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Radiocurability by targeting tumor necrosis factor-alpha using a bispecific antibody in carcinoembryonic antigen transgenic mice

Authors :
André Pèlegrin
Bruno Robert
David Azria
Lore Santoro
Frédéric Bibeau
Sophie Gourgou
Christel Larbouret
Pierre Martineau
Isabelle Teulon
Christine Linard
Jean-Pierre Pouget
Immunociblage et radiobiologie en oncologie
Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Institut de Radioprotection et de Sûreté Nucléaire (IRSN)
Unité de biostatistiques en Oncologie
CRLC Val d'Aurelle
Laboratoire d'anatomo-pathologie
CRLCC Val d'Aurelle - Paul Lamarque
Institut de Recherche en Infectiologie de Montpellier (IRIM)
Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
'Comité de l'Hérault de la Ligue Nationale Contre le Cancer' and 'Fondation Gustave et Simone Prévot'
Le Ster, Yves
Source :
International Journal of Radiation Oncology-Biology-Physics, International Journal of Radiation Oncology-Biology-Physics, Elsevier, 2007, 69 (4), pp.1231-7. ⟨10.1016/j.ijrobp.2007.07.2372⟩, International Journal of Radiation Oncology, Biology, Physics, International Journal of Radiation Oncology, Biology, Physics, 2007, 69 (4), pp.1231-7. ⟨10.1016/j.ijrobp.2007.07.2372⟩
Publication Year :
2007
Publisher :
HAL CCSD, 2007.

Abstract

International audience; PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) enhances radiotherapy (RT) killing of tumor cells in vitro and in vivo. To overcome systemic side effects, we used a bispecific antibody (BsAb) directed against carcinoembryonic antigen (CEA) and TNF-alpha to target this cytokine in a CEA-expressing colon carcinoma. We report the evaluation of this strategy in immunocompetent CEA-transgenic mice. METHODS AND MATERIALS: The murine CEA-transfected colon carcinoma MC-38 was used for all experiments. In vitro, clonogenic assays were performed after RT alone, TNF-alpha alone, and RT plus TNF-alpha. In vivo, the mice were randomly assigned to treatment groups: control, TNF-alpha, BsAb, BsAb plus TNF-alpha, RT, RT plus TNF-alpha, and RT plus BsAb plus TNF-alpha. Measurements of endogenous TNF-alpha mRNA levels and evaluation of necrosis (histologic evaluation) were assessed per treatment group. RESULTS: In vitro, combined RT plus TNF-alpha resulted in a significant decrease in the survival fraction at 2 Gy compared with RT alone (p < 0.00001). In vivo, we observed a complete response in 5 (50%) of 10, 2 (20%) of 10, 2 (18.2%) of 11, and 0 (0%) of 12 treated mice in the RT plus BsAb plus TNF-alpha, RT plus TNF-alpha, RT alone, and control groups, respectively. This difference was statistically significant when TNF-alpha was targeted with the BsAb (p = 0.03). The addition of exogenous TNF-alpha to RT significantly increased the endogenous TNF-alpha mRNA level, particularly when TNF-alpha was targeted with BsAb (p < 0.01). The percentages of necrotic area were significantly augmented in the RT plus BsAb plus TNF-alpha group. CONCLUSION: These results suggest that targeting TNF-alpha with the BsAb provokes RT curability in a CEA-expressing digestive tumor syngenic model and could be considered as a solid rationale for clinical trials.

Details

Language :
English
ISSN :
03603016 and 1879355X
Database :
OpenAIRE
Journal :
International Journal of Radiation Oncology-Biology-Physics, International Journal of Radiation Oncology-Biology-Physics, Elsevier, 2007, 69 (4), pp.1231-7. ⟨10.1016/j.ijrobp.2007.07.2372⟩, International Journal of Radiation Oncology, Biology, Physics, International Journal of Radiation Oncology, Biology, Physics, 2007, 69 (4), pp.1231-7. ⟨10.1016/j.ijrobp.2007.07.2372⟩
Accession number :
edsair.doi.dedup.....8ef7a0afd304a959776e1f38bf032b25
Full Text :
https://doi.org/10.1016/j.ijrobp.2007.07.2372⟩