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

Paillas, Salomé; Boudousq, Vincent; Piron, Bérengère; Kersual, Nathalie; Bardiès, Manuel; Chouin, Nicolas; Bascoul-Mollevi, Caroline; Arnaud, François-Xavier; Pèlegrin, André; Navarro-Teulon, Isabelle; Pouget, Jean‐Pierre

doi:10.1016/j.nucmedbio.2013.02.001

Cited by 30 publications

(24 citation statements)

References 30 publications

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“…Boyd et al [66] observed similar killing of bystander HCT116 cells when they were treated with media harvested from either MIBG (accumulating within the cytoplasm) or IUdR (incorporating into DNA) labeled with either 131 I (low LET β-emitter), or 123 I (high LET Auger emitter). An independence of bystander effect generation of radionuclide sub-cellular location was also indicated by Paillas et al [67] for HCT116 p53-/-and p53+/+ colorectal carcinoma cells. The direct effects of 125 I-labeled monoclonal antibodies targeting the membrane bond, non-internalizing carcinoembryonic antigen (CEA), and internalizing, cytoplasm reaching epidermal growth factor receptor (HER1) were different; anti-CEA 125 I-mAbs were much more cytotoxic than anti-HER1 125 I-mAbs in both p53-/-and p53+/+ HCT116 cells.…”

Section: In Vitro Studies Of Radionuclide Induced Bystander Effectsupporting

confidence: 59%

Radionuclides in radiation-induced bystander effect; may it share in radionuclide therapy?

Wideł¹

2017

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For many years in radiobiology and radiotherapy predominated the conviction that cellular DNA is the main target for ionizing radiation, however, the view has changed in the past 20 years. Nowadays, it is assumed that not only directed (targeted) radiation effect, but also an indirect (non-targeted) effect may contribute to the result of radiation treatment. Non-targeted effect is relatively well recognized after external beam irradiation in vitro and in vivo, and comprises such phenomena like radiation-induced bystander effect (RIBE), genomic instability, adaptive response and abscopal (out of field) effect. These stress-induced and molecular signaling mediated phenomena appear in non-targeted cells as variety responses resembling that observed in directly hit cells. Bystander effects can be both detrimental and beneficial in dependence on dose, dose-rate, cell type, genetic status and experimental condition. Less is known about radionuclide-induced non-targeted effects in radionuclide therapy, although, based on characteristics of the radionuclide radiation, on experiments in vitro utilizing classical and 3-D cell cultures, and preclinical study on animals it seems obvious that exposure to radionuclide is accompanied by various bystander effects, mostly damaging, less often protective. This review summarizes existing data on radionuclide induced bystander effects comprising radionuclides emitting beta- and alpha-particles and Auger electrons used in tumor radiotherapy and diagnostics. So far, separation of the direct effect of radionuclide decay from crossfire and bystander effects in clinical targeted radionuclide therapy is impossible because of the lack of methods to assess whether, and to what extent bystander effect is involved in human organism. Considerations on this topic are also included.

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Section: In Vitro Studies Of Radionuclide Induced Bystander Effectsupporting

confidence: 59%

Radionuclides in radiation-induced bystander effect; may it share in radionuclide therapy?

Wideł¹

2017

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“…This protraction in inducing DSBs observed for short lived 188 Re can explain the equal efficacy of 188 Re-C1P5 and 177 Lu-C1P5 toward tumor growth arrest in spite of 1.4 times higher radiation dose to the tumor for 177 Lu-C1P5 than for 188 Re-C1P5 mAb. Observation of gamma H2AX staining several days after RIT administration emphasizes the different complex and protracted in time mechanisms involved in RIT effects on the tumor as even bystander cells in RIT experiments exhibit gamma H2AX staining [27] while in the case of external beam radiation, such staining can be observed only within hours post irradiation [28].…”

Section: Discussionmentioning

confidence: 99%

Beta emitters rhenium‐188 and lutetium‐177 are equally effective in radioimmunotherapy of HPV‐positive experimental cervical cancer

et al. 2015

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Cervical cancer caused by the infection with the human papillomavirus (HPV) remains the fourth leading killer of women worldwide. Therefore, more efficacious treatments are needed. We are developing radioimmunotherapy (RIT) of HPV‐positive cervical cancers by targeting E6 and E7 viral oncoproteins expressed by the cancer cells with the radiolabeled monoclonal antibodies (mAbs). To investigate the influence of different radionuclides on the RIT efficacy—we performed RIT of experimental cervical cancer with Rhenium‐188 (188Re) and Lutetium‐177 (177Lu)‐labeled mAb C1P5 to E6. The biodistribution of 188Re‐ and 177Lu‐labeled C1P5 was performed in nude female mice bearing CasKi cervical cancer xenografts and the radiation dosimetry calculations for the tumors and organs were carried out. For RIT the mice were treated with 7.4 MBq of either 188Re‐C1P5 or 177Lu‐C1P5 or left untreated, and observed for their tumor size for 28 days. The levels of 188Re‐ and 177Lu‐C1P5 mAbs‐induced double‐strand breaks in CasKi tumors were compared on days 5 and 10 post treatment by staining with anti‐gamma H2AX antibody. The radiation doses to the heart and lungs were similar for both 177Lu‐C1P5 and 188Re‐C1P5. The dose to the liver was five times higher for 177Lu‐C1P5. The doses to the tumor were 259 and 181 cGy for 177Lu‐C1P5 and 188Re‐C1P5, respectively. RIT with either 177Lu‐C1P5 or 188Re‐C1P5 was equally effective in inhibiting tumor growth when each was compared to the untreated controls (P = 0.001). On day 5 there was a pronounced staining for gamma H2AX foci in 177Lu‐C1P5 group only and on day 10 it was observed in both 177Lu‐C1P5 and 188Re‐C1P5 groups. 188Re‐ and 177Lu‐labeled mAbs were equally effective in arresting the growth of CasKi cervical tumors. Thus, both of these radionuclides are candidates for the clinical trials of this approach in patients with advanced, recurrent or metastatic cervical cancer.

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“…It is most likely that the additional Auger and conversion electrons emitted by 161 Tb influenced the radiotoxicity too. The shortrange electrons exert their greatest toxicity effects only after internalisation or on the cell membrane of the target cell [30][31][32][33]. Inside the cell, Auger electrons are able to deposit high energy around the decay site which leads to ionisation and excitations, chemical transmutations, local effects of charged species, and nuclear recoil [30,34].…”

Section: Discussionmentioning

confidence: 99%

Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model

Grünberg

Lindenblatt

Dorrer

et al. 2014

Eur J Nucl Med Mol Imaging

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

Abstract: 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.

Cited by 30 publications

References 30 publications

Radionuclides in radiation-induced bystander effect; may it share in radionuclide therapy?

Radionuclides in radiation-induced bystander effect; may it share in radionuclide therapy?

Beta emitters rhenium‐188 and lutetium‐177 are equally effective in radioimmunotherapy of HPV‐positive experimental cervical cancer

Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model

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