title: Apoptosis and p53 are not involved in the anti-tumor efficacy of ¹²⁵I-labeled monoclonal antibodies targeting the cell membrane.
abstract: BACKGROUND
  (125)I-labeled monoclonal antibodies ((125)I-mAbs) can efficiently treat small solid tumors. Here, we investigated the role of apoptosis, autophagy and mitotic catastrophe in (125)I-mAb toxicity in p53(-/-) and p53(+/+) cancer cells.
  
  
  METHODS
  We exposed p53(-/-) and p53(+/+) HCT116 cells to increasing activities of internalizing (cytoplasmic location) anti-HER1 (125)I-mAbs, or non-internalizing (cell surface location) anti-CEA (125)I-mAbs. For each targeting model we established the relationship between survival and mean nucleus absorbed dose using the MIRD formalism.
  
  
  RESULTS
  In both p53(-/-) and p53(+/+) HCT116 cells, anti-CEA (125)I-mAbs were more cytotoxic per Gy than anti-HER1 (125)I-mAbs. Sensitivity to anti-CEA (125)I-mAbs was p53-independent, while sensitivity to anti-HER1 (125)I-mAbs was higher in p53(-/-) HCT 116 cells, suggesting that they act through different signaling pathways. Apoptosis was only induced in p53(+/+) HCT116 cells and could not explain cell membrane radiation sensitivity. Inhibition of autophagy did not modify the cell response to (125)I-mAbs. By contrast, mitotic death was similarly induced in both p53(-/-) and p53(+/+) HCT116 cells by the two types of (125)I-mAbs. We also showed using medium transfer experiments that γ-H2AX foci were produced in bystander cells.
  
  
  CONCLUSIONS
  Cell membrane sensitivity to (125)I-mAbs is not mediated by apoptosis and is p53-independent. Bystander effects-mediated mitotic death could be involved in the efficacy of (125)I-mAbs binding cell surface receptors.
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.
authors.forename: Salomé
authors.initials: S
authors.lastname: Paillas
authors.forename: Vincent
authors.initials: V
authors.lastname: Boudousq
authors.forename: Bérengère
authors.initials: B
authors.lastname: Piron
authors.forename: Nathalie
authors.initials: N
authors.lastname: Kersual
authors.forename: Manuel
authors.initials: M
authors.lastname: Bardiès
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chouin
authors.forename: Caroline
authors.initials: C
authors.lastname: Bascoul-Mollevi
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Arnaud
authors.forename: André
authors.initials: A
authors.lastname: Pèlegrin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Navarro-Teulon
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pouget
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D024201:Bystander Effect / Q000528:radiation effects; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism* / Q000528:radiation effects; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D066246:ErbB Receptors / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D058990:Molecular Targeted Therapy; D021381:Protein Transport / Q000528:radiation effects; D016499:Radioimmunotherapy; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007457:Iodine Radioisotopes; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors