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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: School of Cancer and Imaging Sciences, CRUK Paterson Institute for Cancer Research, University of Manchester, United Kingdom.
authors.forename: Andrey
authors.initials: A
authors.lastname: Ivanov
authors.forename: Sergei
authors.initials: S
authors.lastname: Krysov
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cragg
authors.forename: Tim
authors.initials: T
authors.lastname: Illidge
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System; D009369:Neoplasms / Q000628:therapy*; D016499:Radioimmunotherapy / Q000379:methods*; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D048049:Extracellular Signal-Regulated MAP Kinases; C119496:tositumomab I-131