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.

2.50
Hdl Handle:
http://hdl.handle.net/10541/56674
Title:
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.
Authors:
Ivanov, Andrei; Krysov, Sergei; Cragg, Mark S; Illidge, Timothy M ( 0000-0003-3191-7324 )
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.
Affiliation:
School of Cancer and Imaging Sciences, CRUK Paterson Institute for Cancer Research, University of Manchester, United Kingdom.
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
Issue Date:
1-Aug-2008
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
Appears in Collections:
All Paterson Institute for Cancer Research; School of Cancer and Imaging Sciences

Full metadata record

DC FieldValue Language
dc.contributor.authorIvanov, Andrei-
dc.contributor.authorKrysov, Sergei-
dc.contributor.authorCragg, Mark S-
dc.contributor.authorIllidge, Timothy M-
dc.date.accessioned2009-03-20T14:52:54Z-
dc.date.available2009-03-20T14:52:54Z-
dc.date.issued2008-08-01-
dc.identifier.citationRadiation 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.en
dc.identifier.issn1078-0432-
dc.identifier.pmid18676767-
dc.identifier.doi10.1158/1078-0432.CCR-07-5072-
dc.identifier.urihttp://hdl.handle.net/10541/56674-
dc.description.abstractPURPOSE: 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.en
dc.language.isoenen
dc.subjectTargeted Radiation Therapyen
dc.subjectAnti-CD20 Monoclonal Antibodyen
dc.subjectLymphoma, B-Cellen
dc.subjectCell Line, Tumour-
dc.subject.meshAntibodies, Monoclonal-
dc.subject.meshAntigens, CD20-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshApoptosis-
dc.subject.meshCell Line, Tumor-
dc.subject.meshDNA Fragmentation-
dc.subject.meshDrug Resistance, Neoplasm-
dc.subject.meshExtracellular Signal-Regulated MAP Kinases-
dc.subject.meshGene Silencing-
dc.subject.meshHumans-
dc.subject.meshMAP Kinase Signaling System-
dc.subject.meshNeoplasms-
dc.subject.meshRadioimmunotherapy-
dc.subject.meshSignal Transduction-
dc.titleRadiation 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.en
dc.typeArticleen
dc.contributor.departmentSchool of Cancer and Imaging Sciences, CRUK Paterson Institute for Cancer Research, University of Manchester, United Kingdom.en
dc.identifier.journalClinical Cancer Researchen
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