arise from Brca1 7/7 : p53 7/7 cells, probably due to additional mutations that are a consequence of the accumulating DNA damage. We believe that the increased incidence of such additional mutations accounts for the mechanism of tumorigenesis associated with Brca1 mutations in humans.

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Section: Discussionmentioning

confidence: 99%

“…The hypersensitivity of Brca1 117/7 cells to g-irradiation provided compelling evidence that BRCA1 is involved in DNA double-strand break repair (Ritter et al, 1977). If this is the case, gross chromosomal changes should be observable in Brca1 117/7 embryos.…”

Section: Brca1 117/7 Embryos Show Chromosomal Instabilitymentioning

confidence: 99%

A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability

et al. 1998

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“…The biological effects of high linear energy transfer (LET) radiotherapy with heavy-ion are more pronounced than low-LET radiation, such as X-rays or gamma rays (6). High LET radiations are suitable for local control of tumors because of its high relative biological effectiveness, and reduced oxygen enhancement ratio.…”

Section: Introductionmentioning

confidence: 99%

Synergistic growth suppression induced in esophageal squamous cell carcinoma cells by combined treatment with docetaxel and heavy carbon-ion beam irradiation

Kitabayashi

Shimada²,

Yamada³

et al. 2006

Oncol Rep

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Abstract. Heavy carbon-ion beam therapy has revealed several potential advantages over X-rays. Heavy-ion therapy has been applied for various solid tumors including esophageal squamous cell carcinoma (SCC). Although the local control rate of carbon ion radiotherapy for esophageal cancer has revealed better rates than that of conventional radiotherapy, some patients have shown resistance to the treatment. No study has evaluated whether anti-cancer drugs can enhance the anti-tumor effect of heavy carbon-ion beam irradiation. Therefore, we evaluated the efficacy of docetaxel, fluorouracil, cisplatinum, doxorubicin and gemcitabine to enhance the anti-tumor effects of heavy carbon-ion beam irradiation on human esophageal SCC cells in both in vitro and in vivo experiments. Fluorouracil, cisplatinum, doxorubicin and gemcitabine showed only additive anti-tumor effects. On the other hand, growth suppression was significantly potentiated by the combined treatment with heavy carbon-ion beam and docetaxel as compared to that treated with either agent alone. These data suggest that heavy carbon-ion beam irradiation combined with docetaxel may be a potentially useful therapeutic strategy for locally advanced esophageal SCC.

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“…of 100 to 150 keV/µm . In contrast, if the irradiations are made in a 10 cm spread Bragg peak of the same particle beams, the initial rate of rejoining approaches that observed after X-ray irradiations, where approximately 50 per cent of the breaks are rejoined within 10min of the end of irradiation (Roots and Smith 1975) irrespective of the initial damage level at least up to several thousand rad . This reflects a large component of relatively low-LET radiation when the Bragg peak is spread by the use of a ridge filter .…”

Section: Introductionmentioning

confidence: 96%

Rejoining Capacity of DNA Breaks Induced by Accelerated Carbon and Neon Ions in the Spread Bragg Peak

Roots¹,

Yang²,

Craise³

et al. 1980

International Journal of Radiation Biology and Related Studies

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High-LET radiations induce a large proportion of non-rejoining DNA breaks

Cited by 342 publications

References 18 publications

A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability

A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability

Synergistic growth suppression induced in esophageal squamous cell carcinoma cells by combined treatment with docetaxel and heavy carbon-ion beam irradiation

Rejoining Capacity of DNA Breaks Induced by Accelerated Carbon and Neon Ions in the Spread Bragg Peak

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