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

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• 作者：Salomé ; Paillas^a ; ¹ ; Vincent Boudousq^a ; ¹ ; Bé ; rengè ; re Piron^a ; Nathalie Kersual^a ; Manuel Bardiè ; s^b ; Nicolas Chouin^c ; Caroline Bascoul-Mollevi^d ; Franç ; ois-Xavier Arnaud^e ; André ; Pè ; legrin^a ; Isabelle Navarro-Teulon^a ; Jean-Pierre Pouget^a ; ^{jean-pierre.pouget@inserm.fr}
• 关键词：Radioimmunotherapy ; Auger electrons ; p53 ; Apoptosis ; 125I-mAbs
• 刊名：Nuclear Medicine and Biology
• 出版年：2013
• 出版时间：May, 2013
• 年：2013
• 卷：40
• 期：4
• 页码：471-480
• 全文大小：1060 K

文摘

Introduction

¹²⁵I-labeled monoclonal antibodies (¹²⁵I-mAbs) can efficiently treat small solid tumors. Here, we investigated the role of apoptosis, autophagy and mitotic catastrophe in ¹²⁵I-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 ¹²⁵I-mAbs, or non-internalizing (cell surface location) anti-CEA ¹²⁵I-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 ¹²⁵I-mAbs were more cytotoxic per Gy than anti-HER1 ¹²⁵I-mAbs. Sensitivity to anti-CEA ¹²⁵I-mAbs was p53-independent, while sensitivity to anti-HER1 ¹²⁵I-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 ¹²⁵I-mAbs. By contrast, mitotic death was similarly induced in both p53^?/? and p53^+/+ HCT116 cells by the two types of ¹²⁵I-mAbs. We also showed using medium transfer experiments that ¦Ã-H2AX foci were produced in bystander cells.

Conclusion

Cell membrane sensitivity to ¹²⁵I-mAbs is not mediated by apoptosis and is p53-independent. Bystander effects-mediated mitotic death could be involved in the efficacy of ¹²⁵I-mAbs binding cell surface receptors.