Relationship Between Induction of Phosphorylated H2AX and Survival in Breast Cancer Cells Exposed to <sup>111</sup>In-DTPA-hEGF

Cai, Zhongli; Chen, Zhuo; Bailey, Kristy; Scollard, Deborah A.; Reilly, Raymond M.; Vallis, Katherine A.

doi:10.2967/jnumed.108.051805

Cited by 55 publications

(63 citation statements)

References 25 publications

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“…For example, 111 In-labeled diethylenetriaminepentaacetic acid human epidermal growth factor ( 111 In-DTPA-hEGF) is a targeted Auger electron-emitting radiotherapeutic agent discovered in our laboratory that is selectively bound, internalized, and translocated to the nucleus of epidermal growth factor receptor-overexpressing breast cancer cells, where it causes DNA double-strand breaks and cell death (1)(2)(3). 111 In-DTPA-hEGF exhibited potent antiproliferative effects in vitro on epidermal growth factor receptor-overexpressing MDA-MB-468 human breast cancer cells as well as strong antitumor effects in vivo in athymic mice implanted subcutaneously with MDA-MB-468 tumor xenografts (4,5).…”

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confidence: 99%

Cellular Dosimetry of ¹¹¹In Using Monte Carlo N-Particle Computer Code: Comparison with Analytic Methods and Correlation with In Vitro Cytotoxicity

Cai

Pignol²,

Chan³

et al. 2010

J Nucl Med

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Our objective was to compare Monte Carlo N-particle (MCNP) self-and cross-doses from 111 In to the nucleus of breast cancer cells with doses calculated by reported analytic methods (Goddu et al. and Farragi et al.). A further objective was to determine whether the MCNP-predicted surviving fraction (SF) of breast cancer cells exposed in vitro to 111 In-labeled diethylenetriaminepentaacetic acid human epidermal growth factor ( 111 In-DTPAhEGF) could accurately predict the experimentally determined values. The MCNP-predicted SF for monolayer MDA-MB-468, MDA-MB-231, and MCF-7 cells agreed with the experimental data (relative error of 3.1%, 21.0%, and 1.7%). The single-cell and cell cluster models were less accurate in predicting the SF. For MDA-MB-468 cells, relative error was 8.1% using the singlecell model and 254% to 267% using the cell cluster model. Individual cell-line dimensions had large effects on S values and were needed to estimate doses and SF accurately. Conclusion: MCNP simulation compared well with the reported analytic methods in the calculation of subcellular S values for single cells and cell clusters. Application of a monolayer model was most accurate in predicting the SF of breast cancer cells exposed in vitro to 111 In-DTPA-hEGF.

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confidence: 99%

Cellular Dosimetry of ¹¹¹In Using Monte Carlo N-Particle Computer Code: Comparison with Analytic Methods and Correlation with In Vitro Cytotoxicity

Cai

Pignol²,

Chan³

et al. 2010

J Nucl Med

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“…In the nucleus, EGFR plays a role in transactivation of target genes (26). It is known that 111 In-DTPA-hEGF localization in the nuclei of EGFR-overexpressing cells is necessary for its Auger electron-mediated DNA damage and cytotoxicity (2). The purpose of the current study was to clarify whether nuclear translocation of 111 In-DTPA-hEGF results from continued interaction of the EGF moiety of the radiopharmaceutical with EGFR as it is routed through the cell.…”

Section: Discussionmentioning

confidence: 99%

“…MDA-MB-468 cells contain wild-type K-Ras, and this may explain the absence of additivity because farnesyltransferase inhibitors are known to be less effective in cells of this genotype (35). MCF-7 cells have low EGFR expression and are unresponsive to 111 In-DTPA-hEGF; thus, they would not be expected to exhibit synergy when exposed to other agents (2).…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of EGFR and the resulting upregulation of EGFR-mediated signaling have been observed in several tumor types, including breast cancer, non-small cell lung cancer, and head and neck squamous cell carcinoma. Reilly's group has exploited the EGF-EGFR axis in a Trojan horse approach to deliver the Auger electron-emitting isotope 111 In, as 111 In-labeled human EGF ( 111 In-DTPA-hEGF), to the nucleus of EGFR-overexpressing cancer cells for molecularly targeted radiation therapy (2)(3)(4)(5). Good correlation between EGFR expression and 111 In-DTPA-hEGF uptake, nuclear localization, DNA damage, and cell kill was demonstrated in a panel of breast cancer cell lines (2).…”

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confidence: 99%

“…Reilly's group has exploited the EGF-EGFR axis in a Trojan horse approach to deliver the Auger electron-emitting isotope 111 In, as 111 In-labeled human EGF ( 111 In-DTPA-hEGF), to the nucleus of EGFR-overexpressing cancer cells for molecularly targeted radiation therapy (2)(3)(4)(5). Good correlation between EGFR expression and 111 In-DTPA-hEGF uptake, nuclear localization, DNA damage, and cell kill was demonstrated in a panel of breast cancer cell lines (2). In the in vivo setting, 111 In-DTPAhEGF inhibited growth of MDA-MB-468 xenografts in athymic mice.…”

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confidence: 99%

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ErbB-2 Blockade and Prenyltransferase Inhibition Alter Epidermal Growth Factor and Epidermal Growth Factor Receptor Trafficking and Enhance ¹¹¹In-DTPA-hEGF Auger Electron Radiation Therapy

Cornelissen

Darbar²,

Hernandez³

et al. 2011

J Nucl Med

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The intracellular distribution of Auger electron-emitting radiopharmaceuticals is a determinant of cytotoxicity. However, the mechanisms by which these agents are routed through the cell are ill understood. The aim of this study was to investigate how trafficking of 111 In-labeled human epidermal growth factor ( 111 In-DTPA-hEGF) relates to that of the EGF receptor (EGFR) and whether coadministration of agents that modulate EGFR signaling alters the efficacy of 111 In-DTPA-hEGF. Methods: The spatiotemporal interaction between AlexaFluor488-EGF (AF488-EGF) and Cy3-conjugated anti-EGFR antibody (Cy3-anti-EGFR) was studied in the breast cancer cell line MDA-MB-468 using fluorescence resonance energy transfer and 2-photon fluorescence lifetime imaging. 111 In internalization and nuclear fractionation assays were performed to investigate the effect of the ErbB-2-blocking antibody trastuzumab and a prenyltransferase inhibitor, L-778,123, on the subcellular localization of 111 In-DTPA-hEGF in MDA-MB-468 (1.3 · 10 6 EGFR per cell; ErbB-2 negative) and 231-H2N (0.2 · 10 6 EGFR per cell; 0.4 · 10 5 ErbB-2 per cell) cell lines. The cytotoxicity of 111 In-DTPA-hEGF (0-64 nM) plus trastuzumab (0-50 mg/mL) or L-778,123 (0-22.5 mM) was measured using clonogenic assays in a panel of breast cancer cell lines that express different levels of EGFR and ErB-2. Clonogenic survival data were used to calculate combination indices. Tumor growth inhibition was measured in vivo in 231-H2N xenograft-bearing mice treated with 111 In-DTPA-hEGF plus trastuzumab or L-788,123. Results: Using fluorescence resonance energy transfer, we showed that EGF interacts with EGFR in the cytoplasm and nucleus after internalization of the ligand-receptor complex in MDA-MB-468 cells. Nuclear localization of 111 In-DTPA-hEGF is enhanced by trastuzumab and L-788,123. Trastuzumab and L-788,123 sensitized 231-H2N cells to 111 In-DTPA-hEGF. Nuclear localization and cytotoxicity of 111 In-DTPA-hEGF were significantly increased in 231-H2N xenografts by cotreatment with L-788,123 (P , 0.0001). Conclusion: The therapeutic efficacy of 111 In-DTPA-hEGF is increased through the coadministration of selected molecularly targeted drugs that modulate EGFR signaling and trafficking.

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Preclinical Cell and Tumor Models for Evaluating Radiopharmaceuticals in Oncology

Chambers

Turley

Lewis

et al. 2010

Monoclonal Antibody and Peptide‐Targeted Radiotherapy of Cancer

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Relationship Between Induction of Phosphorylated H2AX and Survival in Breast Cancer Cells Exposed to ¹¹¹In-DTPA-hEGF

Cited by 55 publications

References 25 publications

Cellular Dosimetry of ¹¹¹In Using Monte Carlo N-Particle Computer Code: Comparison with Analytic Methods and Correlation with In Vitro Cytotoxicity

Cellular Dosimetry of ¹¹¹In Using Monte Carlo N-Particle Computer Code: Comparison with Analytic Methods and Correlation with In Vitro Cytotoxicity

ErbB-2 Blockade and Prenyltransferase Inhibition Alter Epidermal Growth Factor and Epidermal Growth Factor Receptor Trafficking and Enhance ¹¹¹In-DTPA-hEGF Auger Electron Radiation Therapy

Preclinical Cell and Tumor Models for Evaluating Radiopharmaceuticals in Oncology

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Relationship Between Induction of Phosphorylated H2AX and Survival in Breast Cancer Cells Exposed to 111In-DTPA-hEGF

Cited by 55 publications

References 25 publications

Cellular Dosimetry of 111In Using Monte Carlo N-Particle Computer Code: Comparison with Analytic Methods and Correlation with In Vitro Cytotoxicity

Cellular Dosimetry of 111In Using Monte Carlo N-Particle Computer Code: Comparison with Analytic Methods and Correlation with In Vitro Cytotoxicity

ErbB-2 Blockade and Prenyltransferase Inhibition Alter Epidermal Growth Factor and Epidermal Growth Factor Receptor Trafficking and Enhance 111In-DTPA-hEGF Auger Electron Radiation Therapy

Preclinical Cell and Tumor Models for Evaluating Radiopharmaceuticals in Oncology

Contact Info

Product

Resources

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Relationship Between Induction of Phosphorylated H2AX and Survival in Breast Cancer Cells Exposed to ¹¹¹In-DTPA-hEGF

Cellular Dosimetry of ¹¹¹In Using Monte Carlo N-Particle Computer Code: Comparison with Analytic Methods and Correlation with In Vitro Cytotoxicity

Cellular Dosimetry of ¹¹¹In Using Monte Carlo N-Particle Computer Code: Comparison with Analytic Methods and Correlation with In Vitro Cytotoxicity

ErbB-2 Blockade and Prenyltransferase Inhibition Alter Epidermal Growth Factor and Epidermal Growth Factor Receptor Trafficking and Enhance ¹¹¹In-DTPA-hEGF Auger Electron Radiation Therapy