DNA damage-centered signaling pathways are effectively activated during low dose-rate Auger radioimmunotherapy

Piron, Bérengère; Paillas, Salomé; Boudousq, Vincent; Pèlegrin, André; Bascoul-Mollevi, Caroline; Chouin, Nicolas; Navarro-Teulon, Isabelle; Pouget, Jean‐Pierre

doi:10.1016/j.nucmedbio.2014.01.012

Cited by 26 publications

(27 citation statements)

References 37 publications

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“…ROS contribute to “chronic” oxidative stress and the subsequent DNA damage, including the formation of micronuclei in nontargeted cells ( 3 , 44 ). This is in agreement with our previous finding that the abundance of micronuclei in cells exposed to 125 I-mAbs was not correlated with the mean absorbed dose to the nucleus ( 48 , 50 ). The involvement of oxidative stress in EBRT-induced nontargeted effects has been extensively reviewed by Havaki et al ( 20 ).…”

Section: Discussionsupporting

confidence: 93%

“…Furthermore, the cytotoxicity of noninternalizing mAbs was greater than that achieved by internalizing 125 I-mAbs ( 50 , 53 ) and was not due to inefficient detection of DNA damage related to low absorbed dosage. We proposed that, instead, nontargeted effects could be involved ( 48 ). This is in agreement with the work by Xue et al in 2002 showing in vivo that nontargeted effects are produced by LS174T cells radiolabeled with the DNA base analog 5-[(125)I]iodo-2′-deoxyuridine ( 125 I-UdR), indicating that Auger electrons can kill cells beyond their path length ( 66 ).…”

Section: Introductionmentioning

confidence: 99%

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Localized Irradiation of Cell Membrane by Auger Electrons Is Cytotoxic Through Oxidative Stress-Mediated Nontargeted Effects

Paillas

Ladjohounlou

Lozza

et al. 2016

Antioxidants & Redox Signaling

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Aims: We investigated whether radiation-induced nontargeted effects are involved in the cytotoxic effects of anticell surface monoclonal antibodies labeled with Auger electron emitters, such as iodine 125 (monoclonal antibodies labeled with 125I [125I-mAbs]). Results: We showed that the cytotoxicity of 125I-mAbs targeting the cell membrane of p53+/+ HCT116 colon cancer cells is mainly due to nontargeted effects. Targeted and nontargeted cytotoxicities were inhibited in vitro following lipid raft disruption with Methyl-β-cyclodextrin (MBCD) or filipin or use of radical oxygen species scavengers. 125I-mAb efficacy was associated with acid sphingomyelinase activation and modulated through activation of the AKT, extracellular signal-related kinase ½ (ERK1/2), p38 kinase, c-Jun N-terminal kinase (JNK) signaling pathways, and also of phospholipase C-γ (PLC-γ), proline-rich tyrosine kinase 2 (PYK-2), and paxillin, involved in Ca2+ fluxes. Moreover, the nontargeted response induced by directing 5-[(125)I]iodo-2′-deoxyuridine to the nucleus was comparable to that of 125I-mAb against cell surface receptors. In vivo, we found that the statistical significance of tumor growth delay induced by 125I-mAb was removed after MBCD treatment and observed oxidative DNA damage beyond the expected Auger electron range. These results suggest the involvement of nontargeted effects in vivo also. Innovation: Low-energy Auger electrons, such as those emitted by 125I, have a short tissue range and are usually targeted to the nucleus to maximize their cytotoxicity. In this study, we show that targeting the cancer cell surface with 125I-mAbs produces a lipid raft-mediated nontargeted response that compensates for the inferior efficacy of non-nuclear targeting. Conclusion: Our findings describe the mechanisms involved in the efficacy of 125I-mAbs targeting the cancer cell surface. Antioxid. Redox Signal. 25, 467–484.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Localized Irradiation of Cell Membrane by Auger Electrons Is Cytotoxic Through Oxidative Stress-Mediated Nontargeted Effects

Paillas

Ladjohounlou

Lozza

et al. 2016

Antioxidants & Redox Signaling

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“…However, the highly localized energy deposition associated with Auger electrons and alpha particles is also an attractive tool to investigate the biological effects of ionizing radiations at the subcellular scale and has shown the weaknesses of a completely DNA-centered conception of TRT effects. Indeed, we and others have demonstrated that extra-nuclear targets are also involved in targeted and non-targeted responses ( 74 – 78 ). The existence of non-targeted effects may affect the absorbed dose–effect relationship.…”

Section: Targeted Radionuclide Therapymentioning

confidence: 89%

“…Several hypotheses have been proposed to explain this effect, including TRT-mediated synchronization of cells in a radiosensitive cell cycle phase or defects in the detection of low levels of DNA damage. However, these mechanisms cannot be generalized ( 78 ) and TRT biology still needs to be investigated for each TRT situation. Models and notions have been developed to reduce the discrepancies between the theoretical dose–effect relationship and the real biological effects measured in human patients using clearly identified endpoints (creatinine values, for example).…”

Section: Targeted Radionuclide Therapymentioning

confidence: 99%

Introduction to Radiobiology of Targeted Radionuclide Therapy

et al. 2015

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During the last decades, new radionuclide-based targeted therapies have emerged as efficient tools for cancer treatment. Targeted radionuclide therapies (TRTs) are based on a multidisciplinary approach that involves the cooperation of specialists in several research fields. Among them, radiobiologists investigate the biological effects of ionizing radiation, specifically the molecular and cellular mechanisms involved in the radiation response. Most of the knowledge about radiation effects concerns external beam radiation therapy (EBRT) and radiobiology has then strongly contributed to the development of this therapeutic approach. Similarly, radiobiology and dosimetry are also assumed to be ways for improving TRT, in particular in the therapy of solid tumors, which are radioresistant. However, extrapolation of EBRT radiobiology to TRT is not straightforward. Indeed, the specific physical characteristics of TRT (heterogeneous and mixed irradiation, protracted exposure, and low absorbed dose rate) differ from those of conventional EBRT (homogeneous irradiation, short exposure, and high absorbed dose rate), and consequently the response of irradiated tissues might be different. Therefore, specific TRT radiobiology needs to be explored. Determining dose–effect correlation is also a prerequisite for rigorous preclinical radiobiology studies because dosimetry provides the necessary referential to all TRT situations. It is required too for developing patient-tailored TRT in the clinic in order to estimate the best dose for tumor control, while protecting the healthy tissues, thereby improving therapeutic efficacy. Finally, it will allow to determine the relative contribution of targeted effects (assumed to be dose-related) and non-targeted effects (assumed to be non-dose-related) of ionizing radiation. However, conversely to EBRT where it is routinely used, dosimetry is still challenging in TRT. Therefore, it constitutes with radiobiology, one of the main challenges of TRT in the future.

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“…20 225 Ac decays into 4 alpha-emitting daughter particles, 2 of which emit an imageable gamma ray, and 225 Ac-radiolabeled full length antibodies have been efficacious in tumor-cell killing in in vitro and in vivo preclinical studies, 21,22 as well as clinical studies. 3,23 Auger emitters, such as 125 I, have low energy and are considered to have high LET (4-26 keV/μm) with a very short path length of 2-500 nm 24 (Figure 2). Similar to alpha emitters, Auger emitters may be more suitable for limiting damage to normal tissues compared with betaemitters 25 ; however, strategies must be devised for intracellular delivery, preferably in the vicinity of the cell nucleus.…”

Section: Radionuclides For Imaging and Therapymentioning

confidence: 99%

Aligning physics and physiology: Engineering antibodies for radionuclide delivery

Tsai

2018

Labelled Comp Radiopharmac

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The exquisite specificity of antibodies and antibody fragments renders them excellent agents for targeted delivery of radionuclides. Radiolabeled antibodies and fragments have been successfully used for molecular imaging and radioimmunotherapy (RIT) of cell surface targets in oncology and immunology. Protein engineering has been used for antibody humanization essential for clinical applications, as well as optimization of important characteristics including pharmacokinetics, biodistribution, and clearance. Although intact antibodies have high potential as imaging and therapeutic agents, challenges include long circulation time in blood, which leads to later imaging time points post-injection and higher blood absorbed dose that may be disadvantageous for RIT. Using engineered fragments may address these challenges, as size reduction and removal of Fc function decreases serum half-life. Radiolabeled fragments and pretargeting strategies can result in high contrast images within hours to days, and a reduction of RIT toxicity in normal tissues. Additionally, fragments can be engineered to direct hepatic or renal clearance, which may be chosen based on the application and disease setting. This review discusses aligning the physical properties of radionuclides (positron, gamma, beta, alpha, and Auger emitters) with antibodies and fragments and highlights recent advances of engineered antibodies and fragments in preclinical and clinical development for imaging and therapy.

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DNA damage-centered signaling pathways are effectively activated during low dose-rate Auger radioimmunotherapy

Cited by 26 publications

References 37 publications

Localized Irradiation of Cell Membrane by Auger Electrons Is Cytotoxic Through Oxidative Stress-Mediated Nontargeted Effects

Localized Irradiation of Cell Membrane by Auger Electrons Is Cytotoxic Through Oxidative Stress-Mediated Nontargeted Effects

Introduction to Radiobiology of Targeted Radionuclide Therapy

Aligning physics and physiology: Engineering antibodies for radionuclide delivery

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