Apoptosis and p53 are not involved in the anti-tumor efficacy of 125I-labeled monoclonal antibodies targeting the cell membrane

Introduction: I-125-labeled monoclonal antibodies (I-125-mAbs) can efficiently treat small solid tumors. Here, we investigated the role of apoptosis, autophagy and mitotic catastrophe in I-125-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 I-125-mAbs, or non-internalizing (cell surface location) anti-CEA I-125-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 I-125-mAbs were more cytotoxic per Gy than anti-HER1 I-125-mAbs. Sensitivity to anti-CEA I-125-mAbs was p53-independent, while sensitivity to anti-HER1 I-125-mAbs was higher in p53(-/-) HCT116 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 I-125-mAbs. By contrast, mitotic death was similarly induced in both p53(-/-) and p53(+/+) HCT116 cells by the two types of I-125-mAbs. We also showed using medium transfer experiments that gamma-H2AX foci were produced in bystander cells. Conclusion: Cell membrane sensitivity to I-125-mAbs is not mediated by apoptosis and is p53-independent. Bystander effects-mediated mitotic death could be involved in the efficacy of I-125-mAbs binding cell surface receptors. (C) 2013 Elsevier Inc. All rights reserved.