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    Radiation therapy with tositumomab (B1) anti-CD20 monoclonal antibody initiates extracellular signal-regulated kinase/mitogen-activated protein kinase-dependent cell death that overcomes resistance to apoptosis.

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    Authors
    Ivanov, Andrei
    Krysov, Sergei
    Cragg, Mark S
    Illidge, Timothy M
    Affiliation
    School of Cancer and Imaging Sciences, CRUK Paterson Institute for Cancer Research, University of Manchester, United Kingdom.
    Issue Date
    2008-08-01
    
    Metadata
    Show full item record
    Abstract
    PURPOSE: The use of targeted radiation therapy (RT) in conjunction with anti-CD20 monoclonal antibodies (mAb) delivers high clinical response rates in B-cell lymphomas as part of radioimmunotherapy. The mechanisms underlying these impressive responses, particularly in patients whose lymphomas have become refractory to chemotherapy, are poorly understood. EXPERIMENTAL DESIGN: In this study, we have investigated the signaling pathways and mode of cell death induced in B-cell lymphoma cells after the combination of RT and either type I (rituximab) or type II (tositumomab/B1) anti-CD20 mAb. RESULTS: Increased tumor cell death was observed when RT was combined with tositumomab, but not rituximab. This additive cell death was found to be mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)-dependent and could be reversed with mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitors, as well as small interfering RNA targeting MEK1/2. Furthermore, we found that this increased death was associated with ERK1/2 nuclear accumulation after tositumomab treatment, which was enhanced in combination with RT. Importantly, although Bcl-2 overexpression resulted in resistance to RT-induced apoptosis, it had no effect on the tumor cell death induced by tositumomab plus RT, indicating a nonapoptotic form of cell death. CONCLUSIONS: These findings indicate that RT and type II anti-CD20 mAb combine to stimulate a prodeath function of the MEK-ERK1/2 pathway, which is able to overcome apoptotic resistance potentially explaining the efficacy of this modality in treating patients with chemoresistant disease.
    Citation
    Radiation therapy with tositumomab (B1) anti-CD20 monoclonal antibody initiates extracellular signal-regulated kinase/mitogen-activated protein kinase-dependent cell death that overcomes resistance to apoptosis. 2008, 14 (15):4925-34 Clin. Cancer Res.
    Journal
    Clinical Cancer Research
    URI
    http://hdl.handle.net/10541/56674
    DOI
    10.1158/1078-0432.CCR-07-5072
    PubMed ID
    18676767
    Type
    Article
    Language
    en
    ISSN
    1078-0432
    ae974a485f413a2113503eed53cd6c53
    10.1158/1078-0432.CCR-07-5072
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research
    School of Cancer and Imaging Sciences

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