Differences in the kinetics of γ-H2AX fluorescence decay after exposure to low and high LET radiation

Schmid, Thomas E.; Dollinger, G.; Beisker, Wolfgang; Hable, V.; Greubel, C.; Auer, S.; Mittag, Anja; Tárnok, Attila; Friedl, Anna A.; Molls, M.; Röper, Barbara

doi:10.3109/09553001003734543

Cited by 75 publications

(73 citation statements)

References 48 publications

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“…Consistent with prior findings, similar numbers of -H2AX foci are formed after low LET and high LET radiation but there are more remaining -H2AX foci at 24 h after high LET radiation (20% of initial foci remaining after alpha particle, 120 keV/µm, compared to less than 10% after gamma ray) [54,97,98]. In addition, the repair of DNA DSB appears to consist of two kinetic components, a fast phase and a slow phase, where most of the DNA DSBs caused by high LET radiation is repaired [97]. Studies in our lab with anti-HER2 Trastuzumab labeled alpha-particle emitter 213 Bi also see the same trend where higher fraction of -H2AX foci remained at 24 h compared to gamma irradiation (unpublished data).…”

Section: Dna Dsb Repair After High Let Radiationsupporting

confidence: 87%

“…Carboxy-terminal phosphorylation of histone H2AX is the earliest cellular response to DNA DSB that accumulates at the sites of DSB quickly (within minutes of the damage) [96]. Consistent with prior findings, similar numbers of -H2AX foci are formed after low LET and high LET radiation but there are more remaining -H2AX foci at 24 h after high LET radiation (20% of initial foci remaining after alpha particle, 120 keV/µm, compared to less than 10% after gamma ray) [54,97,98]. In addition, the repair of DNA DSB appears to consist of two kinetic components, a fast phase and a slow phase, where most of the DNA DSBs caused by high LET radiation is repaired [97].…”

Section: Dna Dsb Repair After High Let Radiationsupporting

confidence: 71%

See 1 more Smart Citation

Alpha Particle Emitter Radiolabeled Antibody for Metastatic Cancer: What Can We Learn from Heavy Ion Beam Radiobiology?

Song¹,

Senthamizhchelvan²,

Hobbs³

et al. 2012

Antibodies

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Alpha-particle emitter labeled monoclonal antibodies are being actively developed for treatment of metastatic cancer due to the high linear energy transfer (LET) and the resulting greater biological efficacy of alpha-emitters. Our knowledge of high LET particle radiobiology derives primarily from accelerated heavy ion beam studies. In heavy ion beam therapy of loco-regional tumors, the modulation of steep transition to very high LET peak as the particle approaches the end of its track (known as the Bragg peak) enables greater delivery of biologically potent radiation to the deep seated tumors while sparing normal tissues surrounding the tumor with the relatively low LET track segment part of the heavy ion beam. Moreover, fractionation of the heavy ion beam can further enhance the peak-to-plateau relative biological effectiveness (RBE) ratio. In contrast, internally delivered alpha particle radiopharmaceutical therapy lack the control of Bragg peak energy deposition and the dose rate is determined by the administered activity, alpha-emitter half-life and biological kinetics of the radiopharmaceutical. The therapeutic ratio of tumor to normal tissue is mainly achieved by tumor specific targeting of the carrier antibody. In this brief overview, we review the radiobiology of high LET radiations learned from ion beam studies and identify the features that are also applicable for the development of alpha-emitter labeled antibodies. The molecular mechanisms underlying DNA double strand break repair response to high LET radiation are also discussed.

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Section: Dna Dsb Repair After High Let Radiationsupporting

confidence: 87%

Section: Dna Dsb Repair After High Let Radiationsupporting

confidence: 71%

Alpha Particle Emitter Radiolabeled Antibody for Metastatic Cancer: What Can We Learn from Heavy Ion Beam Radiobiology?

Song¹,

Senthamizhchelvan²,

Hobbs³

et al. 2012

Antibodies

View full text Add to dashboard Cite

show abstract

“…It is proposed here to asses these irradiation modes by analyzing initial 1-h and late 24-h DNA DSB numbers in HeLa cells, in order to address foci numbers after different repair times. Schmid et al showed that gamma-H2AX loss kinetics follows a bi-exponential decline with two distinct decay time constants independent of LET but with a larger fraction of damage belonging to the larger decay time constant for high-LET irradiation (Schmid et al 2010a). In the current setting, these results were extended to assess the differences in temporal modes between pulsed and continuous irradiation .…”

Section: Introductionmentioning

confidence: 98%

Induction and repair of DNA double-strand breaks assessed by gamma-H2AX foci after irradiation with pulsed or continuous proton beams

Zlobinskaya

Dollinger

Michalski

et al. 2012

Radiat Environ Biophys

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In particle tumor therapy including beam scanning at accelerators, the dose per voxel is delivered within about 100 ms. In contrast, the new technology of laser plasma acceleration will produce ultimately shorter particle packages that deliver the dose within a nanosecond. Here, possible differences for relative biological effectiveness in creating DNA double-strand breaks in pulsed or continuous irradiation mode are studied. HeLa cells were irradiated with 1 or 5 Gy of 20-MeV protons at the Munich tandem accelerator, either at continuous mode (100 ms), or applying a single pulse of 1-ns duration. Cells were fixed 1 h after 1-Gy irradiation and 24 h after 5-Gy irradiation, respectively. A dose-effect curve based on five doses of X-rays was taken as reference. The total number of phosphorylated histone H2AX (gamma-H2AX) foci per cell was determined using a custom-made software macro for gamma-H2AX foci counting. For 1 h after 1-Gy 20-MeV proton exposures, values for the relative biological effectiveness (RBE) of 0.97 ± 0.19 for pulsed and 1.13 ± 0.21 for continuous irradiations were obtained in the first experiment 1.13 ± 0.09 and 1.16 ± 0.09 in the second experiment. After 5 Gy and 24 h, RBE values of 0.99 ± 0.29 and 0.91 ± 0.23 were calculated, respectively. Based on the gamma-H2AX foci numbers obtained, no significant differences in RBE between pulsed and continuous proton irradiation in HeLa cells were detected. These results are well in line with our data on micronucleus induction in HeLa cells.

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“…The majority of DSBs are repaired in 24 h. γH2AX is a hallmark of DSB recognition and repair. Fewer γH2AX foci represent a more rapid repair of DSBs and higher radioresistance (19)(20)(21)(22)(23)(24). RAD51 is an important protein involved in homologous recombination processes.…”

Section: Discussionmentioning

confidence: 99%

SHP-1 overexpression increases the radioresistance of NPC cells by enhancing DSB repair, increasing S phase arrest and decreasing cell apoptosis

Pan

Mou

et al. 2015

Oncology Reports

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Abstract. The present study aimed to investigate the influence of SHP-1 on the radioresistance of the nasopharyngeal carcinoma (NPC) cell line CNE-2 and the relevant underlying mechanisms. The human NPC cell line CNE-2 was transfected with a lentivirus that contained the SHP-1 gene or a nonsense sequence (referred to as LP-H1802Lv201 and LP-NegLv201 cells, respectively). Cells were irradiated with different ionizing radiation (IR) doses. Cell survival, DNA double-strand breaks (DSBs), apoptosis, cell cycle distribution, and the expression of related proteins were assessed using colony formation assay, immunofluorescent assays (IFAs), flow cytometry (FCM) and western blot analyses, respectively. Compared with the control (CNE-2 cells) and LP-NegLv201 cells, LP-H1802Lv201 cells were more resistant to IR. IFAs showed that IR caused less histone H2AX phosphorylation (γH2AX) and RAD51 foci in the LP-H1802Lv201 cells. Compared with the control and LP-NegLv201 cells, LP-H1802Lv201 cells showed increased S phase arrest. After IR, the apoptotic rate of the LP-H1802Lv201 cells was lower in contrast to the control and LP-NegLv201 cells. Western blot analyses showed that IR increased the phosphorylation of ataxia telangiectasia mutated (ATM) kinase, checkpoint kinase 2 (CHK2), ataxia telangiectasia and Rad3-related (ATR) protein, checkpoint kinase 1 (CHK1) and p53. In LP-H1802Lv201 cells, the phosphorylation levels of ATM and CHK2 were significantly increased while the p53 phosphorylation level was decreased compared to these levels in the control and LP-NegLv201 cells. Phosphorylation of ATR and CHK1 did not show significant differences in the three cell groups. Overexpression of SHP-1 in the CNE-2 cells led to radioresistance and the radioresistance was related to enhanced DNA DSB repair, increased S phase arrest and decreased cell apoptosis.

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Differences in the kinetics of γ-H2AX fluorescence decay after exposure to low and high LET radiation

Abstract: gamma-H2AX loss kinetics follows a bi-exponential decline with two definite decay times independent of LET. The higher contribution of the slow component determined for carbon ion exposure is thought to reflect the increased amount of complex DSB induced by high LET radiation.

Cited by 75 publications

References 48 publications

Alpha Particle Emitter Radiolabeled Antibody for Metastatic Cancer: What Can We Learn from Heavy Ion Beam Radiobiology?

Alpha Particle Emitter Radiolabeled Antibody for Metastatic Cancer: What Can We Learn from Heavy Ion Beam Radiobiology?

Induction and repair of DNA double-strand breaks assessed by gamma-H2AX foci after irradiation with pulsed or continuous proton beams

SHP-1 overexpression increases the radioresistance of NPC cells by enhancing DSB repair, increasing S phase arrest and decreasing cell apoptosis

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